Cancer

Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations. 

In this issue:

• Vaccinations
• Mental Health and Related Disorders
• LGBTQ+ Veterans
• Military Sexual Trauma
• Sleep Disorders
• Respiratory Illnesses
• HIV Care in the VA
• Rheumatologic Diseases
• The Cancer-Obesity Connection
• Skin Health for Active-Duty Personnel
• Contraception
• Chronic Kidney Disease
• Cardiovascular Diseases
• Neurologic Disorders
• Hearing, Vision, and Balance

Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue: 

Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN

Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations. 

In this issue:

• Vaccinations
• Mental Health and Related Disorders
• LGBTQ+ Veterans
• Military Sexual Trauma
• Sleep Disorders
• Respiratory Illnesses
• HIV Care in the VA
• Rheumatologic Diseases
• The Cancer-Obesity Connection
• Skin Health for Active-Duty Personnel
• Contraception
• Chronic Kidney Disease
• Cardiovascular Diseases
• Neurologic Disorders
• Hearing, Vision, and Balance

Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue: 

Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN

Federal Health Care Data Trends (click to view the digital edition) is a special supplement to Federal Practitioner highlighting the latest research and study outcomes related to the health of veteran and active-duty populations. 

In this issue:

• Vaccinations
• Mental Health and Related Disorders
• LGBTQ+ Veterans
• Military Sexual Trauma
• Sleep Disorders
• Respiratory Illnesses
• HIV Care in the VA
• Rheumatologic Diseases
• The Cancer-Obesity Connection
• Skin Health for Active-Duty Personnel
• Contraception
• Chronic Kidney Disease
• Cardiovascular Diseases
• Neurologic Disorders
• Hearing, Vision, and Balance

Federal Practitioner would like to thank the following experts for their review of content and helpful guidance in developing this issue: 

Kelvin N.V. Bush, MD, FACC, CCDS; Sonya Borrero, MD, MS; Kenneth L. Cameron, PhD, MPH, ATC, FNATA; Jason DeViva, PhD; Ellen Lockard Edens, MD; Leonard E. Egede, MD, MS; Amy Justice, MD, PhD; Stephanie Knudson, MD; Willis H. Lyford, MD; Sarah O. Meadows, PhD; Tamara Schult, PhD, MPH; Eric L. Singman, MD, PhD; Art Wallace, MD, PhD; Elizabeth Waterhouse, MD, FAAN

About one in four patients with non–small cell lung cancer (NSCLC) have an unsatisfactory antibody response to the Omicron variant following COVID-19 vaccination, according to a new study.

The study was published in the Journal of Clinical Oncology.

“Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant,” wrote the authors, who were led by Rafi Ahmed, PhD, Emory University, Atlanta.

Researchers found that 18% had no detectable antibody at all and active treatment type had no association with vaccine response.

Researchers examined antibody titers among 82 NSCLC patients and 53 healthy volunteers. They collected blood samples longitudinally for analysis. While most patients had binding and neutralizing antibody titers that were comparable with healthy volunteers, 25% had poor responses, which led to six- to sevenfold lower titers than healthy controls. There was no association between worse vaccine responses and history of programmed death–1 monotherapy, chemotherapy, or both in combination. Receipt of a booster vaccine improved binding and neutralizing antibody titers to both the wild type and the Omicron variant, but 2-4 months after the booster there was a five- to sevenfold decrease in neutralizing titers to both the wild type and Omicron variant.

“This study indicates both the need to monitor our patients with lung cancer for response to COVID-19 mRNA vaccines, identify the nonresponders for follow-up and further attempts at immunization, and continue collecting and analyzing clinicodemographic information and biospecimens from our patients,” wrote the authors of an accompanying editorial.

Although the findings reveal potential concerns, the good news is that most patients NSCLC patients do respond normally to COVID-19 vaccination, said John D. Minna, MD, University of Texas Southwestern Medical Center, Dallas, lead author of the editorial.

He offered some advice to physicians. “You can test your patients using currently available [Clinical Laboratory Improvement Amendments]–approved lab tests to determine what their antibody titers are. This should be done after boosting since titers will go down after time. We know that if a patient has lung cancer and they do get infected with SARS-CoV-2 that potentially they could develop serious COVID-19 disease. Besides giving antiviral treatment, it is important that they be closely monitored for symptoms of progression so if they need to be hospitalized it can be done in a prudent manner,” said Dr. Minna, who is director of the Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern Medical Center.

No clinical details have emerged that might predict which patients have an insufficient response to vaccination. “When we started these studies, a lot of us thought that anyone who did not develop a good antibody response would be weak or sicker. For example, [patients with] late-stage disease, or having had a lot of therapy, or perhaps immune checkpoint blockade. However, none of these things are correlated. The main advice we are giving our lung cancer patients are to get vaccinated, get boosted (double boosted), and just do the smart thing to protect yourself from exposure,” he said.

For example, when traveling on a plane, patients should wear a mask. They should also avoid large indoor events. He also recommended that, following vaccination and boosters, patients seek out CLIA-certified tests to get their titer checked.

“Upon any COVID infection, even if their titer is at or above 80%, patients should see their physician to consider treatment with Paxlovid (nirmatrelvir/ritonavir), which has emergency use authorization. For patients with a lower titer, it’s important to seek out a physician and consider Paxlovid and possibly antibody therapy. But these are individual decisions to be made with your doctor,” Dr. Minna said.

The next important research question is what happens to T-cell immune response following vaccination. “We know that a good cellular immune response is also important in preventing infection and severe infection, but we don’t yet know which persons (with or without cancer) have good T-cell responses. This information will also likely impact what we tell our patients and will add to the antibody data,” he said.

Studies are ongoing to determine specific T-cell responses to mRNA vaccines, and how well those T-cell responses respond to SARS-CoV-2 infection in the laboratory.

About one in four patients with non–small cell lung cancer (NSCLC) have an unsatisfactory antibody response to the Omicron variant following COVID-19 vaccination, according to a new study.

The study was published in the Journal of Clinical Oncology.

“Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant,” wrote the authors, who were led by Rafi Ahmed, PhD, Emory University, Atlanta.

Researchers found that 18% had no detectable antibody at all and active treatment type had no association with vaccine response.

Researchers examined antibody titers among 82 NSCLC patients and 53 healthy volunteers. They collected blood samples longitudinally for analysis. While most patients had binding and neutralizing antibody titers that were comparable with healthy volunteers, 25% had poor responses, which led to six- to sevenfold lower titers than healthy controls. There was no association between worse vaccine responses and history of programmed death–1 monotherapy, chemotherapy, or both in combination. Receipt of a booster vaccine improved binding and neutralizing antibody titers to both the wild type and the Omicron variant, but 2-4 months after the booster there was a five- to sevenfold decrease in neutralizing titers to both the wild type and Omicron variant.

“This study indicates both the need to monitor our patients with lung cancer for response to COVID-19 mRNA vaccines, identify the nonresponders for follow-up and further attempts at immunization, and continue collecting and analyzing clinicodemographic information and biospecimens from our patients,” wrote the authors of an accompanying editorial.

Although the findings reveal potential concerns, the good news is that most patients NSCLC patients do respond normally to COVID-19 vaccination, said John D. Minna, MD, University of Texas Southwestern Medical Center, Dallas, lead author of the editorial.

He offered some advice to physicians. “You can test your patients using currently available [Clinical Laboratory Improvement Amendments]–approved lab tests to determine what their antibody titers are. This should be done after boosting since titers will go down after time. We know that if a patient has lung cancer and they do get infected with SARS-CoV-2 that potentially they could develop serious COVID-19 disease. Besides giving antiviral treatment, it is important that they be closely monitored for symptoms of progression so if they need to be hospitalized it can be done in a prudent manner,” said Dr. Minna, who is director of the Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern Medical Center.

No clinical details have emerged that might predict which patients have an insufficient response to vaccination. “When we started these studies, a lot of us thought that anyone who did not develop a good antibody response would be weak or sicker. For example, [patients with] late-stage disease, or having had a lot of therapy, or perhaps immune checkpoint blockade. However, none of these things are correlated. The main advice we are giving our lung cancer patients are to get vaccinated, get boosted (double boosted), and just do the smart thing to protect yourself from exposure,” he said.

For example, when traveling on a plane, patients should wear a mask. They should also avoid large indoor events. He also recommended that, following vaccination and boosters, patients seek out CLIA-certified tests to get their titer checked.

“Upon any COVID infection, even if their titer is at or above 80%, patients should see their physician to consider treatment with Paxlovid (nirmatrelvir/ritonavir), which has emergency use authorization. For patients with a lower titer, it’s important to seek out a physician and consider Paxlovid and possibly antibody therapy. But these are individual decisions to be made with your doctor,” Dr. Minna said.

The next important research question is what happens to T-cell immune response following vaccination. “We know that a good cellular immune response is also important in preventing infection and severe infection, but we don’t yet know which persons (with or without cancer) have good T-cell responses. This information will also likely impact what we tell our patients and will add to the antibody data,” he said.

Studies are ongoing to determine specific T-cell responses to mRNA vaccines, and how well those T-cell responses respond to SARS-CoV-2 infection in the laboratory.

About one in four patients with non–small cell lung cancer (NSCLC) have an unsatisfactory antibody response to the Omicron variant following COVID-19 vaccination, according to a new study.

The study was published in the Journal of Clinical Oncology.

“Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant,” wrote the authors, who were led by Rafi Ahmed, PhD, Emory University, Atlanta.

Researchers found that 18% had no detectable antibody at all and active treatment type had no association with vaccine response.

Researchers examined antibody titers among 82 NSCLC patients and 53 healthy volunteers. They collected blood samples longitudinally for analysis. While most patients had binding and neutralizing antibody titers that were comparable with healthy volunteers, 25% had poor responses, which led to six- to sevenfold lower titers than healthy controls. There was no association between worse vaccine responses and history of programmed death–1 monotherapy, chemotherapy, or both in combination. Receipt of a booster vaccine improved binding and neutralizing antibody titers to both the wild type and the Omicron variant, but 2-4 months after the booster there was a five- to sevenfold decrease in neutralizing titers to both the wild type and Omicron variant.

“This study indicates both the need to monitor our patients with lung cancer for response to COVID-19 mRNA vaccines, identify the nonresponders for follow-up and further attempts at immunization, and continue collecting and analyzing clinicodemographic information and biospecimens from our patients,” wrote the authors of an accompanying editorial.

Although the findings reveal potential concerns, the good news is that most patients NSCLC patients do respond normally to COVID-19 vaccination, said John D. Minna, MD, University of Texas Southwestern Medical Center, Dallas, lead author of the editorial.

He offered some advice to physicians. “You can test your patients using currently available [Clinical Laboratory Improvement Amendments]–approved lab tests to determine what their antibody titers are. This should be done after boosting since titers will go down after time. We know that if a patient has lung cancer and they do get infected with SARS-CoV-2 that potentially they could develop serious COVID-19 disease. Besides giving antiviral treatment, it is important that they be closely monitored for symptoms of progression so if they need to be hospitalized it can be done in a prudent manner,” said Dr. Minna, who is director of the Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern Medical Center.

No clinical details have emerged that might predict which patients have an insufficient response to vaccination. “When we started these studies, a lot of us thought that anyone who did not develop a good antibody response would be weak or sicker. For example, [patients with] late-stage disease, or having had a lot of therapy, or perhaps immune checkpoint blockade. However, none of these things are correlated. The main advice we are giving our lung cancer patients are to get vaccinated, get boosted (double boosted), and just do the smart thing to protect yourself from exposure,” he said.

For example, when traveling on a plane, patients should wear a mask. They should also avoid large indoor events. He also recommended that, following vaccination and boosters, patients seek out CLIA-certified tests to get their titer checked.

“Upon any COVID infection, even if their titer is at or above 80%, patients should see their physician to consider treatment with Paxlovid (nirmatrelvir/ritonavir), which has emergency use authorization. For patients with a lower titer, it’s important to seek out a physician and consider Paxlovid and possibly antibody therapy. But these are individual decisions to be made with your doctor,” Dr. Minna said.

The next important research question is what happens to T-cell immune response following vaccination. “We know that a good cellular immune response is also important in preventing infection and severe infection, but we don’t yet know which persons (with or without cancer) have good T-cell responses. This information will also likely impact what we tell our patients and will add to the antibody data,” he said.

Studies are ongoing to determine specific T-cell responses to mRNA vaccines, and how well those T-cell responses respond to SARS-CoV-2 infection in the laboratory.

High oral cavity doses of radiotherapy are associated with greater risk of taste dysfunction in patients with head and neck cancer, finds a new study from JAMA Otolaryngology–Head & Neck Surgery.

Taste dysfunction can affect up to 90% of patients undergoing radiotherapy for head and neck cancer. While the ability to taste usually returns after the treatment concludes, some patients can still feel the lingering effects of radiotherapy on taste function long after the treatment concludes. It can lead to weight loss and dry mouth which can, in turn, negatively affect quality of life.

“Taste dysfunction has profound effects on quality of life in patients with head and neck cancer, and the oral cavity dose could be significantly lower with modern radiotherapy techniques,” wrote the researchers, who were led by Miao-Fen Chen, MD, PhD, of Chang Gung University, Taoyuan City, Taiwan. “This study provides useful dose constraints of the oral cavity that may be associated with reduced taste dysfunction.”

Degradation of taste is an important quality of life factor for head and neck cancer patients. A 2021 systematic review published in the journal Radiotherapy and Oncology found that acute taste dysfunction affected 96% of patients as measured objectively, and 79% as measured subjectively. While most patients recover an estimated 23-53% of patients experience long-term dysfunction.

In 2019, a study published in the journal Chemical Senses found that 31% of head and neck cancer patients had long-term changes to taste at 27 months after intensity-modulated radiotherapy (IMRT), with dysfunction associated with glossectomy and oral cavity radiation doses greater than 50 Gy, but the study only used one quality of life subjective measure to evaluate taste function.

In the new JAMA study, researchers reported the results of a longitudinal using the whole-mouth solution method for basic tastes, including salt, sweet, sour, and bitter.
 

Study methodology

The study included 87 patients (mean age, 58 years; 90% men) who were enrolled between 2017 and 2020 from a single hospital. 45 patients received primary intensity-modulated radiotherapy and 42 received postoperative radiotherapy. 78 patients received volumetric arc therapy, and 9 received intensity-modulated radiotherapy. The radiotherapy was directed to minimize the effect on the parotid glands and oral cavity.

Researchers measured taste dysfunction according to detection thresholds based on solutions with different concentrations. After moving the solution around the mouth and spitting it out, patients were asked to identify taste components. Following a water rinse, they tested a solution with another concentration of taste components. A number was assigned based on the concentration level they were able to detect, with nigher numbers indicating greater sensitivity.

Two to four weeks after initiation of radiotherapy, there were drops in taste scores for salt (4.7 to 1.4), sweet (4.2 to 1.8), sour (4.5 to 2.3), and bitter (4.7 to 1.2). 1 week after radiotherapy, those mean scores increased to 2.6, 2.6, 2.9, and 2.3 respectively. Over the following 3 months, mean scores reflected general recovery to near preradiotherapy levels (4.2, 3.9, 4.1, and 4.0, respectively). At 6 months and 1 year, the scores were equivalent to preradiotherapy levels.

Objective taste tests were performed on 81 participants. 33.3% had taste dysfunction 6 months after radiotherapy. 6 months after, 8.9% had taste dysfunction. At 3 months following radiotherapy, taste dysfunction was associated with an oral cavity mean dose of 4,000 cGy or higher (relative risk, 2.87; 95% confidence interval, 1.21-6.81) or 5,000 cGy or higher (RR, 2.04; 95% CI, 1.12-3.72). At 6 months, taste dysfunction was predicted by glossectomy (RR, 5.63; 95% CI, 1.12-28.15) and oral cavity mean dose 5,000 cGy or greater (RR, 7.79; 95% CI, 0.93-64.92).

The researchers quantified the relationship between mean oral cavity dose and probability of developing taste dysfunction at 3 and 6 months. 3 months after radiotherapy, 25 Gy predicted a 15% chance, 38 Gy predicted a 25% chance, and 60 Gy predicted a 50% chance. At 6 months, the numbers were 57, 60, and 64 Gy.

The study was limited by being conducted at a single center and its small sample size, and it recruited patients varied significantly in treatment modality and disease subtype.

High oral cavity doses of radiotherapy are associated with greater risk of taste dysfunction in patients with head and neck cancer, finds a new study from JAMA Otolaryngology–Head & Neck Surgery.

Taste dysfunction can affect up to 90% of patients undergoing radiotherapy for head and neck cancer. While the ability to taste usually returns after the treatment concludes, some patients can still feel the lingering effects of radiotherapy on taste function long after the treatment concludes. It can lead to weight loss and dry mouth which can, in turn, negatively affect quality of life.

“Taste dysfunction has profound effects on quality of life in patients with head and neck cancer, and the oral cavity dose could be significantly lower with modern radiotherapy techniques,” wrote the researchers, who were led by Miao-Fen Chen, MD, PhD, of Chang Gung University, Taoyuan City, Taiwan. “This study provides useful dose constraints of the oral cavity that may be associated with reduced taste dysfunction.”

Degradation of taste is an important quality of life factor for head and neck cancer patients. A 2021 systematic review published in the journal Radiotherapy and Oncology found that acute taste dysfunction affected 96% of patients as measured objectively, and 79% as measured subjectively. While most patients recover an estimated 23-53% of patients experience long-term dysfunction.

In 2019, a study published in the journal Chemical Senses found that 31% of head and neck cancer patients had long-term changes to taste at 27 months after intensity-modulated radiotherapy (IMRT), with dysfunction associated with glossectomy and oral cavity radiation doses greater than 50 Gy, but the study only used one quality of life subjective measure to evaluate taste function.

In the new JAMA study, researchers reported the results of a longitudinal using the whole-mouth solution method for basic tastes, including salt, sweet, sour, and bitter.
 

Study methodology

The study included 87 patients (mean age, 58 years; 90% men) who were enrolled between 2017 and 2020 from a single hospital. 45 patients received primary intensity-modulated radiotherapy and 42 received postoperative radiotherapy. 78 patients received volumetric arc therapy, and 9 received intensity-modulated radiotherapy. The radiotherapy was directed to minimize the effect on the parotid glands and oral cavity.

Researchers measured taste dysfunction according to detection thresholds based on solutions with different concentrations. After moving the solution around the mouth and spitting it out, patients were asked to identify taste components. Following a water rinse, they tested a solution with another concentration of taste components. A number was assigned based on the concentration level they were able to detect, with nigher numbers indicating greater sensitivity.

Two to four weeks after initiation of radiotherapy, there were drops in taste scores for salt (4.7 to 1.4), sweet (4.2 to 1.8), sour (4.5 to 2.3), and bitter (4.7 to 1.2). 1 week after radiotherapy, those mean scores increased to 2.6, 2.6, 2.9, and 2.3 respectively. Over the following 3 months, mean scores reflected general recovery to near preradiotherapy levels (4.2, 3.9, 4.1, and 4.0, respectively). At 6 months and 1 year, the scores were equivalent to preradiotherapy levels.

Objective taste tests were performed on 81 participants. 33.3% had taste dysfunction 6 months after radiotherapy. 6 months after, 8.9% had taste dysfunction. At 3 months following radiotherapy, taste dysfunction was associated with an oral cavity mean dose of 4,000 cGy or higher (relative risk, 2.87; 95% confidence interval, 1.21-6.81) or 5,000 cGy or higher (RR, 2.04; 95% CI, 1.12-3.72). At 6 months, taste dysfunction was predicted by glossectomy (RR, 5.63; 95% CI, 1.12-28.15) and oral cavity mean dose 5,000 cGy or greater (RR, 7.79; 95% CI, 0.93-64.92).

The researchers quantified the relationship between mean oral cavity dose and probability of developing taste dysfunction at 3 and 6 months. 3 months after radiotherapy, 25 Gy predicted a 15% chance, 38 Gy predicted a 25% chance, and 60 Gy predicted a 50% chance. At 6 months, the numbers were 57, 60, and 64 Gy.

The study was limited by being conducted at a single center and its small sample size, and it recruited patients varied significantly in treatment modality and disease subtype.

High oral cavity doses of radiotherapy are associated with greater risk of taste dysfunction in patients with head and neck cancer, finds a new study from JAMA Otolaryngology–Head & Neck Surgery.

Taste dysfunction can affect up to 90% of patients undergoing radiotherapy for head and neck cancer. While the ability to taste usually returns after the treatment concludes, some patients can still feel the lingering effects of radiotherapy on taste function long after the treatment concludes. It can lead to weight loss and dry mouth which can, in turn, negatively affect quality of life.

“Taste dysfunction has profound effects on quality of life in patients with head and neck cancer, and the oral cavity dose could be significantly lower with modern radiotherapy techniques,” wrote the researchers, who were led by Miao-Fen Chen, MD, PhD, of Chang Gung University, Taoyuan City, Taiwan. “This study provides useful dose constraints of the oral cavity that may be associated with reduced taste dysfunction.”

Degradation of taste is an important quality of life factor for head and neck cancer patients. A 2021 systematic review published in the journal Radiotherapy and Oncology found that acute taste dysfunction affected 96% of patients as measured objectively, and 79% as measured subjectively. While most patients recover an estimated 23-53% of patients experience long-term dysfunction.

In 2019, a study published in the journal Chemical Senses found that 31% of head and neck cancer patients had long-term changes to taste at 27 months after intensity-modulated radiotherapy (IMRT), with dysfunction associated with glossectomy and oral cavity radiation doses greater than 50 Gy, but the study only used one quality of life subjective measure to evaluate taste function.

In the new JAMA study, researchers reported the results of a longitudinal using the whole-mouth solution method for basic tastes, including salt, sweet, sour, and bitter.
 

Study methodology

The study included 87 patients (mean age, 58 years; 90% men) who were enrolled between 2017 and 2020 from a single hospital. 45 patients received primary intensity-modulated radiotherapy and 42 received postoperative radiotherapy. 78 patients received volumetric arc therapy, and 9 received intensity-modulated radiotherapy. The radiotherapy was directed to minimize the effect on the parotid glands and oral cavity.

Researchers measured taste dysfunction according to detection thresholds based on solutions with different concentrations. After moving the solution around the mouth and spitting it out, patients were asked to identify taste components. Following a water rinse, they tested a solution with another concentration of taste components. A number was assigned based on the concentration level they were able to detect, with nigher numbers indicating greater sensitivity.

Two to four weeks after initiation of radiotherapy, there were drops in taste scores for salt (4.7 to 1.4), sweet (4.2 to 1.8), sour (4.5 to 2.3), and bitter (4.7 to 1.2). 1 week after radiotherapy, those mean scores increased to 2.6, 2.6, 2.9, and 2.3 respectively. Over the following 3 months, mean scores reflected general recovery to near preradiotherapy levels (4.2, 3.9, 4.1, and 4.0, respectively). At 6 months and 1 year, the scores were equivalent to preradiotherapy levels.

Objective taste tests were performed on 81 participants. 33.3% had taste dysfunction 6 months after radiotherapy. 6 months after, 8.9% had taste dysfunction. At 3 months following radiotherapy, taste dysfunction was associated with an oral cavity mean dose of 4,000 cGy or higher (relative risk, 2.87; 95% confidence interval, 1.21-6.81) or 5,000 cGy or higher (RR, 2.04; 95% CI, 1.12-3.72). At 6 months, taste dysfunction was predicted by glossectomy (RR, 5.63; 95% CI, 1.12-28.15) and oral cavity mean dose 5,000 cGy or greater (RR, 7.79; 95% CI, 0.93-64.92).

The researchers quantified the relationship between mean oral cavity dose and probability of developing taste dysfunction at 3 and 6 months. 3 months after radiotherapy, 25 Gy predicted a 15% chance, 38 Gy predicted a 25% chance, and 60 Gy predicted a 50% chance. At 6 months, the numbers were 57, 60, and 64 Gy.

The study was limited by being conducted at a single center and its small sample size, and it recruited patients varied significantly in treatment modality and disease subtype.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

CHICAGO – Pembrolizumab has shown promise as adjuvant therapy for stage IIB and IIC melanoma, shows the first interim analysis of the phase 3 KEYNOTE-716 study recently published in The Lancet.

The findings meet an unmet need as the recurrence risk in stage IIB and IIC melanoma is “underrecognized,” said author Georgina Long, MD, comedical director of the Melanoma Institute Australia, University of Sydney.

In fact, their risk of recurrence is similar to patients with stage IIIB disease, wrote David Killock, PhD, in a related commentary published in Nature Reviews.

The adjuvant treatment resulted in an 89% recurrence-free survival in patients who received pembrolizumab, compared with 83% of patients in the placebo group (hazard ratio, 0.65; P = .0066). These findings were used as the basis for Food and Drug Administration approval of pembrolizumab (Keytruda, Merck) for this patient population in December 2021.

Despite the positive findings, Dr. Killock called for more research on distant metastasis-free survival, overall survival, and quality of life data to “establish the true clinical benefit of adjuvant pembrolizumab.”

At the annual meeting of the American Society of Clinical Oncology, Dr. Long presented the third interim analysis which showed pembrolizumab reduced recurrence and distant metastases at 24 months, although the clinical benefit was relatively small at an approximately 8% improvement in recurrence-free survival and about a 6% improvement in distant metastasis-free survival. About 83% in the pembrolizumab group had treatment-related toxicities versus 64% in the placebo group. There were no deaths caused by treatment. About 90% of pembrolizumab-related endocrinopathies led to long-term hormone replacement.

In a discussion that followed the presentation at ASCO, Charlotte Eielson Ariyan, MD, PhD, said the results are bittersweet. Higher-risk stage IIC patients have a risk of recurrence of about 40%. “It’s high, but the absolute risk reduction is about 8%. This is a very personalized discussion with the patient and the physician in understanding their risk of toxicity is about 17% and higher than their absolute risk reduction with the treatment. For me, this is a bitter pill to swallow because you’re treating people longer and you’re not sure if you’re really helping them. Until we can further define who the highest-risk patients are, I think it’s hard to give it to everyone,” said Dr. Ariyan, who is a surgeon with Memorial Sloan Kettering Cancer Center, New York.

In addition to weighing short-term benefits and toxicity, there are longer-term concerns. Toxicity experienced from PD-1 inhibitors in the adjuvant setting could impact future treatment decisions. “We’re very lucky here in melanoma to know that systemic therapies are effective and we can cure people who recur. I would argue this is why we probably will never really see a difference in the survival benefit in this group because people who cross over will probably do well,” Dr. Ariyan said.

During the Q&A session, Vernon Sondek, MD, Moffitt Cancer Center, Tampa, encouraged physician colleagues to have an open mind about treatments. “Beware of dogma. We thought that adjuvant immunotherapy works much better in patients with ulcerated primary tumors. That’s a dogma in some parts of the world. Yet the T4a patients in KEYNOTE-716 dramatically outperformed the ulcerated T3b and T4b [patients]. We still don’t know what we don’t know.”
 

The study details

KEYNOTE-716 included 976 patients 12 years or older with newly diagnosed completely resected stage IIB or IIC melanoma with a negative sentinel lymph node. Patients were randomized to placebo or 200 mg pembrolizumab every 3 weeks, or 2 mg/kg in pediatric patients, over 17 cycles. Almost 40% of patients were age 65 or older. T3b and T4b were the most common melanoma subcategories at 41% and 35%, respectively.

The planned third interim analysis occurred after the occurrence of 146 distant metastases. After a median follow-up of 27.4 months, distant metastasis-free survival favored the pembrolizumab group (HR, 0.64; P = .0029). At 24 months, the pembrolizumab group had a higher distant metastasis-free survival at 88.1% versus 82.2% and a lower recurrence rate at 81.2% versus 72.8% (HR, 0.64; 95% confidence interval, 0.50-0.84).

At 24 months, only the T4a patients had a statistically significant reduction in distant metastases at 58% (HR, 0.42; 95% CI, 0.19-0.96), although there were numerical reductions in T3a (HR, 0.71; 95% CI, 0.41-1.22) and T4b (HR, 0.70; 95% CI, 0.44-1.33) patients. Of patients experiencing a distant metastasis, 73% of the placebo group had a first distant metastasis to the lung compared with 49% of the pembrolizumab group.

Dr. Long has held consulting or advisory roles for Merck Sharpe & Dohme, which funded this study.

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

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

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

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

Estrogen exposure helps protect against colorectal cancer (CRC), and in some instances, the protection is site specific, a new analysis finds.

In a 17-year study involving almost 5,000 women, researchers from Germany found that hormone replacement therapy, oral contraceptive use, pregnancy, breastfeeding, and menopause at age 50 or older were all significantly associated with reductions in CRC risk.

Interestingly, the reduced risk of CRC observed for pregnancy and breastfeeding only applied to proximal colon cancer, while the association with oral contraceptive use was confined to the distal colon and rectum.

The results were published online in JNCI Cancer Spectrum.

CRC is the second most common cause of cancer death. It is responsible for more than one million deaths globally, according to the latest figures from the Global Burden of Disease 2019 Cancer Collaboration.

And sex seems to make a difference. The Global Burden analysis, echoing previous data, found that CRC is less common among women and that fewer women die from the disease.

Little, however, is known about the mechanisms of estrogen signaling in CRC or the impact of reproductive factors on CRC, despite a large amount of literature linking CRC risk to exogenous estrogens, such as hormone replacement therapy and oral contraceptives.

In the current analysis, the team recruited 2,650 patients with CRC from 20 German cancer centers between 2003 and 2020. Researchers used standardized questionnaires to garner the women’s reproductive histories.

A matched control group of 2,175 participants who did not have a history of CRC was randomly selected from population registries. All analyses were adjusted for known CRC risk factors, such as age; body mass index; education level; family history; having previously undergone large-bowel endoscopy; diabetes; and smoking status.

The researchers found that each pregnancy was associated with a small but significant 9% reduction in CRC risk (odds ratio, 0.91), specifically in the proximal colon (OR, 0.86).

Overall, breastfeeding for a year or longer was associated with a significantly lower CRC risk, compared with never breastfeeding (OR, 0.74), but the results were only significant for the proximal colon (OR, 0.58).

Oral contraceptive use for 9 years or longer was associated with a lower CRC risk (OR, 0.75) but was only significant for the distal colon (OR, 0.63). Hormone replacement therapy was associated with a lower risk of CRC irrespective of tumor location (OR, 0.76). And using both was linked to a 42% CRC risk reduction (OR, 0.58).

Although age at menarche was not associated with CRC risk, menopause at age 50 or older was associated with a significant 17% lower risk of CRC.

In an email interview, lead author Tobias Niedermaier, PhD, expressed surprise at two of the findings. The first was the small association between pregnancies and CRC risk, “despite the strong increase in estrogen levels during pregnancy,” he said. He speculated that pregnancy-related increases in insulin levels may have “largely offset the protection effects of estrogen exposure during pregnancy.”

The second surprise was that the age at menarche did not have a bearing on CRC risk, which could be because “exposure to estrogen levels in younger ages [is] less relevant with respect to CRC risk, because CRC typically develops at comparably old age.”

John Marshall, MD, who was not involved in the research, commented that such studies “put a lot of pressure on people to perform in a certain way to modify their personal risk of something.” However, “we would not recommend people alter their life choices for reproduction for this,” said Dr. Marshall, chief of the Division of Hematology/Oncology at Georgetown University, Washington, D.C.

Dr. Niedermaier agreed that “while this knowledge will certainly not change a woman’s decision on family planning,” he noted that the findings “could influence current CRC screening strategies, for example, by risk-adapted screening intervals [and] start and stop ages of screening.”

Dr. Niedermaier and colleagues’ work was funded by the German Research Council, the German Federal Ministry of Education and Research, and the Interdisciplinary Research Program of the National Center for Tumor Diseases. Dr. Niedermaier has disclosed no relevant financial relationships. Dr. Marshall writes a column that appears regularly on Medscape: Marshall on Oncology. He has served as speaker or member of a speakers’ bureau for Genentech, Amgen, Bayer, Celgene Corporation, and Caris Life Sciences.

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

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Long thought to be untreatable, KRAS is one of the most difficult to treat oncogenic drivers responsible for approximately 25% of all tumors, including 68% of pancreatic tumors and 20% of all non–small cell lung cancers (NSCLC).

We now have a treatment – sotorasib – for patients with locally advanced or metastatic NSCLC that is driven by a KRAS mutation (G12C). And, now, there is a second treatment – adagrasib – under study, which, according to a presentation recently made at the annual meeting of the American Society of Clinical Oncology, looks promising.

Ras is a membrane-bound regulatory protein (G protein) belonging to the family of guanosine triphosphatases (GTPases). Ras functions as a guanosine diphosphate/triphosphate binary switch by cycling between the active GTP-bound and the inactive GDP-bound states in response to extracellular stimuli. The KRAS (G12C) mutation affects the active form of KRAS and results in abnormally high concentrations of GTP-bound KRAS leading to hyperactivation of downstream oncogenic pathways and uncontrolled cell growth, specifically of ERK and MEK signaling pathways.

At the ASCO annual meeting in June, Spira and colleagues reported the results of cohort A of the KRYSTAL-1 study evaluating adagrasib as second-line therapy patients with advanced solid tumors harboring a KRAS (G12C) mutation. Like sotorasib, adagrasib is a KRAS (G12C) inhibitor that irreversibly and selectively binds KRAS (G12C), locking it in its inactive state. In this study, patients had to have failed first-line chemotherapy and immunotherapy with 43% of lung cancer patients responding. The 12-month overall survival (OS) was 51%, median overall survival was 12.6 and median progression-free survival (PFS) was 6.5 months. Twenty-five patients with KRAS (G12C)–mutant NSCLC and active, untreated central nervous system metastases received adagrasib in a phase 1b cohort. The intracranial overall response rate was 31.6% and median intracranial PFS was 4.2 months. Systemic ORR was 35.0% (7/20), the disease control rate was 80.0% (16/20) and median duration of response was 9.6 months. Based on these data, a phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS (G12C) mutant NSCLC is ongoing.

The Food and Drug Administration approval of sotorasib in 2021 was, in part, based on the results of a single-arm, phase 2, second-line study of patients who had previously received platinum-based chemotherapy and/or immunotherapy. An ORR rate of 37.1% was reported with a median PFS of 6.8 months and median OS of 12.5 months leading to the FDA approval. Responses were observed across the range of baseline PD-L1 expression levels: 48% of PD-L1 negative, 39% with PD-L1 between 1%-49%, and 22% of patients with a PD-L1 of greater than 50% having a response.

The major toxicities observed in these studies were gastrointestinal (diarrhea, nausea, vomiting) and hepatic (elevated liver enzymes). About 97% of patients on adagrasib experienced any treatment-related adverse events, and 43% experienced a grade 3 or 4 treatment-related adverse event leading to dose reduction in 52% of patients, a dose interruption in 61% of patients, and a 7% discontinuation rate. About 70% of patients treated with sotorasib had a treatment-related adverse event of any grade, and 21% reported grade 3 or 4 treatment-related adverse events.

A subgroup in the KRYSTAL-1 trial reported an intracranial ORR of 32% in patients with active, untreated CNS metastases. Median overall survival has not yet reached concordance between systemic and intracranial disease control was 88%. In addition, preliminary data from two patients with untreated CNS metastases from a phase 1b cohort found cerebrospinal fluid concentrations of adagrasib with a mean ratio of unbound brain-to-plasma concentration of 0.47, which is comparable or exceeds values for known CNS-penetrant tyrosine kinase inhibitors.

Unfortunately, KRAS (G12C) is not the only KRAS mutation out there. There are a myriad of others, such as G12V and G12D. Hopefully, we will be seeing more drugs aimed at this set of important mutations. Another question, of course, is when and if these drugs will move to the first-line setting.

Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.

Racial differences in cancer outcomes are widespread. Studies indicate that Black people face higher rates of mortality for most cancers than their White counterparts. To bridge this racial gap, researchers need to investigate the biological effects of structural racism and discrimination on cancer outcomes, experts say.

“As a physician, I always like to think that I can influence care in that if I just find the right drugs, help patients understand what their options are, it will help them,” said Ruth Carlos, MD, a radiologist with the University of Michigan Hospital, Ann Arbor. But these things alone are often not enough, because a large proportion of the variation in cancer outcomes is attributable to neighborhood social conditions and the physical environment. “It is incredibly important for us to start to understand just how the neighborhood exerts this effect.”

In a commentary published in the Journal of Clinical Oncology, Dr. Carlos and colleagues highlighted the limitations of previous studies aimed at identifying the causes of racial differences in cancer outcomes. They call upon researchers to turn instead to the long-underexamined biological effects of structural racism and discrimination that contribute to these differences.

In the past, studies on the role of race in health outcomes largely looked at race as a proxy for genetic predisposition. But such an interpretation is flawed, because no genes are specific for a racial or ethnic group, Dr. Carlos and coauthors wrote. Researchers have shown that the vast majority of genetic variation occurs within, rather than between groups.

In an analysis published in Science, researchers reported that within-group differences account for more than 90% of genetic variation.

“Using race in these analyses was not necessarily wrong, but the inferences may have been flawed or incomplete,” Dr. Carlos said. On one hand, looking at genetic predisposition has led to important insights, such as the link between mutations in the BRCA gene and increased risk for breast and ovarian cancer.

However, genetic variation alone is not enough to explain the disparities in cancer outcomes between racial and ethnic groups. The fact that breast cancer can be more aggressive in Black women raises several questions, Dr. Carlos said. Is the cancer worse because Black women have a specific genetic predisposition? Is it worse because Black women exist in a society that marginalizes them and exposes them to increased stress, which in turn produces bad outcomes? Or, could it be both?

Despite progress in the screening, diagnosis and treatment of breast cancer, Black women are 40% more likely to die from the disease than White women. At the time of diagnosis, Black women are more likely to have high-grade, more aggressive breast cancer molecular subtypes, and to have had their cancer spread to the lymph nodes. They also tend to be diagnosed at more advanced stages of breast cancer while at the same time, experience higher rates of false-positive screening results.

Although researchers have hypothesized that genetic differences related to African or European ancestry might contribute, studies have not turned up any differences in cancer susceptibility genes by race. Other factors, such as racial differences in the stage of presentation, molecular subtypes, and disparities in treatment, have also emerged as potential culprits.

In her commentary, Dr. Carlos and colleagues wrote that disparities in breast cancer outcomes previously attributed to race need to be examined from multiple angles. This means looking at both the complex interactions between social conditions and policies, which encompass racism both at the individual and structural level, and stressors such as the experience of discrimination in addition to potential biological and genetic contributions.

Many studies now provide evidence for the harmful effects of racism on health. For breast cancer, specifically, studies also suggest that factors such as racial segregation can influence the stage at which Black women get diagnosed and their likelihood of dying from the disease.

However, an important question that remains is what biological changes occur in women exposed to the kind of persistent low-level stress that is associated with structural racism and discrimination, Dr. Carlos said. “We don’t know what stress pathways actually manifest in the body and how they eventually produce the disease.” Studies to address this issue are important, “especially if you would like to develop interventions to prevent or mitigate disease.”

To address this issue, Dr. Carlos and colleagues called upon the research community to conduct both studies that delineate the underlying biology as well as those that test potential interventions – particularly those associated with breast cancer screening outcomes – to try to shed light on why Black women receive more false positives and diagnoses of more aggressive cancer.

Interventions that can target these specific biological pathways could potentially reduce the negative effects of structural racism and discrimination as well as the effects of other social factors that contribute to breast cancer outcomes, “to ultimately help enhance clinical outcomes and close persistent disparities gaps,” the authors wrote.

Racial differences in cancer outcomes are widespread. Studies indicate that Black people face higher rates of mortality for most cancers than their White counterparts. To bridge this racial gap, researchers need to investigate the biological effects of structural racism and discrimination on cancer outcomes, experts say.

“As a physician, I always like to think that I can influence care in that if I just find the right drugs, help patients understand what their options are, it will help them,” said Ruth Carlos, MD, a radiologist with the University of Michigan Hospital, Ann Arbor. But these things alone are often not enough, because a large proportion of the variation in cancer outcomes is attributable to neighborhood social conditions and the physical environment. “It is incredibly important for us to start to understand just how the neighborhood exerts this effect.”

In a commentary published in the Journal of Clinical Oncology, Dr. Carlos and colleagues highlighted the limitations of previous studies aimed at identifying the causes of racial differences in cancer outcomes. They call upon researchers to turn instead to the long-underexamined biological effects of structural racism and discrimination that contribute to these differences.

In the past, studies on the role of race in health outcomes largely looked at race as a proxy for genetic predisposition. But such an interpretation is flawed, because no genes are specific for a racial or ethnic group, Dr. Carlos and coauthors wrote. Researchers have shown that the vast majority of genetic variation occurs within, rather than between groups.

In an analysis published in Science, researchers reported that within-group differences account for more than 90% of genetic variation.

“Using race in these analyses was not necessarily wrong, but the inferences may have been flawed or incomplete,” Dr. Carlos said. On one hand, looking at genetic predisposition has led to important insights, such as the link between mutations in the BRCA gene and increased risk for breast and ovarian cancer.

However, genetic variation alone is not enough to explain the disparities in cancer outcomes between racial and ethnic groups. The fact that breast cancer can be more aggressive in Black women raises several questions, Dr. Carlos said. Is the cancer worse because Black women have a specific genetic predisposition? Is it worse because Black women exist in a society that marginalizes them and exposes them to increased stress, which in turn produces bad outcomes? Or, could it be both?

Despite progress in the screening, diagnosis and treatment of breast cancer, Black women are 40% more likely to die from the disease than White women. At the time of diagnosis, Black women are more likely to have high-grade, more aggressive breast cancer molecular subtypes, and to have had their cancer spread to the lymph nodes. They also tend to be diagnosed at more advanced stages of breast cancer while at the same time, experience higher rates of false-positive screening results.

Although researchers have hypothesized that genetic differences related to African or European ancestry might contribute, studies have not turned up any differences in cancer susceptibility genes by race. Other factors, such as racial differences in the stage of presentation, molecular subtypes, and disparities in treatment, have also emerged as potential culprits.

In her commentary, Dr. Carlos and colleagues wrote that disparities in breast cancer outcomes previously attributed to race need to be examined from multiple angles. This means looking at both the complex interactions between social conditions and policies, which encompass racism both at the individual and structural level, and stressors such as the experience of discrimination in addition to potential biological and genetic contributions.

Many studies now provide evidence for the harmful effects of racism on health. For breast cancer, specifically, studies also suggest that factors such as racial segregation can influence the stage at which Black women get diagnosed and their likelihood of dying from the disease.

However, an important question that remains is what biological changes occur in women exposed to the kind of persistent low-level stress that is associated with structural racism and discrimination, Dr. Carlos said. “We don’t know what stress pathways actually manifest in the body and how they eventually produce the disease.” Studies to address this issue are important, “especially if you would like to develop interventions to prevent or mitigate disease.”

To address this issue, Dr. Carlos and colleagues called upon the research community to conduct both studies that delineate the underlying biology as well as those that test potential interventions – particularly those associated with breast cancer screening outcomes – to try to shed light on why Black women receive more false positives and diagnoses of more aggressive cancer.

Interventions that can target these specific biological pathways could potentially reduce the negative effects of structural racism and discrimination as well as the effects of other social factors that contribute to breast cancer outcomes, “to ultimately help enhance clinical outcomes and close persistent disparities gaps,” the authors wrote.

Racial differences in cancer outcomes are widespread. Studies indicate that Black people face higher rates of mortality for most cancers than their White counterparts. To bridge this racial gap, researchers need to investigate the biological effects of structural racism and discrimination on cancer outcomes, experts say.

“As a physician, I always like to think that I can influence care in that if I just find the right drugs, help patients understand what their options are, it will help them,” said Ruth Carlos, MD, a radiologist with the University of Michigan Hospital, Ann Arbor. But these things alone are often not enough, because a large proportion of the variation in cancer outcomes is attributable to neighborhood social conditions and the physical environment. “It is incredibly important for us to start to understand just how the neighborhood exerts this effect.”

In a commentary published in the Journal of Clinical Oncology, Dr. Carlos and colleagues highlighted the limitations of previous studies aimed at identifying the causes of racial differences in cancer outcomes. They call upon researchers to turn instead to the long-underexamined biological effects of structural racism and discrimination that contribute to these differences.

In the past, studies on the role of race in health outcomes largely looked at race as a proxy for genetic predisposition. But such an interpretation is flawed, because no genes are specific for a racial or ethnic group, Dr. Carlos and coauthors wrote. Researchers have shown that the vast majority of genetic variation occurs within, rather than between groups.

In an analysis published in Science, researchers reported that within-group differences account for more than 90% of genetic variation.

“Using race in these analyses was not necessarily wrong, but the inferences may have been flawed or incomplete,” Dr. Carlos said. On one hand, looking at genetic predisposition has led to important insights, such as the link between mutations in the BRCA gene and increased risk for breast and ovarian cancer.

However, genetic variation alone is not enough to explain the disparities in cancer outcomes between racial and ethnic groups. The fact that breast cancer can be more aggressive in Black women raises several questions, Dr. Carlos said. Is the cancer worse because Black women have a specific genetic predisposition? Is it worse because Black women exist in a society that marginalizes them and exposes them to increased stress, which in turn produces bad outcomes? Or, could it be both?

Despite progress in the screening, diagnosis and treatment of breast cancer, Black women are 40% more likely to die from the disease than White women. At the time of diagnosis, Black women are more likely to have high-grade, more aggressive breast cancer molecular subtypes, and to have had their cancer spread to the lymph nodes. They also tend to be diagnosed at more advanced stages of breast cancer while at the same time, experience higher rates of false-positive screening results.

Although researchers have hypothesized that genetic differences related to African or European ancestry might contribute, studies have not turned up any differences in cancer susceptibility genes by race. Other factors, such as racial differences in the stage of presentation, molecular subtypes, and disparities in treatment, have also emerged as potential culprits.

In her commentary, Dr. Carlos and colleagues wrote that disparities in breast cancer outcomes previously attributed to race need to be examined from multiple angles. This means looking at both the complex interactions between social conditions and policies, which encompass racism both at the individual and structural level, and stressors such as the experience of discrimination in addition to potential biological and genetic contributions.

Many studies now provide evidence for the harmful effects of racism on health. For breast cancer, specifically, studies also suggest that factors such as racial segregation can influence the stage at which Black women get diagnosed and their likelihood of dying from the disease.

However, an important question that remains is what biological changes occur in women exposed to the kind of persistent low-level stress that is associated with structural racism and discrimination, Dr. Carlos said. “We don’t know what stress pathways actually manifest in the body and how they eventually produce the disease.” Studies to address this issue are important, “especially if you would like to develop interventions to prevent or mitigate disease.”

To address this issue, Dr. Carlos and colleagues called upon the research community to conduct both studies that delineate the underlying biology as well as those that test potential interventions – particularly those associated with breast cancer screening outcomes – to try to shed light on why Black women receive more false positives and diagnoses of more aggressive cancer.

Interventions that can target these specific biological pathways could potentially reduce the negative effects of structural racism and discrimination as well as the effects of other social factors that contribute to breast cancer outcomes, “to ultimately help enhance clinical outcomes and close persistent disparities gaps,” the authors wrote.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.

Findings from a cohort study highlight a potential role of tumor grade for predicting mucosal head and neck squamous cell carcinoma response to immunotherapy, researchers report in JAMA Otolaryngology–Head & Neck Surgery.

The analysis, which was among patients with either high-grade or low-grade recurrent or metastatic mucosal head and neck squamous cell carcinoma (HNSCC) tumors, revealed that tumor grade was independently associated with immunotherapy response.

“Generally, one would expect high-grade tumors to do worse because they are more aggressive,” said Rajarsi Mandal, MD, the study’s lead author. “But it’s thought that high-grade tumors have higher degrees of chromosomal instability with a lot more mutations generated throughout the genome of these tumors ... and we know that higher mutation rates correlate with higher responses to immunotherapy.”

Researchers found that the proportion of patients having a beneficial response to immunotherapy was larger for patients with high grade tumors (12 of 35; 34.3%) than those with low grade tumors (2 of 25, 8.0%) (difference, 26.3%; 95% confidence interval, 7.3%-45.3%). The odds of having a clinically beneficial response to immunotherapy was increased 5.35-fold (95% CI, 1.04-27.37) in patients with high-grade tumors. Among four patients with low-grade tumors and eight patients with high-grade tumors with available tumor mutational burden data, the mean tumor mutational burden was greater for patients with high-grade tumors (mean [standard deviation], 8.6 [5.4] mut/Mb; n = 8) than for patients with low grade tumors (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference, 5.0 mut/Mb; 95% CI, −1.4 to 11.4 mut/Mb; Cohen d, 1.2).

“High tumor grade is not a guarantee but it possibly provides an easy biomarker and a good rationale to say that there’s a better chance the patient will respond to immune checkpoint inhibition,” said Dr. Mandal who is a head and neck cancer surgeon with the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.

Previous studies of HNSCC tumors that are refractory to traditional therapies, including surgery, chemotherapy, and radiation therapy, have demonstrated a clinically beneficial response to immune checkpoint inhibitors (ICIs). An association between increased tumor mutational burden and beneficial response to ICIs has been shown in other cancers.

Researchers hypothesized that tumor histological grade may be associated with responses to immune checkpoint blockade, and designed their study to examine the association between tumor grade and immunotherapy response in patients treated with ICIs for recurrent or metastatic mucosal HNSCC.

In a single-center retrospective cohort study, investigators reviewed the medical records of 60 adult patients (mean age, 64.6 years; 85% male) with a primary mucosal HNSCC tumor treated with an immune checkpoint inhibitor (pembrolizumab, nivolumab, ipilimumab, or durvalumab) treated between July 1, 2015, and Jan. 22, 2020. They stratified them into those with low grade tumors (well differentiated and moderately differentiated) and those with high grade tumors (poorly differentiated). A clinically beneficial immunotherapy response, defined as complete response or partial response was the primary outcome.

Thirty-eight patients in the study cohort were current or former smokers. The most common primary tumor sight was at the oropharynx. Outcomes among those with high-grade tumors were improved, compared with those with low-grade tumors, for median progression-free survival (5.9 months vs. 3.3 months), median overall survival (16.6 months vs. 15.0 months, and risk of death (hazard ratio, 0.94).

The study’s main limitation was its small sample size and small number of patients who had a clinically beneficial immunotherapy response.

Dr. Mandal had no conflicts of interest to disclose.