Immuno-oncology

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

HAMBURG, Germany — The human microbiome comprises 39 to 44 billion microbes. That is ten times more than the number of cells in our body. Hendrik Poeck, MD, managing senior physician of internal medicine at the University Hospital Regensburg, illustrated this point at the annual meeting of the German Society for Hematology and Medical Oncology. If the gut microbiome falls out of balance, then “intestinal dysbiosis potentially poses a risk for the pathogenesis of local and systemic diseases,” explained Dr. Poeck.

Cancers and their therapies can also be influenced in this way. “Microbial diversity affects whether a tumor grows, whether it leads to inflammation, immune escape mechanisms or genomic instability, or whether therapeutic resistances develop,” said Dr. Poeck.

Microbial diversity could be beneficial for cancer therapy, too. The composition of the microbiome varies significantly from host to host and can mutate. These properties make it a target for precision microbiotics, which involves using the gut microbiome as a biomarker to predict various physical reactions and to develop individualized diets.

Microbiome and Pathogenesis

The body’s microbiome fulfills a barrier function, especially where the body is exposed to an external environment: at the epidermis and the internal mucous membranes, in the gastrointestinal tract, and in the lungs, chest, and urogenital system.

Association studies on humans and experimental manipulations on mouse models of cancer showed that certain microorganisms can have either protective or harmful effects on cancer development, on the progression of a malignant disease, and on the response to therapy.

A Master Regulator?

Disruptions of the microbial system in the gut, as occur during antibiotic therapy, can have significant effects on a patient’s response to immunotherapy. Taking antibiotics shortly before or after starting therapy with immune checkpoint inhibitors (ICIs) significantly affected both overall survival (OS) and progression-free survival (PFS), as reported in a recent review and meta-analysis, for example.

Proton pump inhibitors also affect the gut microbiome and reduce the response to immunotherapy; this effect was demonstrated by an analysis of data from more than 2700 cancer patients that was recently presented at the annual meeting of the European Society for Medical Oncology (ESMO).

The extent to which the gut microbiome influences the efficacy of an ICI or predicts said efficacy was examined in a retrospective analysis published in Science in 2018, which Dr. Poeck presented. Resistance to ICI correlated with the relative frequency of the bacteria Akkermansia muciniphila in the gut of patients with cancer. In mouse models, the researchers restored the efficacy of the PD-1 blockade through a stool transplant.

Predicting Immunotherapy Response

If A muciniphila is present, can the composition of the microbiome act as a predictor for an effective ICI therapy?

Laurence Zitvogel, MD, PhD, and her working group at the National Institute of Health and Medical Research in Villejuif, France, performed a prospective study in 338 patients with non–small cell lung cancer and examined the prognostic significance of the fecal bacteria A muciniphila (Akk). The “Akkerman status” (low Akk vs high Akk) in a patient’s stool correlated with an increased objective response rate and a longer OS, independently of PD-L1 expression, antibiotics, and performance status. The OS for low Akk was 13.4 months, vs 18.8 months for high Akk in first-line treatment.

These results are promising, said Dr. Poeck. But there is no one-size-fits-all solution. No conclusions can be drawn from one bacterium on the efficacy of therapies in humans, since “the entirety of the bacteria is decisive,” said Dr. Poeck. In addition to the gut microbiome, the composition of gut metabolites influences the response to immunotherapies, as shown in a study with ICI.

Therapeutic Interventions

One possible therapeutic intervention to restore the gut microbiome is fecal microbiota transplantation (FMT). In a phase 1 study presented by Dr. Poeck, FMT was effective in the treatment of 20 patients with melanoma with ICI in an advanced and treatment-naive stage. Seven days after the patients received FMT, the first cycle with anti-PD-1 immunotherapy was initiated, with a total administration of three to four cycles. After 12 weeks, most patients were in complete or partial remission, as evidenced on imaging.

However, FMT also carries some risks. Two cases of sepsis with multiresistant Escherichia coli occurred, as well as other serious infections. Since then, there has been an FDA condition for extended screening of the donor stool, said Dr. Poeck. Nevertheless, this intervention is promising. A search of the keywords “FMT in cancer/transplant setting” reveals 46 currently clinical studies on clinicaltrials.gov.

Nutritional Interventions

Dr. Poeck advises caution about over-the-counter products. These products usually contain only a few species, such as Lactobacillus and Bifidobacterium. “Over-the-counter probiotics can even delay the reconstitution of the microbiome after antibiotics,” said Dr. Poeck, according to a study. In some studies, the response rates were significantly lower after probiotic intake or led to controversial results, according to Dr. Poeck.

In contrast, Dr. Poeck said prebiotics (that is, a fiber-rich diet with indigestible carbohydrates) were promising. During digestion, prebiotics are split into short-chain fatty acids by bacterial enzymes and promote the growth of certain microbiota.

In this way, just 20 g of extremely fiber-rich food had a significant effect on PFS in 128 patients with melanoma undergoing anti-PD-1 immunotherapy. With 20 g of fiber-rich food per day, the PFS was stable over 60 months. The most significant benefit was observed in patients with a sufficient fiber intake who were not taking probiotics.

What to Recommend?

In summary, Dr. Poeck said that it is important to “budget” well, particularly with antibiotic administration, and to strive for calculated therapy with as narrow a spectrum as possible. For patients who experience complications such as cytokine release syndrome as a reaction to cell therapy, delaying the use of antibiotics is important. However, it is often difficult to differentiate this syndrome from neutropenic fever. The aim should be to avoid high-risk antibiotics, if clinically justifiable. Patients should avoid taking antibiotics for 30 days before starting immunotherapy.

Regarding nutritional interventions, Dr. Poeck referred to the recent Onkopedia recommendation for nutrition after cancer and the 10 nutritional rules of the German Nutrition Society. According to Dr. Poeck, the important aspects of these recommendations are a fiber-rich diet (> 20 g/d) from various plant products and avoiding artificial sweeteners and flavorings, as well as ultraprocessed (convenience) foods. In addition, meat should be consumed only in moderation, and as little processed meat as possible should be consumed. In addition, regular (aerobic and anaerobic) physical activity is important.

“Looking ahead into the future,” said Dr. Poeck, “we need a uniform and functional understanding and we need a randomized prediction for diagnosis.”


This article was translated from the Medscape German edition.

A version of this article appeared on Medscape.com.

HAMBURG, Germany — The human microbiome comprises 39 to 44 billion microbes. That is ten times more than the number of cells in our body. Hendrik Poeck, MD, managing senior physician of internal medicine at the University Hospital Regensburg, illustrated this point at the annual meeting of the German Society for Hematology and Medical Oncology. If the gut microbiome falls out of balance, then “intestinal dysbiosis potentially poses a risk for the pathogenesis of local and systemic diseases,” explained Dr. Poeck.

Cancers and their therapies can also be influenced in this way. “Microbial diversity affects whether a tumor grows, whether it leads to inflammation, immune escape mechanisms or genomic instability, or whether therapeutic resistances develop,” said Dr. Poeck.

Microbial diversity could be beneficial for cancer therapy, too. The composition of the microbiome varies significantly from host to host and can mutate. These properties make it a target for precision microbiotics, which involves using the gut microbiome as a biomarker to predict various physical reactions and to develop individualized diets.

Microbiome and Pathogenesis

The body’s microbiome fulfills a barrier function, especially where the body is exposed to an external environment: at the epidermis and the internal mucous membranes, in the gastrointestinal tract, and in the lungs, chest, and urogenital system.

Association studies on humans and experimental manipulations on mouse models of cancer showed that certain microorganisms can have either protective or harmful effects on cancer development, on the progression of a malignant disease, and on the response to therapy.

A Master Regulator?

Disruptions of the microbial system in the gut, as occur during antibiotic therapy, can have significant effects on a patient’s response to immunotherapy. Taking antibiotics shortly before or after starting therapy with immune checkpoint inhibitors (ICIs) significantly affected both overall survival (OS) and progression-free survival (PFS), as reported in a recent review and meta-analysis, for example.

Proton pump inhibitors also affect the gut microbiome and reduce the response to immunotherapy; this effect was demonstrated by an analysis of data from more than 2700 cancer patients that was recently presented at the annual meeting of the European Society for Medical Oncology (ESMO).

The extent to which the gut microbiome influences the efficacy of an ICI or predicts said efficacy was examined in a retrospective analysis published in Science in 2018, which Dr. Poeck presented. Resistance to ICI correlated with the relative frequency of the bacteria Akkermansia muciniphila in the gut of patients with cancer. In mouse models, the researchers restored the efficacy of the PD-1 blockade through a stool transplant.

Predicting Immunotherapy Response

If A muciniphila is present, can the composition of the microbiome act as a predictor for an effective ICI therapy?

Laurence Zitvogel, MD, PhD, and her working group at the National Institute of Health and Medical Research in Villejuif, France, performed a prospective study in 338 patients with non–small cell lung cancer and examined the prognostic significance of the fecal bacteria A muciniphila (Akk). The “Akkerman status” (low Akk vs high Akk) in a patient’s stool correlated with an increased objective response rate and a longer OS, independently of PD-L1 expression, antibiotics, and performance status. The OS for low Akk was 13.4 months, vs 18.8 months for high Akk in first-line treatment.

These results are promising, said Dr. Poeck. But there is no one-size-fits-all solution. No conclusions can be drawn from one bacterium on the efficacy of therapies in humans, since “the entirety of the bacteria is decisive,” said Dr. Poeck. In addition to the gut microbiome, the composition of gut metabolites influences the response to immunotherapies, as shown in a study with ICI.

Therapeutic Interventions

One possible therapeutic intervention to restore the gut microbiome is fecal microbiota transplantation (FMT). In a phase 1 study presented by Dr. Poeck, FMT was effective in the treatment of 20 patients with melanoma with ICI in an advanced and treatment-naive stage. Seven days after the patients received FMT, the first cycle with anti-PD-1 immunotherapy was initiated, with a total administration of three to four cycles. After 12 weeks, most patients were in complete or partial remission, as evidenced on imaging.

However, FMT also carries some risks. Two cases of sepsis with multiresistant Escherichia coli occurred, as well as other serious infections. Since then, there has been an FDA condition for extended screening of the donor stool, said Dr. Poeck. Nevertheless, this intervention is promising. A search of the keywords “FMT in cancer/transplant setting” reveals 46 currently clinical studies on clinicaltrials.gov.

Nutritional Interventions

Dr. Poeck advises caution about over-the-counter products. These products usually contain only a few species, such as Lactobacillus and Bifidobacterium. “Over-the-counter probiotics can even delay the reconstitution of the microbiome after antibiotics,” said Dr. Poeck, according to a study. In some studies, the response rates were significantly lower after probiotic intake or led to controversial results, according to Dr. Poeck.

In contrast, Dr. Poeck said prebiotics (that is, a fiber-rich diet with indigestible carbohydrates) were promising. During digestion, prebiotics are split into short-chain fatty acids by bacterial enzymes and promote the growth of certain microbiota.

In this way, just 20 g of extremely fiber-rich food had a significant effect on PFS in 128 patients with melanoma undergoing anti-PD-1 immunotherapy. With 20 g of fiber-rich food per day, the PFS was stable over 60 months. The most significant benefit was observed in patients with a sufficient fiber intake who were not taking probiotics.

What to Recommend?

In summary, Dr. Poeck said that it is important to “budget” well, particularly with antibiotic administration, and to strive for calculated therapy with as narrow a spectrum as possible. For patients who experience complications such as cytokine release syndrome as a reaction to cell therapy, delaying the use of antibiotics is important. However, it is often difficult to differentiate this syndrome from neutropenic fever. The aim should be to avoid high-risk antibiotics, if clinically justifiable. Patients should avoid taking antibiotics for 30 days before starting immunotherapy.

Regarding nutritional interventions, Dr. Poeck referred to the recent Onkopedia recommendation for nutrition after cancer and the 10 nutritional rules of the German Nutrition Society. According to Dr. Poeck, the important aspects of these recommendations are a fiber-rich diet (> 20 g/d) from various plant products and avoiding artificial sweeteners and flavorings, as well as ultraprocessed (convenience) foods. In addition, meat should be consumed only in moderation, and as little processed meat as possible should be consumed. In addition, regular (aerobic and anaerobic) physical activity is important.

“Looking ahead into the future,” said Dr. Poeck, “we need a uniform and functional understanding and we need a randomized prediction for diagnosis.”


This article was translated from the Medscape German edition.

A version of this article appeared on Medscape.com.

HAMBURG, Germany — The human microbiome comprises 39 to 44 billion microbes. That is ten times more than the number of cells in our body. Hendrik Poeck, MD, managing senior physician of internal medicine at the University Hospital Regensburg, illustrated this point at the annual meeting of the German Society for Hematology and Medical Oncology. If the gut microbiome falls out of balance, then “intestinal dysbiosis potentially poses a risk for the pathogenesis of local and systemic diseases,” explained Dr. Poeck.

Cancers and their therapies can also be influenced in this way. “Microbial diversity affects whether a tumor grows, whether it leads to inflammation, immune escape mechanisms or genomic instability, or whether therapeutic resistances develop,” said Dr. Poeck.

Microbial diversity could be beneficial for cancer therapy, too. The composition of the microbiome varies significantly from host to host and can mutate. These properties make it a target for precision microbiotics, which involves using the gut microbiome as a biomarker to predict various physical reactions and to develop individualized diets.

Microbiome and Pathogenesis

The body’s microbiome fulfills a barrier function, especially where the body is exposed to an external environment: at the epidermis and the internal mucous membranes, in the gastrointestinal tract, and in the lungs, chest, and urogenital system.

Association studies on humans and experimental manipulations on mouse models of cancer showed that certain microorganisms can have either protective or harmful effects on cancer development, on the progression of a malignant disease, and on the response to therapy.

A Master Regulator?

Disruptions of the microbial system in the gut, as occur during antibiotic therapy, can have significant effects on a patient’s response to immunotherapy. Taking antibiotics shortly before or after starting therapy with immune checkpoint inhibitors (ICIs) significantly affected both overall survival (OS) and progression-free survival (PFS), as reported in a recent review and meta-analysis, for example.

Proton pump inhibitors also affect the gut microbiome and reduce the response to immunotherapy; this effect was demonstrated by an analysis of data from more than 2700 cancer patients that was recently presented at the annual meeting of the European Society for Medical Oncology (ESMO).

The extent to which the gut microbiome influences the efficacy of an ICI or predicts said efficacy was examined in a retrospective analysis published in Science in 2018, which Dr. Poeck presented. Resistance to ICI correlated with the relative frequency of the bacteria Akkermansia muciniphila in the gut of patients with cancer. In mouse models, the researchers restored the efficacy of the PD-1 blockade through a stool transplant.

Predicting Immunotherapy Response

If A muciniphila is present, can the composition of the microbiome act as a predictor for an effective ICI therapy?

Laurence Zitvogel, MD, PhD, and her working group at the National Institute of Health and Medical Research in Villejuif, France, performed a prospective study in 338 patients with non–small cell lung cancer and examined the prognostic significance of the fecal bacteria A muciniphila (Akk). The “Akkerman status” (low Akk vs high Akk) in a patient’s stool correlated with an increased objective response rate and a longer OS, independently of PD-L1 expression, antibiotics, and performance status. The OS for low Akk was 13.4 months, vs 18.8 months for high Akk in first-line treatment.

These results are promising, said Dr. Poeck. But there is no one-size-fits-all solution. No conclusions can be drawn from one bacterium on the efficacy of therapies in humans, since “the entirety of the bacteria is decisive,” said Dr. Poeck. In addition to the gut microbiome, the composition of gut metabolites influences the response to immunotherapies, as shown in a study with ICI.

Therapeutic Interventions

One possible therapeutic intervention to restore the gut microbiome is fecal microbiota transplantation (FMT). In a phase 1 study presented by Dr. Poeck, FMT was effective in the treatment of 20 patients with melanoma with ICI in an advanced and treatment-naive stage. Seven days after the patients received FMT, the first cycle with anti-PD-1 immunotherapy was initiated, with a total administration of three to four cycles. After 12 weeks, most patients were in complete or partial remission, as evidenced on imaging.

However, FMT also carries some risks. Two cases of sepsis with multiresistant Escherichia coli occurred, as well as other serious infections. Since then, there has been an FDA condition for extended screening of the donor stool, said Dr. Poeck. Nevertheless, this intervention is promising. A search of the keywords “FMT in cancer/transplant setting” reveals 46 currently clinical studies on clinicaltrials.gov.

Nutritional Interventions

Dr. Poeck advises caution about over-the-counter products. These products usually contain only a few species, such as Lactobacillus and Bifidobacterium. “Over-the-counter probiotics can even delay the reconstitution of the microbiome after antibiotics,” said Dr. Poeck, according to a study. In some studies, the response rates were significantly lower after probiotic intake or led to controversial results, according to Dr. Poeck.

In contrast, Dr. Poeck said prebiotics (that is, a fiber-rich diet with indigestible carbohydrates) were promising. During digestion, prebiotics are split into short-chain fatty acids by bacterial enzymes and promote the growth of certain microbiota.

In this way, just 20 g of extremely fiber-rich food had a significant effect on PFS in 128 patients with melanoma undergoing anti-PD-1 immunotherapy. With 20 g of fiber-rich food per day, the PFS was stable over 60 months. The most significant benefit was observed in patients with a sufficient fiber intake who were not taking probiotics.

What to Recommend?

In summary, Dr. Poeck said that it is important to “budget” well, particularly with antibiotic administration, and to strive for calculated therapy with as narrow a spectrum as possible. For patients who experience complications such as cytokine release syndrome as a reaction to cell therapy, delaying the use of antibiotics is important. However, it is often difficult to differentiate this syndrome from neutropenic fever. The aim should be to avoid high-risk antibiotics, if clinically justifiable. Patients should avoid taking antibiotics for 30 days before starting immunotherapy.

Regarding nutritional interventions, Dr. Poeck referred to the recent Onkopedia recommendation for nutrition after cancer and the 10 nutritional rules of the German Nutrition Society. According to Dr. Poeck, the important aspects of these recommendations are a fiber-rich diet (> 20 g/d) from various plant products and avoiding artificial sweeteners and flavorings, as well as ultraprocessed (convenience) foods. In addition, meat should be consumed only in moderation, and as little processed meat as possible should be consumed. In addition, regular (aerobic and anaerobic) physical activity is important.

“Looking ahead into the future,” said Dr. Poeck, “we need a uniform and functional understanding and we need a randomized prediction for diagnosis.”


This article was translated from the Medscape German edition.

A version of this article appeared on Medscape.com.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

Originally developed for the treatment of refractory epilepsy, the ketogenic diet is distinguished by its high-fat, moderate-protein, and low-carbohydrate food program. Preclinical models provide emerging evidence that a ketogenic diet can have therapeutic potential for a broad range of cancers. The Warburg effect is a condition where cancer cells increase the uptake and fermentation of glucose to produce lactate for their metabolism, which is called aerobic glycolysis. Lactate is the key driver of cancer angiogenesis and proliferation.^1,2

The ketogenic diet promotes a metabolic shift from glycolysis to mitochondrial metabolism in normal cells while cancer cells have dysfunction in their mitochondria due to damage in cellular respiration. The ketogenic diet creates a metabolic state whereby blood glucose levels are reduced, and blood ketone bodies (D-β-hydroxybutyrate and acetoacetate) are elevated. In normal cells, the ketogenic diet causes a decrease in glucose intake for glycolysis, which makes them unable to produce enough substrate to enter the tricarboxylic acid (TCA) cycle for adenosine triphosphate (ATP) production. Fatty acid oxidation plays a key role in ketone body synthesis as a “super fuel” that enter the TCA cycle as an alternative pathway to generate ATP. On the other hand, cancer cells are unable to use ketone bodies to produce ATP for energy and metabolism due to mitochondrial defects. Lack of energy subsequently leads to the inhibition of proliferation and survival of cancer cells.^3,4

CASE PRESENTATION

A 69-year-old veteran had iron deficiency anemia (hemoglobin, 6.5 g/dL) about 5 years previously. He underwent a colonoscopy that revealed a near circumferential ulcerated mass measuring 7 cm in the transverse colon. Biopsy results showed mucinous adenocarcinoma of the colon with a foci of signet ring cells (Figure 2).

The patient received adjuvant treatment with FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin), but within several months he developed pancreatic and worsening omental metastasis seen on PET/CT. He was then started on FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) plus bevacizumab 16 months after his initial diagnosis. He underwent a pancreatic mastectomy that confirmed adenocarcinoma 9 months later. Afterward, he briefly resumed FOLFIRI and bevacizumab. Next-generation sequencing testing with Foundation One CDx revealed a wild-type (WT) KRAS with a high degree of tumor mutation burden of 37 muts/Mb, BRAF V600E mutation, and high microsatellite instability (MSI-H).

The purpose of this case report is to describe whether a patient receiving active cancer treatment was able to tolerate the ketogenic diet in conjunction with chemotherapy or immunotherapy. Most literature published on the subject evaluated the tolerability and response of the ketogenic diet after the failure of standard therapy. Our patient was diagnosed with stage III mucinous colon adenocarcinoma. He received adjuvant chemotherapy but quickly developed metastatic disease to the pancreas and omentum. We started him on encorafenib and cetuximab based on the BEACON study that showed improvement in response rate and survival when compared with standard chemotherapy for patients with BRAF V600E mutation.⁵ Unfortunately, his cancer quickly progressed within 4 months and again did not respond to pembrolizumab despite MSI-H, which lasted for another 4 months.

We suggested the ketogenic diet and the patient agreed. He started the diet along with trifluridine/tipiracil, and bevacizumab in January 2021. The patient’s metastatic cancer stabilized for 9 months until his disease progressed again. He was started on doublet immune checkpoint inhibitors ipilimumab and nivolumab based on his MSI-H and high tumor mutation burden with the continuation of the ketogenic diet until now. The CheckMate 142 study revealed that the combination of ipilimumab and nivolumab in patients with MSI-H previously treated for metastatic colon cancer showed some benefit.⁶

Our patient had the loss of nuclear expression of MLH1 and PMS2 (zero tumor stained) but no evidence of the loss expression of MSH2 and MSH6 genes (99% tumor stained). About 8% to 12% of patients with metastatic colon cancer have BRAF V600E mutations that are usually mucinous type, poorly differentiated, and located in the right side of the colon, which portends to a poor prognosis. Tumor DNA mismatch repair damage results in genetic hypermutability and leads to MSI that is sensitive to treatment with checkpoint inhibitors, as in our patient. Only about 3% of MSI-H tumors are due to germline mutations such as Lynch syndrome (hereditary nonpolyposis colorectal cancer). The presence of both MLH1 hypermethylation and BRAF mutation, as in our patient, is a strong indication of somatic rather than germline mutation.⁷

GKI, which represents the ratio of glucose to ketone, was developed to evaluate the efficacy of the ketogenic diet. This index measures the degree of metabolic stress on tumor cells through the decrease of glucose levels and increase of ketone bodies. A GKI of ≤ 1.0 has been suggested as the ideal therapeutic goal for cancer management.⁸ As levels of blood glucose decline, the blood levels of ketone bodies should rise. These 2 lines should eventually intersect at a certain point beyond which one enters the therapeutic zone or therapeutic ketosis zone. This is when tumor growth is expected to slow or cease.⁹ The patient’s ketone (β-hydroxybutyrate) level was initially high (0.71 mmol/L) with a GKI of 8.2. (low ketotic level), which meant he tolerated a rather strict diet for the first several months. This was also reflected in his 18 lb weight loss (almost 10% of body weight) and cancer stabilization, as in our previous publication.¹ Unfortunately, the patient was unable to maintain high ketone and lower GKI levels due to fatigue from depleted carbohydrate intake. He added some carbohydrate snacks in between meals, which improved the fatigue. His ketone level has been < 0.5 mmol/L ever since, albeit his disease continues to be stable. The patient continues his daily work and reports a better QOL, based on the ECOG QLC-C30 form that he completed every 3 months.¹⁰ Currently, the patient is still receiving ipilimumab and nivolumab while maintaining the ketogenic diet with stable metastatic disease on PET/CT.

Ketogenic Diet and Cellular Mechanism of Action

PI3K/Akt (phosphatidylinositol-3-kinase) signaling is one of the most important intracellular pathways for tumor cells. It leads to the inhibition of apoptosis and the promotion of cell proliferation, metabolism, and angiogenesis. Deregulation of the PI3K pathway either via amplification of PI3K by tyrosine kinase growth factor receptors or inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN), which is the negative regulator of the PI3K pathway, contributes to the development of cancer cells.¹¹

A study by Goncalves and colleagues revealed an interesting relationship between the PI3K pathway and the benefit of the ketogenic diet to slow tumor growth. PI3K inhibitors inhibit glucose uptake into skeletal muscle and adipose tissue that activate hepatic glycogenolysis. This event results in hyperglycemia due to the pancreas releasing very high levels of insulin into the blood (hyperinsulinemia) that subsequently reactivate PI3K signaling and cause resistance to PI3K inhibitors. The ketogenic diet reportedly minimized the hyperglycemia and hyperinsulinemia induced by the PI3K inhibitor and enhanced the efficacy of PI3K inhibitors in tumor models. Studies combining PI3K inhibitors and ketogenic diet are underway. Hence, combining the ketogenic diet with chemotherapy or other novel treatment should be the focus of ketogenic diet trials.^12,13

The impact of the ketogenic diet on the growth of murine pancreatic tumors was evaluated by Yang and colleagues. The ketogenic diet decreased glucose concentration that enters the TCA cycle and increased fatty acid oxidation that produces β-hydroxybutyrate. This event promotes the generation of ATP, although with only modest elevations of NADH with less impact on tumor growth. The combination of ketogenic diet and standard chemotherapy substantially raised tumor NADH and suppressed the growth of murine tumor cells, they noted.¹⁴ Furukawa and colleagues compared 10 patients with metastatic colon cancer receiving chemotherapy plus the modified medium-chain triglyceride ketogenic diet for 1 year with 14 patients receiving chemotherapy only. The ketogenic diet group exhibited a response rate of 60% with 5 patients achieving a complete response and a disease control rate of 70%, while the chemotherapy-alone group showed a response rate of only 21% with no complete response and a disease control rate of 64%.¹⁵

The ketogenic diet also reportedly stimulates cytokine and CD4+ and CD8+ T-cell production that stimulates T-cell killing activity. The ketogenic diet may overcome several immune escape mechanisms by downregulating the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on tumor-infiltrating lymphocytes.¹⁶ Our patient tolerated the combination of the ketogenic diet with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor) without significant toxicities and stabilization of his disease.

Future Directions

We originally presented the abstract and poster of this case report at the Association of VA Hematology/Oncology annual meeting in San Diego, California, in September 2022.¹⁷ Based on our previous experience, we are now using a modified Atkins diet, which is a less strict diet consisting of 60% fat, 30% protein, and 10% carbohydrates combined with chemotherapy and/or immunotherapy. The composition of fat to carbohydrate plus protein in the traditional ketogenic diet is usually 4:1 or 3:1, while in modified Atkins diet the ratio is 1:1 or 2:1. The benefit of the modified Atkins diet is that patients can consume more protein than a strict ketogenic diet and they can be more liberal in carbohydrate allowances. We are about to open a study protocol of combining a modified Atkin diet and chemotherapy and/or immunotherapy as a first-line treatment for veterans with all types of advanced or metastatic solid tumors at VACCHCS. The study protocol was approved by the VA Office of Research and Development and has been submitted to the VACCHCS Institutional Review Board for review. Once approved, we will start patient recruitment.

CONCLUSIONS

Cancer cells have defects in their mitochondria that prevent them from generating energy for metabolism in the absence of glucose. They also depend on the PI3K signaling pathway to survive. The ketogenic diet has the advantage of affecting cancer cell growth by exploiting these mitochondrial defects and blocking hyperglycemia. There is growing evidence that the ketogenic diet is feasible, tolerable, and reportedly inhibits cancer growth. Our case report and previous publications suggest that the ketogenic diet can be added to chemotherapy and/or immunotherapy as an adjunct to standard-of-care cancer treatment while maintaining good QOL. We are planning to open a clinical trial using the modified Atkins diet in conjunction with active cancer treatments as first-line therapy for metastatic solid tumors at the VACCHCS. We are also working closely with researchers from several veteran hospitals to do a diet collaborative study. We believe the ketogenic diet is an important part of cancer treatment and has a promising future. More research should be dedicated to this very interesting field.

Acknowledgments

We previously presented this case report in an abstract and poster at the September 2022 AVAHO meeting in San Diego, California.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Implementing stewardship strategies for immune checkpoint inhibitor (ICI) therapy, including personalized weight-based dosing, dose rounding, and pharmacy-level vial sharing, could generate savings of as much as $74 million each year for the Veterans Health Administration (VHA), a new analysis suggests.

That $74 million in savings would translate to nearly 14% less spent on ICI therapy annually.

“Our work suggests that implementing these strategies across the VHA could lead to tens of millions of dollars in annual savings – and that’s just for immunotherapy – without sacrificing outcomes,” first author Alex Bryant, MD, University of Michigan, Ann Arbor, said in an interview.

The study was published in Health Affairs.

ICI therapy is used in about 40 unique cancer indications and, in 2020, accounted for more than $6 billion in Medicare Part B spending.

Two of the most prescribed ICIs – pembrolizumab and nivolumab – initially received their U.S. approval at personalized weight-based doses. But at the request of the manufacturers, the Food and Drug Administration approved “one-size-fits-all” flat doses, despite a lack of data to support this strategy compared with weight-based dosing.

With a fixed dose strategy, “patients with cancer not only tend to get too high a dose of the drug, but costs go up significantly,” Daniel Goldstein, MD, a medical oncologist at the Rabin Medical Center, Petah Tikva, Israel,  told this news organization last year. “Why should we give a higher dose with the same efficacy when that dose will cost significantly more and has the potential to increase adverse events?”

To compare the cost of a weight-based vs. fixed-dose strategy, Dr. Bryant and colleagues conducted a simulation analysis under four stewardship scenarios, using data from the VHA and Medicare drug prices. Strategy one looked at weight-based dosing; strategy two combined weight-based dosing and dose rounding but not single-use vial sharing; strategy three used weight-based dosing and single-use vial sharing but not dose rounding; and strategy four, the most aggressive, combined all three.

ICIs in the VHA national formulary included pembrolizumab, nivolumab, atezolizumab, durvalumab, and cemiplimab-rwlc.

Using an algorithm to extract data, the team identified 49,851 administration events in 8,276 unique patients in 2021 – just over half were pembrolizumab, nearly 23% were nivolumab, and the remaining 26% largely included atezolizumab (12.1%) and durvalumab (11.9%).

The team found that the VHA spends roughly $537 million annually on ICIs. But implementing the stewardship measures that combined weight-based dosing, dose rounding, and vial sharing could save the VHA $74 million, or about 14%, annually on ICIs.

Most of the savings came from dosing changes to pembrolizumab and nivolumab, with greater savings achieved by combining more stewardship strategies. For instance, using strategy one (weight-based dosing alone) could lead to annual pembrolizumab savings of $14 million. Adding dose rounding (strategy two) could reduce pembrolizumab spending by $24 million. And using strategy four, with an unlimited window for vial sharing, could mean annual savings of nearly $60 million.

“Our results should prompt cost-conscious systems and payers to ask whether the amounts of drugs they’re providing to patients and how they go about making those doses are the most cost-effective approaches,” said corresponding author Garth W. Strohbehn, MD, of the University of Michigan and the VA Ann Arbor Healthcare System.

Dr. Strohbehn said the prospect of adopting these strategies hinges on several factors, with financial incentives at the prescriber and medical center level likely being the most influential.

“In fee-for-service systems, reimbursement scales with the amount of drug administered, so there can be a financial disincentive to decreasing overall drug usage,” Dr. Strohbehn explained.

“Conversely, integrated systems such as Kaiser Permanente or the VHA and large self-insured employers are incentivized to contain costs and take great care of patients, so they may be more inclined to promote these strategies,” he added.

However, Adam C. Powell, PhD, president, Payer+Provider Syndicate, who wasn’t involved in the analysis, cautioned that such a shift may come with unintended consequences.

The Infrastructure, Investment, and Jobs Act of 2021 let the Centers for Medicare and Medicaid Services seek reimbursement for discarded drugs – in effect, changing the reimbursement model for medications. That led pharmaceutical manufacturers to respond in kind by changing the dosing model, Dr. Powell said. 

“Drugs that previously had personalized weight-based dosing were moved to uniform flat dosing, eliminating the potential for the manufacturer to have to issue a reimbursement if the patient’s personalized dose fell short of the amount in the single-use vial,” Dr. Powell added.  

If there is a substantial migration to weight-based dosing, “it is possible that pharmaceutical manufacturers will rethink their dosing and pricing models, just as happened previously,” he cautioned.

However, these strategies could also provide relief for another escalating issue: drug shortages. Especially in the current moment, having a stewardship mindset, “might be helpful in navigating drug shortages,” Dr. Strohbehn said.

This research had no commercial funding. Dr. Bryant, Dr. Strohbehn, and Dr. Powell report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Implementing stewardship strategies for immune checkpoint inhibitor (ICI) therapy, including personalized weight-based dosing, dose rounding, and pharmacy-level vial sharing, could generate savings of as much as $74 million each year for the Veterans Health Administration (VHA), a new analysis suggests.

That $74 million in savings would translate to nearly 14% less spent on ICI therapy annually.

“Our work suggests that implementing these strategies across the VHA could lead to tens of millions of dollars in annual savings – and that’s just for immunotherapy – without sacrificing outcomes,” first author Alex Bryant, MD, University of Michigan, Ann Arbor, said in an interview.

The study was published in Health Affairs.

ICI therapy is used in about 40 unique cancer indications and, in 2020, accounted for more than $6 billion in Medicare Part B spending.

Two of the most prescribed ICIs – pembrolizumab and nivolumab – initially received their U.S. approval at personalized weight-based doses. But at the request of the manufacturers, the Food and Drug Administration approved “one-size-fits-all” flat doses, despite a lack of data to support this strategy compared with weight-based dosing.

With a fixed dose strategy, “patients with cancer not only tend to get too high a dose of the drug, but costs go up significantly,” Daniel Goldstein, MD, a medical oncologist at the Rabin Medical Center, Petah Tikva, Israel,  told this news organization last year. “Why should we give a higher dose with the same efficacy when that dose will cost significantly more and has the potential to increase adverse events?”

To compare the cost of a weight-based vs. fixed-dose strategy, Dr. Bryant and colleagues conducted a simulation analysis under four stewardship scenarios, using data from the VHA and Medicare drug prices. Strategy one looked at weight-based dosing; strategy two combined weight-based dosing and dose rounding but not single-use vial sharing; strategy three used weight-based dosing and single-use vial sharing but not dose rounding; and strategy four, the most aggressive, combined all three.

ICIs in the VHA national formulary included pembrolizumab, nivolumab, atezolizumab, durvalumab, and cemiplimab-rwlc.

Using an algorithm to extract data, the team identified 49,851 administration events in 8,276 unique patients in 2021 – just over half were pembrolizumab, nearly 23% were nivolumab, and the remaining 26% largely included atezolizumab (12.1%) and durvalumab (11.9%).

The team found that the VHA spends roughly $537 million annually on ICIs. But implementing the stewardship measures that combined weight-based dosing, dose rounding, and vial sharing could save the VHA $74 million, or about 14%, annually on ICIs.

Most of the savings came from dosing changes to pembrolizumab and nivolumab, with greater savings achieved by combining more stewardship strategies. For instance, using strategy one (weight-based dosing alone) could lead to annual pembrolizumab savings of $14 million. Adding dose rounding (strategy two) could reduce pembrolizumab spending by $24 million. And using strategy four, with an unlimited window for vial sharing, could mean annual savings of nearly $60 million.

“Our results should prompt cost-conscious systems and payers to ask whether the amounts of drugs they’re providing to patients and how they go about making those doses are the most cost-effective approaches,” said corresponding author Garth W. Strohbehn, MD, of the University of Michigan and the VA Ann Arbor Healthcare System.

Dr. Strohbehn said the prospect of adopting these strategies hinges on several factors, with financial incentives at the prescriber and medical center level likely being the most influential.

“In fee-for-service systems, reimbursement scales with the amount of drug administered, so there can be a financial disincentive to decreasing overall drug usage,” Dr. Strohbehn explained.

“Conversely, integrated systems such as Kaiser Permanente or the VHA and large self-insured employers are incentivized to contain costs and take great care of patients, so they may be more inclined to promote these strategies,” he added.

However, Adam C. Powell, PhD, president, Payer+Provider Syndicate, who wasn’t involved in the analysis, cautioned that such a shift may come with unintended consequences.

The Infrastructure, Investment, and Jobs Act of 2021 let the Centers for Medicare and Medicaid Services seek reimbursement for discarded drugs – in effect, changing the reimbursement model for medications. That led pharmaceutical manufacturers to respond in kind by changing the dosing model, Dr. Powell said. 

“Drugs that previously had personalized weight-based dosing were moved to uniform flat dosing, eliminating the potential for the manufacturer to have to issue a reimbursement if the patient’s personalized dose fell short of the amount in the single-use vial,” Dr. Powell added.  

If there is a substantial migration to weight-based dosing, “it is possible that pharmaceutical manufacturers will rethink their dosing and pricing models, just as happened previously,” he cautioned.

However, these strategies could also provide relief for another escalating issue: drug shortages. Especially in the current moment, having a stewardship mindset, “might be helpful in navigating drug shortages,” Dr. Strohbehn said.

This research had no commercial funding. Dr. Bryant, Dr. Strohbehn, and Dr. Powell report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

Implementing stewardship strategies for immune checkpoint inhibitor (ICI) therapy, including personalized weight-based dosing, dose rounding, and pharmacy-level vial sharing, could generate savings of as much as $74 million each year for the Veterans Health Administration (VHA), a new analysis suggests.

That $74 million in savings would translate to nearly 14% less spent on ICI therapy annually.

“Our work suggests that implementing these strategies across the VHA could lead to tens of millions of dollars in annual savings – and that’s just for immunotherapy – without sacrificing outcomes,” first author Alex Bryant, MD, University of Michigan, Ann Arbor, said in an interview.

The study was published in Health Affairs.

ICI therapy is used in about 40 unique cancer indications and, in 2020, accounted for more than $6 billion in Medicare Part B spending.

Two of the most prescribed ICIs – pembrolizumab and nivolumab – initially received their U.S. approval at personalized weight-based doses. But at the request of the manufacturers, the Food and Drug Administration approved “one-size-fits-all” flat doses, despite a lack of data to support this strategy compared with weight-based dosing.

With a fixed dose strategy, “patients with cancer not only tend to get too high a dose of the drug, but costs go up significantly,” Daniel Goldstein, MD, a medical oncologist at the Rabin Medical Center, Petah Tikva, Israel,  told this news organization last year. “Why should we give a higher dose with the same efficacy when that dose will cost significantly more and has the potential to increase adverse events?”

To compare the cost of a weight-based vs. fixed-dose strategy, Dr. Bryant and colleagues conducted a simulation analysis under four stewardship scenarios, using data from the VHA and Medicare drug prices. Strategy one looked at weight-based dosing; strategy two combined weight-based dosing and dose rounding but not single-use vial sharing; strategy three used weight-based dosing and single-use vial sharing but not dose rounding; and strategy four, the most aggressive, combined all three.

ICIs in the VHA national formulary included pembrolizumab, nivolumab, atezolizumab, durvalumab, and cemiplimab-rwlc.

Using an algorithm to extract data, the team identified 49,851 administration events in 8,276 unique patients in 2021 – just over half were pembrolizumab, nearly 23% were nivolumab, and the remaining 26% largely included atezolizumab (12.1%) and durvalumab (11.9%).

The team found that the VHA spends roughly $537 million annually on ICIs. But implementing the stewardship measures that combined weight-based dosing, dose rounding, and vial sharing could save the VHA $74 million, or about 14%, annually on ICIs.

Most of the savings came from dosing changes to pembrolizumab and nivolumab, with greater savings achieved by combining more stewardship strategies. For instance, using strategy one (weight-based dosing alone) could lead to annual pembrolizumab savings of $14 million. Adding dose rounding (strategy two) could reduce pembrolizumab spending by $24 million. And using strategy four, with an unlimited window for vial sharing, could mean annual savings of nearly $60 million.

“Our results should prompt cost-conscious systems and payers to ask whether the amounts of drugs they’re providing to patients and how they go about making those doses are the most cost-effective approaches,” said corresponding author Garth W. Strohbehn, MD, of the University of Michigan and the VA Ann Arbor Healthcare System.

Dr. Strohbehn said the prospect of adopting these strategies hinges on several factors, with financial incentives at the prescriber and medical center level likely being the most influential.

“In fee-for-service systems, reimbursement scales with the amount of drug administered, so there can be a financial disincentive to decreasing overall drug usage,” Dr. Strohbehn explained.

“Conversely, integrated systems such as Kaiser Permanente or the VHA and large self-insured employers are incentivized to contain costs and take great care of patients, so they may be more inclined to promote these strategies,” he added.

However, Adam C. Powell, PhD, president, Payer+Provider Syndicate, who wasn’t involved in the analysis, cautioned that such a shift may come with unintended consequences.

The Infrastructure, Investment, and Jobs Act of 2021 let the Centers for Medicare and Medicaid Services seek reimbursement for discarded drugs – in effect, changing the reimbursement model for medications. That led pharmaceutical manufacturers to respond in kind by changing the dosing model, Dr. Powell said. 

“Drugs that previously had personalized weight-based dosing were moved to uniform flat dosing, eliminating the potential for the manufacturer to have to issue a reimbursement if the patient’s personalized dose fell short of the amount in the single-use vial,” Dr. Powell added.  

If there is a substantial migration to weight-based dosing, “it is possible that pharmaceutical manufacturers will rethink their dosing and pricing models, just as happened previously,” he cautioned.

However, these strategies could also provide relief for another escalating issue: drug shortages. Especially in the current moment, having a stewardship mindset, “might be helpful in navigating drug shortages,” Dr. Strohbehn said.

This research had no commercial funding. Dr. Bryant, Dr. Strohbehn, and Dr. Powell report no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

CHICAGO – Lenalidomide (Revlimid) is a vital component of early therapy and maintenance for patients with multiple myeloma, but patients in first relapse who have disease that is refractory to lenalidomide have few good options for subsequent lines of therapy and a generally poor prognosis.

New results show that such patients benefit from treatment with the chimeric antigen receptor T-cell (CAR T) construct ciltacabtagene autoleucel (cilta-cel) (Carvykti).

The finding comes from the phase 3 CARTITUDE-4 trial, which was reported at the annual meeting of the American Society of Clinical Oncology (ASCO) and was simultaneously published online in the New England Journal of Medicine.

Patients with lenalidomide-refractory multiple myeloma who received a single infusion of ciltacabtagene autoleucel demonstrated a 74% reduction in the risk for disease progression or death, compared with patients who received the standard of care.

The hazard ratio for death or progression with cilta-cel was 0.26 (P < .001), which “is the best hazard ratio ever reported in this patient population in a randomized clinical setting,” said principal investigator Binod Dhakal, MD, from the Medical College of Wisconsin, Milwaukee.

Dr. Dhakal reported data from the first analysis of the trial. At a median follow-up of 15.9 months, median progression-free survival (PFS), the primary endpoint, had not been reached among 208 patients who received cilta-cel; PFS was 11.8 months for the 211 patients assigned to receive standard of care, which consisted of the physician’s choice of either pomalidomide, bortezomib, and dexamethasone (PVd), or daratumumab, pomalidomide, and dexamethasone (DPd).

Twelve-month PFS rates were 75.9% and 48.6%, respectively, and both the overall response rate (ORR) and the complete response (CR) rate were higher with the CAR T construct than with the standard of care (ORR, 84.6% vs. 67.3%; CR rates, 73.1% and 21.8%, respectively).

“My perspective on Dr. Dakhal and colleague’s data is that myeloma treatment should be revisited in the light of this,” commented invited discussant Asher Chanan-Khan, MD, from the Mayo Clinic Cancer Center in Jacksonville, Fla.

“Early CAR Ts demonstrating efficacy and safety and prior lines of treatment impact survival from CAR T in myeloma. In lymphoma, CAR T is almost replacing, if not already, autotransplant. Can this also be true for multiple myeloma?” he asked.

Dr. Chanan-Khan noted that there are at least four ongoing trials with CAR T targeting either the B-cell maturation antigen (BCMA) alone or in combination with an anti-CD19 CAR T, immune checkpoint inhibitors, or with bortezomib, lenalidomide, and dexamethasone.

Also commenting on the new results, ASCO Expert Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, said in a statement: “Lenalidomide has become a foundation of care for people with myeloma, but as its use has expanded, so has the number of patients whose disease will no longer respond to the treatment. Ciltacabtagene autoleucel has not only shown that it delivers remarkably effective outcomes, compared with patients’ current options, but also that it can be used safely earlier in the treatment phase.”
 

Already approved for refractory myeloma

Cilta-cel is a second-generation CAR T that contains two single-domain antibodies that target BCMA. This target was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

The product is already approved for use in myeloma; it was approved in March 2022 by the U.S. Food and Drug Administration for use in patients with refractory/relapsed multiple myeloma who have already tried four or more therapies. That approval was based on results from phase 1b/2 CARTITUDE-1 trial, which, as previously reported by this news organization, showed that early and deep responses with cilta-cel proved to be durable.

Final results of CARTITUDE-1, reported in a scientific poster at ASCO 2023, showed that almost half of patients (47.5%) who were treated with cilta-cel were free of disease progression at 3 years, and 59.8% had sustained, complete responses. In addition, the median PFS was longer than for any previously reported therapy for heavily pretreated patients with relapsed/refractory multiple myeloma, the authors said.
 

CARTITUDE-4 details

For the CARTITUDE-4 trial, the investigators enrolled patients aged 18 years or older with lenalidomide-refractory multiple myeloma who had experienced relapse after one to three prior lines of therapy that included a prosteasome inhibitor and immunomodulator. After stratification by the choice of PVd or DPd, Multiple Myeloma International Staging System, and number of prior lines of therapy, patients were randomly assigned to receive either cilta-cel or one of the two standard-of-care regimens previously described.

Patients assigned to cilta-cel received one or more cycles of either PVd or DPd as bridging therapy during the period from apheresis to infusion of the CAR T cells.

As already noted, cilta-cel showed superior PFS and response rates and was associated with a significantly higher rate of minimal residual disease (MRD) negativity, compared with standard of care, in the intention-to-treat population: 60.6% vs. 15.6%, which translates into an odds ratio for achieving MRD negativity with CAR T of 8.7 (P < .0001). Among the subset of patients evaluable for MRD, the respective rates were 87.5% and 32.7%.

Overall survival data were not mature at the time of presentation. In all, 39 patients in the cilta-cel arm and 47 in the standard-of-care arm died during the study.

Grade 3 or 4 adverse events occurred in 97% of patients who received cilta-cel and in 94% of those who received standard-of-care therapies. In the cilta-cel arm, 76.1% of patients had cytokine release syndrome (CRS), although only 1.1% of cases were of grade 3 or 4 in severity, and there were no CRS-associated deaths. Eight patients in this arm had immune effector cell–associated neurotoxicity syndrome, all of grade 1 or 2. One patient had grade 1 movement and neurocognitive symptoms, 16 had grade 2 or 3 cranial nerve palsy, and 5 patients had CAR T–related peripheral neuropathy of grade 1, 2, or 3.

The investigators plan to follow patients to determine the long-term effects of ciltacabtagene autoleucel and are currently performing analyses of health-related quality of life, subgroups, and biomarkers.

The study was funded by Janssen and Legend Biotech, which market ciltacabtagene autoleucel. Dr. Dhakal disclosed consulting, speaker’s bureau participation, and institutional research funding from Janssen and others. Several coauthors are employees of the study funders. Dr. Chanan-Khan’s relevant financial information was not available. Dr. Odejide reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – Lenalidomide (Revlimid) is a vital component of early therapy and maintenance for patients with multiple myeloma, but patients in first relapse who have disease that is refractory to lenalidomide have few good options for subsequent lines of therapy and a generally poor prognosis.

New results show that such patients benefit from treatment with the chimeric antigen receptor T-cell (CAR T) construct ciltacabtagene autoleucel (cilta-cel) (Carvykti).

The finding comes from the phase 3 CARTITUDE-4 trial, which was reported at the annual meeting of the American Society of Clinical Oncology (ASCO) and was simultaneously published online in the New England Journal of Medicine.

Patients with lenalidomide-refractory multiple myeloma who received a single infusion of ciltacabtagene autoleucel demonstrated a 74% reduction in the risk for disease progression or death, compared with patients who received the standard of care.

The hazard ratio for death or progression with cilta-cel was 0.26 (P < .001), which “is the best hazard ratio ever reported in this patient population in a randomized clinical setting,” said principal investigator Binod Dhakal, MD, from the Medical College of Wisconsin, Milwaukee.

Dr. Dhakal reported data from the first analysis of the trial. At a median follow-up of 15.9 months, median progression-free survival (PFS), the primary endpoint, had not been reached among 208 patients who received cilta-cel; PFS was 11.8 months for the 211 patients assigned to receive standard of care, which consisted of the physician’s choice of either pomalidomide, bortezomib, and dexamethasone (PVd), or daratumumab, pomalidomide, and dexamethasone (DPd).

Twelve-month PFS rates were 75.9% and 48.6%, respectively, and both the overall response rate (ORR) and the complete response (CR) rate were higher with the CAR T construct than with the standard of care (ORR, 84.6% vs. 67.3%; CR rates, 73.1% and 21.8%, respectively).

“My perspective on Dr. Dakhal and colleague’s data is that myeloma treatment should be revisited in the light of this,” commented invited discussant Asher Chanan-Khan, MD, from the Mayo Clinic Cancer Center in Jacksonville, Fla.

“Early CAR Ts demonstrating efficacy and safety and prior lines of treatment impact survival from CAR T in myeloma. In lymphoma, CAR T is almost replacing, if not already, autotransplant. Can this also be true for multiple myeloma?” he asked.

Dr. Chanan-Khan noted that there are at least four ongoing trials with CAR T targeting either the B-cell maturation antigen (BCMA) alone or in combination with an anti-CD19 CAR T, immune checkpoint inhibitors, or with bortezomib, lenalidomide, and dexamethasone.

Also commenting on the new results, ASCO Expert Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, said in a statement: “Lenalidomide has become a foundation of care for people with myeloma, but as its use has expanded, so has the number of patients whose disease will no longer respond to the treatment. Ciltacabtagene autoleucel has not only shown that it delivers remarkably effective outcomes, compared with patients’ current options, but also that it can be used safely earlier in the treatment phase.”
 

Already approved for refractory myeloma

Cilta-cel is a second-generation CAR T that contains two single-domain antibodies that target BCMA. This target was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

The product is already approved for use in myeloma; it was approved in March 2022 by the U.S. Food and Drug Administration for use in patients with refractory/relapsed multiple myeloma who have already tried four or more therapies. That approval was based on results from phase 1b/2 CARTITUDE-1 trial, which, as previously reported by this news organization, showed that early and deep responses with cilta-cel proved to be durable.

Final results of CARTITUDE-1, reported in a scientific poster at ASCO 2023, showed that almost half of patients (47.5%) who were treated with cilta-cel were free of disease progression at 3 years, and 59.8% had sustained, complete responses. In addition, the median PFS was longer than for any previously reported therapy for heavily pretreated patients with relapsed/refractory multiple myeloma, the authors said.
 

CARTITUDE-4 details

For the CARTITUDE-4 trial, the investigators enrolled patients aged 18 years or older with lenalidomide-refractory multiple myeloma who had experienced relapse after one to three prior lines of therapy that included a prosteasome inhibitor and immunomodulator. After stratification by the choice of PVd or DPd, Multiple Myeloma International Staging System, and number of prior lines of therapy, patients were randomly assigned to receive either cilta-cel or one of the two standard-of-care regimens previously described.

Patients assigned to cilta-cel received one or more cycles of either PVd or DPd as bridging therapy during the period from apheresis to infusion of the CAR T cells.

As already noted, cilta-cel showed superior PFS and response rates and was associated with a significantly higher rate of minimal residual disease (MRD) negativity, compared with standard of care, in the intention-to-treat population: 60.6% vs. 15.6%, which translates into an odds ratio for achieving MRD negativity with CAR T of 8.7 (P < .0001). Among the subset of patients evaluable for MRD, the respective rates were 87.5% and 32.7%.

Overall survival data were not mature at the time of presentation. In all, 39 patients in the cilta-cel arm and 47 in the standard-of-care arm died during the study.

Grade 3 or 4 adverse events occurred in 97% of patients who received cilta-cel and in 94% of those who received standard-of-care therapies. In the cilta-cel arm, 76.1% of patients had cytokine release syndrome (CRS), although only 1.1% of cases were of grade 3 or 4 in severity, and there were no CRS-associated deaths. Eight patients in this arm had immune effector cell–associated neurotoxicity syndrome, all of grade 1 or 2. One patient had grade 1 movement and neurocognitive symptoms, 16 had grade 2 or 3 cranial nerve palsy, and 5 patients had CAR T–related peripheral neuropathy of grade 1, 2, or 3.

The investigators plan to follow patients to determine the long-term effects of ciltacabtagene autoleucel and are currently performing analyses of health-related quality of life, subgroups, and biomarkers.

The study was funded by Janssen and Legend Biotech, which market ciltacabtagene autoleucel. Dr. Dhakal disclosed consulting, speaker’s bureau participation, and institutional research funding from Janssen and others. Several coauthors are employees of the study funders. Dr. Chanan-Khan’s relevant financial information was not available. Dr. Odejide reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – Lenalidomide (Revlimid) is a vital component of early therapy and maintenance for patients with multiple myeloma, but patients in first relapse who have disease that is refractory to lenalidomide have few good options for subsequent lines of therapy and a generally poor prognosis.

New results show that such patients benefit from treatment with the chimeric antigen receptor T-cell (CAR T) construct ciltacabtagene autoleucel (cilta-cel) (Carvykti).

The finding comes from the phase 3 CARTITUDE-4 trial, which was reported at the annual meeting of the American Society of Clinical Oncology (ASCO) and was simultaneously published online in the New England Journal of Medicine.

Patients with lenalidomide-refractory multiple myeloma who received a single infusion of ciltacabtagene autoleucel demonstrated a 74% reduction in the risk for disease progression or death, compared with patients who received the standard of care.

The hazard ratio for death or progression with cilta-cel was 0.26 (P < .001), which “is the best hazard ratio ever reported in this patient population in a randomized clinical setting,” said principal investigator Binod Dhakal, MD, from the Medical College of Wisconsin, Milwaukee.

Dr. Dhakal reported data from the first analysis of the trial. At a median follow-up of 15.9 months, median progression-free survival (PFS), the primary endpoint, had not been reached among 208 patients who received cilta-cel; PFS was 11.8 months for the 211 patients assigned to receive standard of care, which consisted of the physician’s choice of either pomalidomide, bortezomib, and dexamethasone (PVd), or daratumumab, pomalidomide, and dexamethasone (DPd).

Twelve-month PFS rates were 75.9% and 48.6%, respectively, and both the overall response rate (ORR) and the complete response (CR) rate were higher with the CAR T construct than with the standard of care (ORR, 84.6% vs. 67.3%; CR rates, 73.1% and 21.8%, respectively).

“My perspective on Dr. Dakhal and colleague’s data is that myeloma treatment should be revisited in the light of this,” commented invited discussant Asher Chanan-Khan, MD, from the Mayo Clinic Cancer Center in Jacksonville, Fla.

“Early CAR Ts demonstrating efficacy and safety and prior lines of treatment impact survival from CAR T in myeloma. In lymphoma, CAR T is almost replacing, if not already, autotransplant. Can this also be true for multiple myeloma?” he asked.

Dr. Chanan-Khan noted that there are at least four ongoing trials with CAR T targeting either the B-cell maturation antigen (BCMA) alone or in combination with an anti-CD19 CAR T, immune checkpoint inhibitors, or with bortezomib, lenalidomide, and dexamethasone.

Also commenting on the new results, ASCO Expert Oreofe Odejide, MD, of the Dana-Farber Cancer Institute in Boston, said in a statement: “Lenalidomide has become a foundation of care for people with myeloma, but as its use has expanded, so has the number of patients whose disease will no longer respond to the treatment. Ciltacabtagene autoleucel has not only shown that it delivers remarkably effective outcomes, compared with patients’ current options, but also that it can be used safely earlier in the treatment phase.”
 

Already approved for refractory myeloma

Cilta-cel is a second-generation CAR T that contains two single-domain antibodies that target BCMA. This target was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

The product is already approved for use in myeloma; it was approved in March 2022 by the U.S. Food and Drug Administration for use in patients with refractory/relapsed multiple myeloma who have already tried four or more therapies. That approval was based on results from phase 1b/2 CARTITUDE-1 trial, which, as previously reported by this news organization, showed that early and deep responses with cilta-cel proved to be durable.

Final results of CARTITUDE-1, reported in a scientific poster at ASCO 2023, showed that almost half of patients (47.5%) who were treated with cilta-cel were free of disease progression at 3 years, and 59.8% had sustained, complete responses. In addition, the median PFS was longer than for any previously reported therapy for heavily pretreated patients with relapsed/refractory multiple myeloma, the authors said.
 

CARTITUDE-4 details

For the CARTITUDE-4 trial, the investigators enrolled patients aged 18 years or older with lenalidomide-refractory multiple myeloma who had experienced relapse after one to three prior lines of therapy that included a prosteasome inhibitor and immunomodulator. After stratification by the choice of PVd or DPd, Multiple Myeloma International Staging System, and number of prior lines of therapy, patients were randomly assigned to receive either cilta-cel or one of the two standard-of-care regimens previously described.

Patients assigned to cilta-cel received one or more cycles of either PVd or DPd as bridging therapy during the period from apheresis to infusion of the CAR T cells.

As already noted, cilta-cel showed superior PFS and response rates and was associated with a significantly higher rate of minimal residual disease (MRD) negativity, compared with standard of care, in the intention-to-treat population: 60.6% vs. 15.6%, which translates into an odds ratio for achieving MRD negativity with CAR T of 8.7 (P < .0001). Among the subset of patients evaluable for MRD, the respective rates were 87.5% and 32.7%.

Overall survival data were not mature at the time of presentation. In all, 39 patients in the cilta-cel arm and 47 in the standard-of-care arm died during the study.

Grade 3 or 4 adverse events occurred in 97% of patients who received cilta-cel and in 94% of those who received standard-of-care therapies. In the cilta-cel arm, 76.1% of patients had cytokine release syndrome (CRS), although only 1.1% of cases were of grade 3 or 4 in severity, and there were no CRS-associated deaths. Eight patients in this arm had immune effector cell–associated neurotoxicity syndrome, all of grade 1 or 2. One patient had grade 1 movement and neurocognitive symptoms, 16 had grade 2 or 3 cranial nerve palsy, and 5 patients had CAR T–related peripheral neuropathy of grade 1, 2, or 3.

The investigators plan to follow patients to determine the long-term effects of ciltacabtagene autoleucel and are currently performing analyses of health-related quality of life, subgroups, and biomarkers.

The study was funded by Janssen and Legend Biotech, which market ciltacabtagene autoleucel. Dr. Dhakal disclosed consulting, speaker’s bureau participation, and institutional research funding from Janssen and others. Several coauthors are employees of the study funders. Dr. Chanan-Khan’s relevant financial information was not available. Dr. Odejide reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

CHICAGO – In the phase 3 MIRASOL study, the antibody-drug conjugate (ADC) mirvetuximab soravtansine-gynx (MIRV, Elahere, ImmunoGen) produced an overall survival benefit in women with platinum-resistant ovarian cancer.

The conclusion of this study marks the first time that a novel therapy has demonstrated an overall survival (OS) improvement in any phase 3 trial in this population, according to lead investigator Kathleen Moore, MD.

“We believe these data are practice changing and position mirvetuximab [soravtansine] as the new standard of care for patients with folate receptor–alpha positive, platinum-resistant ovarian cancer,” said Dr. Moore during a presentation of the study at a special session of the annual meeting of the American Society of Clinical Oncology devoted solely to the MIRASOL study.
 

New standard of care

Following Dr. Moore’s presentation, Roisin Eilish O’Cearbhaill, MD, served as a discussant, and she confirmed the trial’s importance.

“It has firmly established the role of mirvetuximab [soravtansine] in folate receptor–alpha high-expression, platinum-resistant ovarian cancer,” said Dr. O’Cearbhaill, who is Research director of the gynecologic medical oncology service and clinical director of the solid tumor, cellular therapy service at Memorial Sloan Kettering Cancer Center, New York.

Mirvetuximab soravtansine received accelerated FDA approval in November based on the results of the single-arm SORAYA trial, which demonstrated a progression-free survival (PFS) benefit in platinum-resistant patients who had been previously treated with one to three treatment regimens, at least one of which having included bevacizumab.

The new study compared MIRV with physician choice chemotherapy and found both a PFS and OS benefit in the MIRV arm. The results garnered significant enthusiasm from the audience, and others reacted positively as well.

“The results that she presented are just astounding, with a significant improvement in both progression-free and overall survival. I think certainly the overall survival needs to be highlighted here, because this is a patient population that’s notoriously difficult to treat,” said Ana Valente, MD, a gynecologic oncologist at the Ochsner Health System in New Orleans. Dr. Valente, who did not attend the presentation but was asked to comment on the study, is also a member of the Society of Gynecological Oncologist communications committee.

Unlike SORAYA, MIRASOL was open to patients who had not received bevacizumab, and Dr. Moore and colleagues found similar survival benefits in patients who had not received bevacizumab as in those who had, said Dr. Moore, who is the associate director of clinical research at Stephenson Cancer Center and director of the Oklahoma TSET Phase 1 Program, both in Oklahoma City. This opens the possibility of using MIRV instead of bevacizumab combined with chemotherapy in platinum-resistant patients.

“I think this data really shows you can move right to mirvetuximab [soravtansine] and feel pretty solid about the decision in a biomarker selected [population],” Dr. Moore said, during an interview.
 

Not just for high expression levels

MIRASOL was restricted to patients with high levels of expression of folate receptor–alpha, which is MIRV’s target on the surface of tumor cells. High expression is defined as at least 75% of viable tumor cells exhibiting a minimum of 2+ level membrane staining intensity by immunohistochemistry. That represents about 35% of patients, according to Dr. Moore, but she said that the drug also shows promise in patients with medium levels of folate receptor–alpha expression.

“I think it’s just going to be now starting to get those label extension studies launched to branch it out. Then you account for 60% of your population which [have] medium to high [expression levels], and that’s really where you see benefit,” said Dr. Moore. Medium expression levels of folate receptor–alpha are defined as 50% to greater than 75% of tumor cells with 2+ level membrane staining intensity.

She also noted that the FORWARD II trial combining mirvetuximab soravtansine with bevacizumab in platinum-resistant ovarian cancer is showing good results.

“We have really beautiful data [from FORWARD II]. If I have a medium expresser, I’m using the doublet [of MIRV and bevacizumab], and it works,” said Dr. Moore, while also pointing out that this remains an off-label use.

It’s possible that the drug could be extended even to low expression levels, defined as 25% to less than 50% of tumor cells with 2+ level membrane staining intensity. “[We are] currently working on that strategy with already available data,” said Dr. Moore.

She speculated that the improved OS may be attributed to the reduced toxicity of MIRV, compared with chemotherapy agents, which leaves patients feeling better and more able to pursue other treatments, which in turn may increase survival odds.

Dr. O’Cearbhaill touted the benefits of ADCs and their ability to target powerful cytotoxic agents while limiting side effects, and she is looking forward to more new therapies on the horizon.

“There are four [ADCs] in late stages of development [for platinum-resistant ovarian cancer], so hopefully there will be other ones coming online as well,” Dr. O’Cearbhaill said in an interview. “Then we’ll have to figure out how to sequence them, which drug will be best in class. Will we be just giving one or will be giving ADC followed by ADC?”
 

Study methods and results

The study enrolled 453 patients and randomized them to treatment with MIRV or investigator’s choice of chemotherapy, which could be paclitaxel, pegylated liposomal doxorubicin, or topotecan. The MIRV dose was 6 mg/kg adjusted ideal body weight every 3 weeks. The median age was 62 in the chemotherapy arm and 63 years in the MIRV arm. About 63% of the chemotherapy arm had prior bevacizumab exposure, as did 61% of the MIRV arm.

Median PFS was 5.62 months in the MIRV arm and 3.98 months in the chemotherapy arm (hazard ratio, 0.65; P less than .0001). The overall response rate was 42% in the MIRV arm and 16% in the chemotherapy arm (P < .0001).

The safety outcomes also favored MIRV: 42% experienced grade 3 or higher treatment-emergent adverse events (TEAEs) versus 54% in the chemotherapy group. Severe adverse events were also lower in MIRV, 24% versus 33%. Just 9% of patients in the MIRV discontinued because of TEAEs, compared with 16% in the chemotherapy arm.

MIRV was associated with blurred vision (41%), keratopathy (32%), and dry eye (28%), but these issues were generally manageable through collaboration with optometrists or ophthalmologists.

Dr. Moore and Dr. O’Cearbhaill reported receiving honoraria, research funding, and travel expenses from numerous pharmaceutical companies. Dr. O’Cearbhaill has consulted for or advised Aptitude Health, Bayer, Carina Biotech, Fresenius Kabi, GlaxoSmithKline, GOG Foundation, Immunogen, R-Pharm, Regeneron, and Seagen.

A new standard of care for patients with chemotherapy-naive persistent, recurrent, or metastatic cervical cancer is first-line therapy with the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) with platinum-based chemotherapy and paclitaxel – with or without bevacizumab.

This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).

“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.

He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.

“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.

At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.

“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”

Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.

“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
 

Promising start

Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.

Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.

In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.

Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
 

Latest results

Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.

In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).

In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).

Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).

Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.

The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
 

Regimen details

Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.

The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.

Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).

KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.

A version of this article first appeared on Medscape.com.

A new standard of care for patients with chemotherapy-naive persistent, recurrent, or metastatic cervical cancer is first-line therapy with the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) with platinum-based chemotherapy and paclitaxel – with or without bevacizumab.

This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).

“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.

He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.

“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.

At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.

“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”

Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.

“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
 

Promising start

Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.

Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.

In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.

Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
 

Latest results

Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.

In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).

In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).

Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).

Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.

The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
 

Regimen details

Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.

The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.

Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).

KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.

A version of this article first appeared on Medscape.com.

A new standard of care for patients with chemotherapy-naive persistent, recurrent, or metastatic cervical cancer is first-line therapy with the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) with platinum-based chemotherapy and paclitaxel – with or without bevacizumab.

This is based on final overall survival results from the phase 3, randomized KEYNOTE-826 study, which showed that adding immunotherapy resulted in a 40% reduction in risk of death, compared with chemotherapy alone, for women with advanced cervical cancers expressing programmed death–ligand 1 (PD-L1).

“At this protocol-specified final analysis of KEYNOTE-826, the addition of immune therapy to chemotherapy with or without the antiangiogenic bevacizumab showed substantial and clinically meaningful improvement in survival,” said lead author Bradley J. Monk, MD, from HonorHealth Research Institute, Phoenix.

He was speaking at a media briefing held prior to the annual meeting of the American Society of Clinical Oncology, where the results were presented.

“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the frontline standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” commented ASCO expert Merry Jennifer Markham, MD, from the University of Florida, Gainesville.

At the briefing, Dr. Monk raised the possibility that adding immunotherapy to the standard of care could offer a chance for cure for some patients with advanced or recurrent cervical cancer.

“Is it possible to cure a widely metastatic cancer, a solid tumor? And I think it probably is,” he said. “There’s a tail to this [survival] curve, and I can’t believe that in my lifetime we as a group, as a team, have sort of figured out – and it’s not enough – that we can actually cure some patients, and if not maybe cure, have them at least live a long time, so it’s exciting.”

Briefing comoderater Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, agreed that the survival benefit “is exciting to see, and in my long career as a breast medical oncologist, I’m pretty sure we cure some metastatic breast cancer. We definitely had patients who lived out their normal life span and died of something else after decades.

“But the definition of cure, sadly, in these situations is that you die of something else without evidence of disease, so we certainly need to do better here and be better able to use the word ‘cure’ in the metastatic setting,” she added.
 

Promising start

Since 2014, the standard of care for treating patients with recurrent, persistent, or metastatic cervical cancer has been chemotherapy with a platinum compound, paclitaxel, and bevacizumab, based on the results of the GOG 240 study.

Immunotherapy with PD-1 inhibitors had previously shown efficacy as monotherapy in second- or later-line therapy for women with cervical cancer, but KEYNOTE 826 was the first study to show a benefit to promoting immunotherapy to the front ranks.

In the first interim analysis of the trial, reported at the 2021 annual meeting of the European Society for Medical Oncology, after a median follow-up of 22 months, the combination of pembrolizumab and chemotherapy demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy plus placebo in a biomarker-selected population, which consisted of patients with a combined positive score (CPS) for PD-L1 of 1 or greater.

Pembrolizumab had no apparent efficacy in patients whose tumors did not have detectable PD-L1, however.
 

Latest results

Now the investigators are reporting the final analysis, conducted after a median follow-up of 39.1 months. The results are those for all comers (308 randomly assigned to receive pembrolizumab plus chemotherapy, and 309 assigned to receive chemotherapy plus placebo), as well as for the biomarker-selected population (consisting of all patients with PD-L1 CPS of 1 or greater) and for the subpopulation of patients with PD-L1 CPS of 10 or greater.

In the all-comers population, the median OS was 26.4 months for patients who received pembrolizumab, compared with 16.8 months for those who received placebo. The 24-month OS rates were 52.1% and 38.7%, respectively. The difference translated into a hazard ratio for death with pembrolizumab of 0.63 (P < .0001).

In the biomarker-selected population (273 assigned to pembrolizumab and 275 assigned to placebo), the respective median OS was 28.6 months versus 16.6 months, with 24-month OS rates of 53.5% versus 39.4%, which translates into an HR for death with pembrolizumab of 0.60 (P < .0001).

Not surprisingly, the best responses to the addition of the PD-1 inhibitor were seen among patients with a PD-L1 CPS of 10 or greater (158 assigned to pembrolizumab and 159 assigned to placebo). In this subgroup, the median OS was 29.6 months with the immune checkpoint inhibitor added to chemotherapy versus 17.4 months for chemotherapy plus placebo. The respective 24-month OS rates were 54.4% and 42.5%, and the HR for overall survival favoring pembrolizumab was 0.58 (P < .0001).

Median PFS 12-month PFS rates also favored pembrolizumab in both the total patient population and the biomarker-selected groups, with median PFS of approximately 10.4 months with pembrolizumab versus approximately 8.2 months with placebo.

The safety profile was manageable, with adverse events as expected from the safety profiles of the individual drugs in the combined regimen. No new safety signals have been seen since the interim analysis, Dr. Monk said.
 

Regimen details

Patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with bevacizumab added at the investigator’s discretion. Approximately two-thirds of patients in each study arm received bevacizumab.

The dual primary endpoints of PFS and OS were each tested sequentially in patients with a PD-L1 CPS of 1 or greater in both the intention-to-treat or “all-comers” population and in patients with a PD-L1 CPS of 10 or greater.

Patient characteristics were generally well balanced between the treatment groups, except that a slightly higher proportion of patients in the pembrolizumab had tumors of squamous cell histology, compared with the placebo group (76.3% vs. 68.3%).

KEYNOTE-826 was funded by Merck. Dr. Monk has received honoraria and has participated in consulting/advising and speaker’s bureau activity with Merck and other companies. Dr. Gralow has had a consulting or advisory role with Genentech and Roche. Dr. Markham has had a consulting/advisory role for GlaxoSmithKline and has received institutional research funding from Merck and other companies.

A version of this article first appeared on Medscape.com.