Immuno-oncology

Although the only pediatric indication for chimeric antigen receptor T-cell therapy currently approved by the Food and Drug Administration is B-lineage acute lymphoblastic leukemia (ALL) that is refractory to at least two frontline induction attempts or is in second or later relapse, clinical trials of CAR-T therapy for pediatric solid tumors are also currently in progress, said Gregory Yanik, MD, from the CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, at the Transplant & Cellular Therapies Meetings.

In his presentation, Dr. Yanik discussed progress in solid tumor studies as well as some issues involving the current use of CAR-T therapy for ALL.

Solid tumor studies

Malignancies such as sarcomas, brain tumors, and neuroblastomas pose unique challenges, “In contrast to hematologic malignancies, the protein we’re targeting may not be present on the cell surface of all the tumor cells. There are lower-expression profiles, and this is a problem. In fact, many people have postulated that with CAR-T for pediatric solid tumors we’ll have to do repeated cycles, almost like we do with chemotherapy,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

There are currently 14 studies of CAR-T for central nervous system tumors in children, targeting either epidermal growth factor receptor (EGFR) in glioblastoma multiforme and high-grade gliomas, HER2 in a variety of CNS tumors, the GD2 antigen on pontine gliomas, and the checkpoint molecular B7H3 in medulloblastomas and pontine gliomas.

“In sarcomas in kids there are currently 12 trials in progress. Most of the targeting epitopes are targeting either HER2 or GD2. Repetitive CAR-T infusions are being used in several of these trials in sarcomas.

For neuroblastomas there are currently 13 studies in progress, nearly all of which target GD2. Some of the trials include combining CAR-T with immune checkpoint inhibitors or C7R, an engineered cytokine driver designed to prevent T-cell exhaustion.

In addition, several trials of tumor pulsed dendritic cell vaccines are underway for treatment of children with Wilms tumor, Dr. Yanik noted.
 

Unresolved procedural questions

It’s still early days in CAR-T therapy, and there are several still unanswered questions regarding optimal therapy for and management of patients undergoing CAR-T procedures, Dr. Yanik said.

For example, the optimal time to collect T cells during apheresis is still unclear, he said. Collecting prior to reinduction therapy raises the risk of transducing leukemic cells, while collecting after reinduction may result in inadequate quantity or quality of cells. Regardless of when cells are collected, apheresis should be performed only when the absolute lymphocyte count is above 500/mcL or the CD3 count is above 150/mcL at the time of apheresis.

In the case tisagenlecleucel (Kymriah), his center typically collects 1x10⁹ CD3 cells regardless of age or weight.

The number of CAR T-cells infused also appears to matter, as responses are improved at CAR-T doses above 1.5x10⁶/kg, while risk for higher-grade cytokine release syndrome (CRS) occurs at higher infusion doses.
 

Blinatumomab or inotuzumab?

Along with CAR-T, two other agents, the bispecific T-cell engager blinatumomab (Blincyto) and the antibody conjugate inotuzumab ozogamicin (Besponsa) are also approved for the treatment of patients with relapsed/refractory B-cell ALL.

Like CAR-T therapy, the primary toxicities associated with blinatumomab are CRS and neurologic adverse events, whereas at inotuzumab is largely associated with hematologic and hepatic toxicities.

The logistics of therapy differ widely, with a 28-day infusion required for blinatumomab, compared with weekly dosing of inotuzumab, and the multiple visits for apheresis and infusion required for CAR-T.

Blinatumomab is approved for both children and adults with relapsed/refractory ALL, but inotuzumab is approved only for adults, and CAR-T with tisagenlecleucel is approved only for children in this indication.
 

CD-19 expression

There is evidence to suggest that CD19 expression prior to CAR-T has an effect on outcomes, Dr. Yanik said.

“Does blinatumomab pre–CAR-T impact outcome? The answer is probably yes,” he said.

He referred to a study by investigators at the Children’s Hospital of Philadelphia showing that, “if you’re giving blinatumomab prior to CAR-T therapy, you’re potentially reducing the cell-surface expression of CD19 on your leukemic blasts, and now while you’re bringing these patients in for CAR-T therapy, you’re getting a much higher population of dim CD19 expressers, and this is associated with a higher relapse rate and lower remission rate.”
 

Predicting relapse

Dr. Yanik referred to a study, currently unpublished, which will show that next-generation sequencing (NGS) is more sensitive than flow cytometry for detection of minimal residual disease (MRD), and that MRD analysis of marrow was more sensitive than analysis of peripheral blood.

“Poor outcomes were seen post CAR-T for patients who were in morphologic remission on day 28 or day 100, but had positive MRD. This especially held true if it was next-gen sequencing MRD-positive at day 100, for which relapse rates were over 95%,” he said.

The absence of B-cells is a surrogate marker for the persistence of CAR-T, and conversely, the recovery of CD19-positive B cells may be a predictor for relapse, especially if the B-cell recovery occurs within the first 6 months following CAR-T infusion.
 

Transplant after CAR-T?

Bone marrow transplant after CAR-T is recommend for patients with high risk of relapse, including those with B-cell recovery within the first 6 months after CAR-T, patients with MRD positivity at days 28 or 100, and patients with mixed lineage leukemia.

“Should we transplant good-risk patients, meaning, if you have NGS-MRD negative patients, is there a role for transplant? You have to look at the risk versus benefit there. These patients may have a cure rate that’s in the 80%-plus range, could we potentially optimize that even more if we consolidate them with an allo[geneic] transplant,” Dr. Yank said.
 

Move CAR-T up front?

A Children’s Oncology Group study is currently examining whether giving CAR-T therapy to patients with MRD of 0.01% or greater following first consolidation could result in lower tumor burden, fewer relapse, and less CRS with CAR-T.

Dr. Yanik reported that he had no conflicts of interest to disclose.

Although the only pediatric indication for chimeric antigen receptor T-cell therapy currently approved by the Food and Drug Administration is B-lineage acute lymphoblastic leukemia (ALL) that is refractory to at least two frontline induction attempts or is in second or later relapse, clinical trials of CAR-T therapy for pediatric solid tumors are also currently in progress, said Gregory Yanik, MD, from the CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, at the Transplant & Cellular Therapies Meetings.

In his presentation, Dr. Yanik discussed progress in solid tumor studies as well as some issues involving the current use of CAR-T therapy for ALL.

Solid tumor studies

Malignancies such as sarcomas, brain tumors, and neuroblastomas pose unique challenges, “In contrast to hematologic malignancies, the protein we’re targeting may not be present on the cell surface of all the tumor cells. There are lower-expression profiles, and this is a problem. In fact, many people have postulated that with CAR-T for pediatric solid tumors we’ll have to do repeated cycles, almost like we do with chemotherapy,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

There are currently 14 studies of CAR-T for central nervous system tumors in children, targeting either epidermal growth factor receptor (EGFR) in glioblastoma multiforme and high-grade gliomas, HER2 in a variety of CNS tumors, the GD2 antigen on pontine gliomas, and the checkpoint molecular B7H3 in medulloblastomas and pontine gliomas.

“In sarcomas in kids there are currently 12 trials in progress. Most of the targeting epitopes are targeting either HER2 or GD2. Repetitive CAR-T infusions are being used in several of these trials in sarcomas.

For neuroblastomas there are currently 13 studies in progress, nearly all of which target GD2. Some of the trials include combining CAR-T with immune checkpoint inhibitors or C7R, an engineered cytokine driver designed to prevent T-cell exhaustion.

In addition, several trials of tumor pulsed dendritic cell vaccines are underway for treatment of children with Wilms tumor, Dr. Yanik noted.
 

Unresolved procedural questions

It’s still early days in CAR-T therapy, and there are several still unanswered questions regarding optimal therapy for and management of patients undergoing CAR-T procedures, Dr. Yanik said.

For example, the optimal time to collect T cells during apheresis is still unclear, he said. Collecting prior to reinduction therapy raises the risk of transducing leukemic cells, while collecting after reinduction may result in inadequate quantity or quality of cells. Regardless of when cells are collected, apheresis should be performed only when the absolute lymphocyte count is above 500/mcL or the CD3 count is above 150/mcL at the time of apheresis.

In the case tisagenlecleucel (Kymriah), his center typically collects 1x10⁹ CD3 cells regardless of age or weight.

The number of CAR T-cells infused also appears to matter, as responses are improved at CAR-T doses above 1.5x10⁶/kg, while risk for higher-grade cytokine release syndrome (CRS) occurs at higher infusion doses.
 

Blinatumomab or inotuzumab?

Along with CAR-T, two other agents, the bispecific T-cell engager blinatumomab (Blincyto) and the antibody conjugate inotuzumab ozogamicin (Besponsa) are also approved for the treatment of patients with relapsed/refractory B-cell ALL.

Like CAR-T therapy, the primary toxicities associated with blinatumomab are CRS and neurologic adverse events, whereas at inotuzumab is largely associated with hematologic and hepatic toxicities.

The logistics of therapy differ widely, with a 28-day infusion required for blinatumomab, compared with weekly dosing of inotuzumab, and the multiple visits for apheresis and infusion required for CAR-T.

Blinatumomab is approved for both children and adults with relapsed/refractory ALL, but inotuzumab is approved only for adults, and CAR-T with tisagenlecleucel is approved only for children in this indication.
 

CD-19 expression

There is evidence to suggest that CD19 expression prior to CAR-T has an effect on outcomes, Dr. Yanik said.

“Does blinatumomab pre–CAR-T impact outcome? The answer is probably yes,” he said.

He referred to a study by investigators at the Children’s Hospital of Philadelphia showing that, “if you’re giving blinatumomab prior to CAR-T therapy, you’re potentially reducing the cell-surface expression of CD19 on your leukemic blasts, and now while you’re bringing these patients in for CAR-T therapy, you’re getting a much higher population of dim CD19 expressers, and this is associated with a higher relapse rate and lower remission rate.”
 

Predicting relapse

Dr. Yanik referred to a study, currently unpublished, which will show that next-generation sequencing (NGS) is more sensitive than flow cytometry for detection of minimal residual disease (MRD), and that MRD analysis of marrow was more sensitive than analysis of peripheral blood.

“Poor outcomes were seen post CAR-T for patients who were in morphologic remission on day 28 or day 100, but had positive MRD. This especially held true if it was next-gen sequencing MRD-positive at day 100, for which relapse rates were over 95%,” he said.

The absence of B-cells is a surrogate marker for the persistence of CAR-T, and conversely, the recovery of CD19-positive B cells may be a predictor for relapse, especially if the B-cell recovery occurs within the first 6 months following CAR-T infusion.
 

Transplant after CAR-T?

Bone marrow transplant after CAR-T is recommend for patients with high risk of relapse, including those with B-cell recovery within the first 6 months after CAR-T, patients with MRD positivity at days 28 or 100, and patients with mixed lineage leukemia.

“Should we transplant good-risk patients, meaning, if you have NGS-MRD negative patients, is there a role for transplant? You have to look at the risk versus benefit there. These patients may have a cure rate that’s in the 80%-plus range, could we potentially optimize that even more if we consolidate them with an allo[geneic] transplant,” Dr. Yank said.
 

Move CAR-T up front?

A Children’s Oncology Group study is currently examining whether giving CAR-T therapy to patients with MRD of 0.01% or greater following first consolidation could result in lower tumor burden, fewer relapse, and less CRS with CAR-T.

Dr. Yanik reported that he had no conflicts of interest to disclose.

Although the only pediatric indication for chimeric antigen receptor T-cell therapy currently approved by the Food and Drug Administration is B-lineage acute lymphoblastic leukemia (ALL) that is refractory to at least two frontline induction attempts or is in second or later relapse, clinical trials of CAR-T therapy for pediatric solid tumors are also currently in progress, said Gregory Yanik, MD, from the CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, at the Transplant & Cellular Therapies Meetings.

In his presentation, Dr. Yanik discussed progress in solid tumor studies as well as some issues involving the current use of CAR-T therapy for ALL.

Solid tumor studies

Malignancies such as sarcomas, brain tumors, and neuroblastomas pose unique challenges, “In contrast to hematologic malignancies, the protein we’re targeting may not be present on the cell surface of all the tumor cells. There are lower-expression profiles, and this is a problem. In fact, many people have postulated that with CAR-T for pediatric solid tumors we’ll have to do repeated cycles, almost like we do with chemotherapy,” he said at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

There are currently 14 studies of CAR-T for central nervous system tumors in children, targeting either epidermal growth factor receptor (EGFR) in glioblastoma multiforme and high-grade gliomas, HER2 in a variety of CNS tumors, the GD2 antigen on pontine gliomas, and the checkpoint molecular B7H3 in medulloblastomas and pontine gliomas.

“In sarcomas in kids there are currently 12 trials in progress. Most of the targeting epitopes are targeting either HER2 or GD2. Repetitive CAR-T infusions are being used in several of these trials in sarcomas.

For neuroblastomas there are currently 13 studies in progress, nearly all of which target GD2. Some of the trials include combining CAR-T with immune checkpoint inhibitors or C7R, an engineered cytokine driver designed to prevent T-cell exhaustion.

In addition, several trials of tumor pulsed dendritic cell vaccines are underway for treatment of children with Wilms tumor, Dr. Yanik noted.
 

Unresolved procedural questions

It’s still early days in CAR-T therapy, and there are several still unanswered questions regarding optimal therapy for and management of patients undergoing CAR-T procedures, Dr. Yanik said.

For example, the optimal time to collect T cells during apheresis is still unclear, he said. Collecting prior to reinduction therapy raises the risk of transducing leukemic cells, while collecting after reinduction may result in inadequate quantity or quality of cells. Regardless of when cells are collected, apheresis should be performed only when the absolute lymphocyte count is above 500/mcL or the CD3 count is above 150/mcL at the time of apheresis.

In the case tisagenlecleucel (Kymriah), his center typically collects 1x10⁹ CD3 cells regardless of age or weight.

The number of CAR T-cells infused also appears to matter, as responses are improved at CAR-T doses above 1.5x10⁶/kg, while risk for higher-grade cytokine release syndrome (CRS) occurs at higher infusion doses.
 

Blinatumomab or inotuzumab?

Along with CAR-T, two other agents, the bispecific T-cell engager blinatumomab (Blincyto) and the antibody conjugate inotuzumab ozogamicin (Besponsa) are also approved for the treatment of patients with relapsed/refractory B-cell ALL.

Like CAR-T therapy, the primary toxicities associated with blinatumomab are CRS and neurologic adverse events, whereas at inotuzumab is largely associated with hematologic and hepatic toxicities.

The logistics of therapy differ widely, with a 28-day infusion required for blinatumomab, compared with weekly dosing of inotuzumab, and the multiple visits for apheresis and infusion required for CAR-T.

Blinatumomab is approved for both children and adults with relapsed/refractory ALL, but inotuzumab is approved only for adults, and CAR-T with tisagenlecleucel is approved only for children in this indication.
 

CD-19 expression

There is evidence to suggest that CD19 expression prior to CAR-T has an effect on outcomes, Dr. Yanik said.

“Does blinatumomab pre–CAR-T impact outcome? The answer is probably yes,” he said.

He referred to a study by investigators at the Children’s Hospital of Philadelphia showing that, “if you’re giving blinatumomab prior to CAR-T therapy, you’re potentially reducing the cell-surface expression of CD19 on your leukemic blasts, and now while you’re bringing these patients in for CAR-T therapy, you’re getting a much higher population of dim CD19 expressers, and this is associated with a higher relapse rate and lower remission rate.”
 

Predicting relapse

Dr. Yanik referred to a study, currently unpublished, which will show that next-generation sequencing (NGS) is more sensitive than flow cytometry for detection of minimal residual disease (MRD), and that MRD analysis of marrow was more sensitive than analysis of peripheral blood.

“Poor outcomes were seen post CAR-T for patients who were in morphologic remission on day 28 or day 100, but had positive MRD. This especially held true if it was next-gen sequencing MRD-positive at day 100, for which relapse rates were over 95%,” he said.

The absence of B-cells is a surrogate marker for the persistence of CAR-T, and conversely, the recovery of CD19-positive B cells may be a predictor for relapse, especially if the B-cell recovery occurs within the first 6 months following CAR-T infusion.
 

Transplant after CAR-T?

Bone marrow transplant after CAR-T is recommend for patients with high risk of relapse, including those with B-cell recovery within the first 6 months after CAR-T, patients with MRD positivity at days 28 or 100, and patients with mixed lineage leukemia.

“Should we transplant good-risk patients, meaning, if you have NGS-MRD negative patients, is there a role for transplant? You have to look at the risk versus benefit there. These patients may have a cure rate that’s in the 80%-plus range, could we potentially optimize that even more if we consolidate them with an allo[geneic] transplant,” Dr. Yank said.
 

Move CAR-T up front?

A Children’s Oncology Group study is currently examining whether giving CAR-T therapy to patients with MRD of 0.01% or greater following first consolidation could result in lower tumor burden, fewer relapse, and less CRS with CAR-T.

Dr. Yanik reported that he had no conflicts of interest to disclose.

The Food and Drug Administration recently announced two new types of cancer that can be treated by the anti–PD-1 antibody pembrolizumab.

The new indications expand the use of pembrolizumab (Keytruda) to include treatment of patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors as well as patients with cutaneous squamous cell carcinoma (cSCC). The FDA announced the new indications just 8 days apart, on June 16 and June 24.

In addition, on June 29, the FDA approved a third new indication for pembrolizumab, this time as first-line treatment for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient colorectal cancer.



The new approvals add to a wide range of oncology indications for which pembrolizumab can be used.

Accelerated approval to treat solid tumors

The FDA granted accelerated approval for pembrolizumab to treat children and adults with unresectable or metastatic TMB-H solid tumors that progressed after previous treatment or in instances where there are no satisfactory alternative treatment options.

The tumor mutational burden must be confirmed by an FDA-approved test. To that end, the FDA approved the FoundationOneCDx assay, which is designed to help physicians determine which patients meet the threshold for TMB-H malignancies (10 or more mutations per megabase).

The efficacy of pembrolizumab in TMB-H solid tumors was investigated in 10 cohorts from the multicenter, open-label KEYNOTE-158 trial. Participants received 200 mg of pembrolizumab intravenously every 3 weeks until their disease progressed or they experienced unacceptable toxicity.

Within this population, 102 patients had tumors that met the TMB-H definition. In this group, the overall response rate was 29%, including a 25% partial response rate and a 4% complete response rate.

The median duration of response was not reached, but 57% of participants experienced a response lasting 12 months or longer, and 50% had a response lasting 24 months or longer.

The most common adverse events associated with pembrolizumab in this trial were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions, the FDA noted.

Safety and efficacy of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
 

New option for recurrent or metastatic cSCC

Physicians treating patients with cSCC that is not curable by surgery or radiation now have pembrolizumab to consider as another treatment option.

The cSCC approval is based on results of the multicenter, open-label KEYNOTE-629 trial. The dosage regimen was 200 mg of pembrolizumab intravenously every 3 weeks until cancer progressed, unacceptable toxicity arose, or 24 months of treatment were completed.

The objective response rate was 34%, and the median duration of response was not reached.

Adverse events were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials, the FDA noted.

The Food and Drug Administration recently announced two new types of cancer that can be treated by the anti–PD-1 antibody pembrolizumab.

The new indications expand the use of pembrolizumab (Keytruda) to include treatment of patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors as well as patients with cutaneous squamous cell carcinoma (cSCC). The FDA announced the new indications just 8 days apart, on June 16 and June 24.

In addition, on June 29, the FDA approved a third new indication for pembrolizumab, this time as first-line treatment for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient colorectal cancer.



The new approvals add to a wide range of oncology indications for which pembrolizumab can be used.

Accelerated approval to treat solid tumors

The FDA granted accelerated approval for pembrolizumab to treat children and adults with unresectable or metastatic TMB-H solid tumors that progressed after previous treatment or in instances where there are no satisfactory alternative treatment options.

The tumor mutational burden must be confirmed by an FDA-approved test. To that end, the FDA approved the FoundationOneCDx assay, which is designed to help physicians determine which patients meet the threshold for TMB-H malignancies (10 or more mutations per megabase).

The efficacy of pembrolizumab in TMB-H solid tumors was investigated in 10 cohorts from the multicenter, open-label KEYNOTE-158 trial. Participants received 200 mg of pembrolizumab intravenously every 3 weeks until their disease progressed or they experienced unacceptable toxicity.

Within this population, 102 patients had tumors that met the TMB-H definition. In this group, the overall response rate was 29%, including a 25% partial response rate and a 4% complete response rate.

The median duration of response was not reached, but 57% of participants experienced a response lasting 12 months or longer, and 50% had a response lasting 24 months or longer.

The most common adverse events associated with pembrolizumab in this trial were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions, the FDA noted.

Safety and efficacy of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
 

New option for recurrent or metastatic cSCC

Physicians treating patients with cSCC that is not curable by surgery or radiation now have pembrolizumab to consider as another treatment option.

The cSCC approval is based on results of the multicenter, open-label KEYNOTE-629 trial. The dosage regimen was 200 mg of pembrolizumab intravenously every 3 weeks until cancer progressed, unacceptable toxicity arose, or 24 months of treatment were completed.

The objective response rate was 34%, and the median duration of response was not reached.

Adverse events were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials, the FDA noted.

The Food and Drug Administration recently announced two new types of cancer that can be treated by the anti–PD-1 antibody pembrolizumab.

The new indications expand the use of pembrolizumab (Keytruda) to include treatment of patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors as well as patients with cutaneous squamous cell carcinoma (cSCC). The FDA announced the new indications just 8 days apart, on June 16 and June 24.

In addition, on June 29, the FDA approved a third new indication for pembrolizumab, this time as first-line treatment for patients with unresectable or metastatic microsatellite instability–high or mismatch repair–deficient colorectal cancer.



The new approvals add to a wide range of oncology indications for which pembrolizumab can be used.

Accelerated approval to treat solid tumors

The FDA granted accelerated approval for pembrolizumab to treat children and adults with unresectable or metastatic TMB-H solid tumors that progressed after previous treatment or in instances where there are no satisfactory alternative treatment options.

The tumor mutational burden must be confirmed by an FDA-approved test. To that end, the FDA approved the FoundationOneCDx assay, which is designed to help physicians determine which patients meet the threshold for TMB-H malignancies (10 or more mutations per megabase).

The efficacy of pembrolizumab in TMB-H solid tumors was investigated in 10 cohorts from the multicenter, open-label KEYNOTE-158 trial. Participants received 200 mg of pembrolizumab intravenously every 3 weeks until their disease progressed or they experienced unacceptable toxicity.

Within this population, 102 patients had tumors that met the TMB-H definition. In this group, the overall response rate was 29%, including a 25% partial response rate and a 4% complete response rate.

The median duration of response was not reached, but 57% of participants experienced a response lasting 12 months or longer, and 50% had a response lasting 24 months or longer.

The most common adverse events associated with pembrolizumab in this trial were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions, the FDA noted.

Safety and efficacy of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.
 

New option for recurrent or metastatic cSCC

Physicians treating patients with cSCC that is not curable by surgery or radiation now have pembrolizumab to consider as another treatment option.

The cSCC approval is based on results of the multicenter, open-label KEYNOTE-629 trial. The dosage regimen was 200 mg of pembrolizumab intravenously every 3 weeks until cancer progressed, unacceptable toxicity arose, or 24 months of treatment were completed.

The objective response rate was 34%, and the median duration of response was not reached.

Adverse events were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials, the FDA noted.

Federal Practitioner is inviting hematology and oncology health care providers and researchers to contribute to the November 2020 special issue on immuno-oncology. The special issue is produced in cooperation with the Association of VA Hematology/Oncology (AVAHO). The journal is especially interested in new research, case studies, review articles, and patient care program descriptions.

Interested authors can send a brief 2 to 3 sentence abstract to [email protected] by May 29, 2020, or submit a completed article directly into Editorial Manager, a web-based manuscript submission and review system. The updated and complete submission guidelines, including details about the style and format, can be found here:

http://www.mdedge.com/fedprac/page/submission-guidelines

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editorial Advisory Association Hematology/Oncology special issue advisory board.

Federal Practitioner is inviting hematology and oncology health care providers and researchers to contribute to the November 2020 special issue on immuno-oncology. The special issue is produced in cooperation with the Association of VA Hematology/Oncology (AVAHO). The journal is especially interested in new research, case studies, review articles, and patient care program descriptions.

Interested authors can send a brief 2 to 3 sentence abstract to [email protected] by May 29, 2020, or submit a completed article directly into Editorial Manager, a web-based manuscript submission and review system. The updated and complete submission guidelines, including details about the style and format, can be found here:

http://www.mdedge.com/fedprac/page/submission-guidelines

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editorial Advisory Association Hematology/Oncology special issue advisory board.

Federal Practitioner is inviting hematology and oncology health care providers and researchers to contribute to the November 2020 special issue on immuno-oncology. The special issue is produced in cooperation with the Association of VA Hematology/Oncology (AVAHO). The journal is especially interested in new research, case studies, review articles, and patient care program descriptions.

Interested authors can send a brief 2 to 3 sentence abstract to [email protected] by May 29, 2020, or submit a completed article directly into Editorial Manager, a web-based manuscript submission and review system. The updated and complete submission guidelines, including details about the style and format, can be found here:

http://www.mdedge.com/fedprac/page/submission-guidelines

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editorial Advisory Association Hematology/Oncology special issue advisory board.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

SAN FRANCISCO – First-line dual immune checkpoint inhibitor therapy for microsatellite instability–high/DNA mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer has impressive durability, an update of the multicohort CheckMate 142 trial shows.

Susan London/MDedge News

“We all know that MSI-H colorectal cancer patients have a poor prognosis,” said lead investigator Heinz-Josef Lenz, MD, codirector of the Colorectal Center and section head of the GI oncology program at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles. First-line chemotherapy in this population yields median overall survival on the order of 20-22 months.

The cohort of 45 patients treated on the phase 2 trial received the programmed death–1 inhibitor nivolumab (Opdivo) every 2 weeks, plus a low dose of the CTLA4 inhibitor ipilimumab (Yervoy) every 6 weeks as first-line therapy for MSI-H metastatic colorectal cancer. (Nivolumab, with or without ipilimumab, has received Food and Drug Administration accelerated approval as second-line therapy based on data from other cohorts in the trial.)

Previously reported initial results, at a median follow-up of 13.8 months, showed that the investigator-assessed objective response rate was 60% (ESMO 2018, Abstract LBA18_PR). As of the update, now at a median follow-up of 19.9 months, that rate was 64%, according to data reported at the 2020 GI Cancers Symposium.

“Nivolumab and ipilimumab demonstrates clinically meaningful durable benefits and may present an option for first-line treatment for MSI-H metastatic colorectal cancer patients,” Dr. Lenz summarized.

“The incredible complete response rates and overall response rates seen are never seen with chemotherapy, and it’s very well tolerated, so if I have a choice, I would start with nivolumab-ipilimumab in first-line MSI-H,” he added. “The [National Comprehensive Cancer Network] guidelines recommend that you can start in first line with this combination if patients are not candidates for chemotherapy. So they leave this door open, that you have an opportunity to use immunotherapy in this patient population.”

Choosing single or dual immunotherapy

Given the so-called financial toxicity of dual nivolumab and ipilimumab therapy and lack of a randomized comparison against single-agent nivolumab, a session attendee said, can clinicians simply use the latter?

“Very importantly, in this clinical trial, ipilimumab was given every 6 weeks. As you know, the 2-week regimens are significantly more toxic,” Dr. Lenz noted. The combination using this low dose has safety similar to that seen with nivolumab alone. And in cross-trial comparisons, at least, “the combination seems to be a little bit more active, so I always choose both,” he said, adding that the financial aspects are beyond his purview.

Susan London/MDedge News

However, session cochair Joseph J.Y. Sung, MD, PhD, MBBS, the Mok Hing Yiu Professor of Medicine in the department of medicine and therapeutics at the Chinese University of Hong Kong, had a different view.

“I think there is still room for a randomized study to prove the combination’s superiority against single immunotherapy,” he said in an interview. “If I’m treating an MSI patient, I would stick to single immunotherapy until I see more evidence that this combination has a substantial improvement in the outcome that is worth the money.”

Study details

The patients studied were unselected for baseline tumor expression of programmed death–ligand 1, with 27% having expression of 1% or greater and 58% having expression below that threshold.

As of the data cutoff for the update, 47% of patients were still on treatment, Dr. Lenz reported at the symposium, sponsored by the American Gastroenterological Association, American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The most common reason for stopping treatment was disease progression.

The investigator-assessed objective response rate, the primary endpoint, consisted of complete responses in 9% of patients and partial responses in 56%. (The rate as assessed by blinded independent central reviewers was 58%, consisting of complete responses in 18% and partial responses in 40%.)

“The high response rate was consistent among all evaluated subgroups,” Dr. Lenz noted, with no differences detected by presence or absence of Lynch syndrome and/or specific microsatellite-related mutations.

Median time to response was 2.6 months, and median duration of response was not reached. Median progression-free and overall survival were also not reached, but 15-month rates were 75% and 84%, respectively.

The rate of grade 3-4 treatment-related adverse events was 20%, and the rate of grade 3-4 serious treatment-related adverse events was 11%. Only 4% of patients discontinued treatment because of such events.

Ongoing trials may take immunotherapy even further in this patient population, according to Dr. Lenz. “We are all waiting for the treatments with the immunotherapy in combination with chemo and bevacizumab in first line. Will that change the efficacy and toxicity?” he elaborated. “You can imagine, in the MSI-H patients with the immunotherapy alone, we haven’t reached median progression-free and overall survival, so it may take a long time to get this data.”

Dr. Lenz reported receiving honoraria from Bayer, Boehringer Ingelheim, Merck Serono, and Roche; consulting or advising with Bayer, Merck Serono, Pfizer, and Roche; receiving travel expenses from Bayer, Merck Serono, and Roche. The trial was funded by Bristol-Myers Squibb. Dr. Sung reported that he had no relevant conflicts of interest.

SOURCE: Lenz H-J et al. 2020 GI Cancers Symposium, Abstract 11.

SAN FRANCISCO – First-line dual immune checkpoint inhibitor therapy for microsatellite instability–high/DNA mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer has impressive durability, an update of the multicohort CheckMate 142 trial shows.

Susan London/MDedge News

“We all know that MSI-H colorectal cancer patients have a poor prognosis,” said lead investigator Heinz-Josef Lenz, MD, codirector of the Colorectal Center and section head of the GI oncology program at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles. First-line chemotherapy in this population yields median overall survival on the order of 20-22 months.

The cohort of 45 patients treated on the phase 2 trial received the programmed death–1 inhibitor nivolumab (Opdivo) every 2 weeks, plus a low dose of the CTLA4 inhibitor ipilimumab (Yervoy) every 6 weeks as first-line therapy for MSI-H metastatic colorectal cancer. (Nivolumab, with or without ipilimumab, has received Food and Drug Administration accelerated approval as second-line therapy based on data from other cohorts in the trial.)

Previously reported initial results, at a median follow-up of 13.8 months, showed that the investigator-assessed objective response rate was 60% (ESMO 2018, Abstract LBA18_PR). As of the update, now at a median follow-up of 19.9 months, that rate was 64%, according to data reported at the 2020 GI Cancers Symposium.

“Nivolumab and ipilimumab demonstrates clinically meaningful durable benefits and may present an option for first-line treatment for MSI-H metastatic colorectal cancer patients,” Dr. Lenz summarized.

“The incredible complete response rates and overall response rates seen are never seen with chemotherapy, and it’s very well tolerated, so if I have a choice, I would start with nivolumab-ipilimumab in first-line MSI-H,” he added. “The [National Comprehensive Cancer Network] guidelines recommend that you can start in first line with this combination if patients are not candidates for chemotherapy. So they leave this door open, that you have an opportunity to use immunotherapy in this patient population.”

Choosing single or dual immunotherapy

Given the so-called financial toxicity of dual nivolumab and ipilimumab therapy and lack of a randomized comparison against single-agent nivolumab, a session attendee said, can clinicians simply use the latter?

“Very importantly, in this clinical trial, ipilimumab was given every 6 weeks. As you know, the 2-week regimens are significantly more toxic,” Dr. Lenz noted. The combination using this low dose has safety similar to that seen with nivolumab alone. And in cross-trial comparisons, at least, “the combination seems to be a little bit more active, so I always choose both,” he said, adding that the financial aspects are beyond his purview.

Susan London/MDedge News

However, session cochair Joseph J.Y. Sung, MD, PhD, MBBS, the Mok Hing Yiu Professor of Medicine in the department of medicine and therapeutics at the Chinese University of Hong Kong, had a different view.

“I think there is still room for a randomized study to prove the combination’s superiority against single immunotherapy,” he said in an interview. “If I’m treating an MSI patient, I would stick to single immunotherapy until I see more evidence that this combination has a substantial improvement in the outcome that is worth the money.”

Study details

The patients studied were unselected for baseline tumor expression of programmed death–ligand 1, with 27% having expression of 1% or greater and 58% having expression below that threshold.

As of the data cutoff for the update, 47% of patients were still on treatment, Dr. Lenz reported at the symposium, sponsored by the American Gastroenterological Association, American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The most common reason for stopping treatment was disease progression.

The investigator-assessed objective response rate, the primary endpoint, consisted of complete responses in 9% of patients and partial responses in 56%. (The rate as assessed by blinded independent central reviewers was 58%, consisting of complete responses in 18% and partial responses in 40%.)

“The high response rate was consistent among all evaluated subgroups,” Dr. Lenz noted, with no differences detected by presence or absence of Lynch syndrome and/or specific microsatellite-related mutations.

Median time to response was 2.6 months, and median duration of response was not reached. Median progression-free and overall survival were also not reached, but 15-month rates were 75% and 84%, respectively.

The rate of grade 3-4 treatment-related adverse events was 20%, and the rate of grade 3-4 serious treatment-related adverse events was 11%. Only 4% of patients discontinued treatment because of such events.

Ongoing trials may take immunotherapy even further in this patient population, according to Dr. Lenz. “We are all waiting for the treatments with the immunotherapy in combination with chemo and bevacizumab in first line. Will that change the efficacy and toxicity?” he elaborated. “You can imagine, in the MSI-H patients with the immunotherapy alone, we haven’t reached median progression-free and overall survival, so it may take a long time to get this data.”

Dr. Lenz reported receiving honoraria from Bayer, Boehringer Ingelheim, Merck Serono, and Roche; consulting or advising with Bayer, Merck Serono, Pfizer, and Roche; receiving travel expenses from Bayer, Merck Serono, and Roche. The trial was funded by Bristol-Myers Squibb. Dr. Sung reported that he had no relevant conflicts of interest.

SOURCE: Lenz H-J et al. 2020 GI Cancers Symposium, Abstract 11.

SAN FRANCISCO – First-line dual immune checkpoint inhibitor therapy for microsatellite instability–high/DNA mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer has impressive durability, an update of the multicohort CheckMate 142 trial shows.

Susan London/MDedge News

“We all know that MSI-H colorectal cancer patients have a poor prognosis,” said lead investigator Heinz-Josef Lenz, MD, codirector of the Colorectal Center and section head of the GI oncology program at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles. First-line chemotherapy in this population yields median overall survival on the order of 20-22 months.

The cohort of 45 patients treated on the phase 2 trial received the programmed death–1 inhibitor nivolumab (Opdivo) every 2 weeks, plus a low dose of the CTLA4 inhibitor ipilimumab (Yervoy) every 6 weeks as first-line therapy for MSI-H metastatic colorectal cancer. (Nivolumab, with or without ipilimumab, has received Food and Drug Administration accelerated approval as second-line therapy based on data from other cohorts in the trial.)

Previously reported initial results, at a median follow-up of 13.8 months, showed that the investigator-assessed objective response rate was 60% (ESMO 2018, Abstract LBA18_PR). As of the update, now at a median follow-up of 19.9 months, that rate was 64%, according to data reported at the 2020 GI Cancers Symposium.

“Nivolumab and ipilimumab demonstrates clinically meaningful durable benefits and may present an option for first-line treatment for MSI-H metastatic colorectal cancer patients,” Dr. Lenz summarized.

“The incredible complete response rates and overall response rates seen are never seen with chemotherapy, and it’s very well tolerated, so if I have a choice, I would start with nivolumab-ipilimumab in first-line MSI-H,” he added. “The [National Comprehensive Cancer Network] guidelines recommend that you can start in first line with this combination if patients are not candidates for chemotherapy. So they leave this door open, that you have an opportunity to use immunotherapy in this patient population.”

Choosing single or dual immunotherapy

Given the so-called financial toxicity of dual nivolumab and ipilimumab therapy and lack of a randomized comparison against single-agent nivolumab, a session attendee said, can clinicians simply use the latter?

“Very importantly, in this clinical trial, ipilimumab was given every 6 weeks. As you know, the 2-week regimens are significantly more toxic,” Dr. Lenz noted. The combination using this low dose has safety similar to that seen with nivolumab alone. And in cross-trial comparisons, at least, “the combination seems to be a little bit more active, so I always choose both,” he said, adding that the financial aspects are beyond his purview.

Susan London/MDedge News

However, session cochair Joseph J.Y. Sung, MD, PhD, MBBS, the Mok Hing Yiu Professor of Medicine in the department of medicine and therapeutics at the Chinese University of Hong Kong, had a different view.

“I think there is still room for a randomized study to prove the combination’s superiority against single immunotherapy,” he said in an interview. “If I’m treating an MSI patient, I would stick to single immunotherapy until I see more evidence that this combination has a substantial improvement in the outcome that is worth the money.”

Study details

The patients studied were unselected for baseline tumor expression of programmed death–ligand 1, with 27% having expression of 1% or greater and 58% having expression below that threshold.

As of the data cutoff for the update, 47% of patients were still on treatment, Dr. Lenz reported at the symposium, sponsored by the American Gastroenterological Association, American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. The most common reason for stopping treatment was disease progression.

The investigator-assessed objective response rate, the primary endpoint, consisted of complete responses in 9% of patients and partial responses in 56%. (The rate as assessed by blinded independent central reviewers was 58%, consisting of complete responses in 18% and partial responses in 40%.)

“The high response rate was consistent among all evaluated subgroups,” Dr. Lenz noted, with no differences detected by presence or absence of Lynch syndrome and/or specific microsatellite-related mutations.

Median time to response was 2.6 months, and median duration of response was not reached. Median progression-free and overall survival were also not reached, but 15-month rates were 75% and 84%, respectively.

The rate of grade 3-4 treatment-related adverse events was 20%, and the rate of grade 3-4 serious treatment-related adverse events was 11%. Only 4% of patients discontinued treatment because of such events.

Ongoing trials may take immunotherapy even further in this patient population, according to Dr. Lenz. “We are all waiting for the treatments with the immunotherapy in combination with chemo and bevacizumab in first line. Will that change the efficacy and toxicity?” he elaborated. “You can imagine, in the MSI-H patients with the immunotherapy alone, we haven’t reached median progression-free and overall survival, so it may take a long time to get this data.”

Dr. Lenz reported receiving honoraria from Bayer, Boehringer Ingelheim, Merck Serono, and Roche; consulting or advising with Bayer, Merck Serono, Pfizer, and Roche; receiving travel expenses from Bayer, Merck Serono, and Roche. The trial was funded by Bristol-Myers Squibb. Dr. Sung reported that he had no relevant conflicts of interest.

SOURCE: Lenz H-J et al. 2020 GI Cancers Symposium, Abstract 11.

The combination of oncolytic immunotherapy and an immune checkpoint inhibitor had promising activity in a phase 2 study including patients with previously treated advanced sarcoma, investigators report.

Responses were seen in about one-third of the patients (30%) at 24 weeks after starting treatment with talimogene laherparepvec (T-VEC) and pembrolizumab, according to the investigators, led by Ciara M. Kelly, MBBChBAO, MD, of the department of sarcoma oncology at Memorial Sloan Kettering Cancer Center, New York.

“To our knowledge, this is one of the highest ORRs [objective response rates] reported in an unselected sarcoma-specific study population evaluating the efficacy of combination immunotherapy,” Dr. Kelly and coauthors wrote in JAMA Oncology.

Two of the patients who responded to the combination had previously failed regimens that included an immune checkpoint inhibitor, suggesting T-VEC might be augmenting the efficacy of pembrolizumab, according to the authors.

Among responders, the mean number of prior treatments was one, while by contrast, most of the study cohort (60%) had three or more prior treatments. “This finding supports the rationale to enroll patients with sarcoma in immunotherapy trials earlier in their treatment course,” Dr. Kelly and colleagues wrote.

In studies of immunotherapy in Merkel cell carcinoma and other cancer types, higher response rates have been seen in patients who were naive to chemotherapy, as opposed to those who were refractory to it.

The present single-institution, phase 2 study by Dr. Kelly and colleagues included 20 adult patients with histologically confirmed locally advanced or metastatic sarcoma. The patients received a fixed dose of pembrolizumab administered intravenously, and had T-VEC injected into palpable lesions, on day 1 of 21-day cycles.

While the ORR was 30% at 24 weeks (7 of 35 patients), an additional patient had a response at 32 weeks, bringing the ORR to 35%, according to the report.

“Maximal response to therapy may take a prolonged period to achieve,” the investigators wrote, noting that the median time to response was 14.4 weeks.

Median duration of response was 56.1 weeks, suggesting the combination provided durable disease control, they added.

Safety was consistent with what was seen in a previous study of T-VEC and pembrolizumab in melanoma. In this sarcoma study, the incidence of grade 3 treatment-related adverse events was 20%, while in studies of conventional chemotherapy in this setting, the rate of those events has been “comparable but generally higher,” the investigators wrote.

Dr. Kelly and colleagues wrote that a randomized clinical trial is the “ideal next step” in the development of the regimen, adding that an expansion of the present phase 2 study is in progress.

The study was funded by Amgen and Merck, with additional grant support from Cycle for Survival and the National Institutes of Health/National Cancer Institute. Dr. Kelly reported disclosures related to Merck, Amgen, Agios Pharmaceuticals, and Exicure. Her coauthors reported disclosures with Regeneron, Novartis, Takeda, and Nektar, among others.

SOURCE: Kelly CM et al. JAMA Oncol. 2020 Jan 23. doi: 10.1001/jamaoncol.2019.6152.

The combination of oncolytic immunotherapy and an immune checkpoint inhibitor had promising activity in a phase 2 study including patients with previously treated advanced sarcoma, investigators report.

Responses were seen in about one-third of the patients (30%) at 24 weeks after starting treatment with talimogene laherparepvec (T-VEC) and pembrolizumab, according to the investigators, led by Ciara M. Kelly, MBBChBAO, MD, of the department of sarcoma oncology at Memorial Sloan Kettering Cancer Center, New York.

“To our knowledge, this is one of the highest ORRs [objective response rates] reported in an unselected sarcoma-specific study population evaluating the efficacy of combination immunotherapy,” Dr. Kelly and coauthors wrote in JAMA Oncology.

Two of the patients who responded to the combination had previously failed regimens that included an immune checkpoint inhibitor, suggesting T-VEC might be augmenting the efficacy of pembrolizumab, according to the authors.

Among responders, the mean number of prior treatments was one, while by contrast, most of the study cohort (60%) had three or more prior treatments. “This finding supports the rationale to enroll patients with sarcoma in immunotherapy trials earlier in their treatment course,” Dr. Kelly and colleagues wrote.

In studies of immunotherapy in Merkel cell carcinoma and other cancer types, higher response rates have been seen in patients who were naive to chemotherapy, as opposed to those who were refractory to it.

The present single-institution, phase 2 study by Dr. Kelly and colleagues included 20 adult patients with histologically confirmed locally advanced or metastatic sarcoma. The patients received a fixed dose of pembrolizumab administered intravenously, and had T-VEC injected into palpable lesions, on day 1 of 21-day cycles.

While the ORR was 30% at 24 weeks (7 of 35 patients), an additional patient had a response at 32 weeks, bringing the ORR to 35%, according to the report.

“Maximal response to therapy may take a prolonged period to achieve,” the investigators wrote, noting that the median time to response was 14.4 weeks.

Median duration of response was 56.1 weeks, suggesting the combination provided durable disease control, they added.

Safety was consistent with what was seen in a previous study of T-VEC and pembrolizumab in melanoma. In this sarcoma study, the incidence of grade 3 treatment-related adverse events was 20%, while in studies of conventional chemotherapy in this setting, the rate of those events has been “comparable but generally higher,” the investigators wrote.

Dr. Kelly and colleagues wrote that a randomized clinical trial is the “ideal next step” in the development of the regimen, adding that an expansion of the present phase 2 study is in progress.

The study was funded by Amgen and Merck, with additional grant support from Cycle for Survival and the National Institutes of Health/National Cancer Institute. Dr. Kelly reported disclosures related to Merck, Amgen, Agios Pharmaceuticals, and Exicure. Her coauthors reported disclosures with Regeneron, Novartis, Takeda, and Nektar, among others.

SOURCE: Kelly CM et al. JAMA Oncol. 2020 Jan 23. doi: 10.1001/jamaoncol.2019.6152.

The combination of oncolytic immunotherapy and an immune checkpoint inhibitor had promising activity in a phase 2 study including patients with previously treated advanced sarcoma, investigators report.

Responses were seen in about one-third of the patients (30%) at 24 weeks after starting treatment with talimogene laherparepvec (T-VEC) and pembrolizumab, according to the investigators, led by Ciara M. Kelly, MBBChBAO, MD, of the department of sarcoma oncology at Memorial Sloan Kettering Cancer Center, New York.

“To our knowledge, this is one of the highest ORRs [objective response rates] reported in an unselected sarcoma-specific study population evaluating the efficacy of combination immunotherapy,” Dr. Kelly and coauthors wrote in JAMA Oncology.

Two of the patients who responded to the combination had previously failed regimens that included an immune checkpoint inhibitor, suggesting T-VEC might be augmenting the efficacy of pembrolizumab, according to the authors.

Among responders, the mean number of prior treatments was one, while by contrast, most of the study cohort (60%) had three or more prior treatments. “This finding supports the rationale to enroll patients with sarcoma in immunotherapy trials earlier in their treatment course,” Dr. Kelly and colleagues wrote.

In studies of immunotherapy in Merkel cell carcinoma and other cancer types, higher response rates have been seen in patients who were naive to chemotherapy, as opposed to those who were refractory to it.

The present single-institution, phase 2 study by Dr. Kelly and colleagues included 20 adult patients with histologically confirmed locally advanced or metastatic sarcoma. The patients received a fixed dose of pembrolizumab administered intravenously, and had T-VEC injected into palpable lesions, on day 1 of 21-day cycles.

While the ORR was 30% at 24 weeks (7 of 35 patients), an additional patient had a response at 32 weeks, bringing the ORR to 35%, according to the report.

“Maximal response to therapy may take a prolonged period to achieve,” the investigators wrote, noting that the median time to response was 14.4 weeks.

Median duration of response was 56.1 weeks, suggesting the combination provided durable disease control, they added.

Safety was consistent with what was seen in a previous study of T-VEC and pembrolizumab in melanoma. In this sarcoma study, the incidence of grade 3 treatment-related adverse events was 20%, while in studies of conventional chemotherapy in this setting, the rate of those events has been “comparable but generally higher,” the investigators wrote.

Dr. Kelly and colleagues wrote that a randomized clinical trial is the “ideal next step” in the development of the regimen, adding that an expansion of the present phase 2 study is in progress.

The study was funded by Amgen and Merck, with additional grant support from Cycle for Survival and the National Institutes of Health/National Cancer Institute. Dr. Kelly reported disclosures related to Merck, Amgen, Agios Pharmaceuticals, and Exicure. Her coauthors reported disclosures with Regeneron, Novartis, Takeda, and Nektar, among others.

SOURCE: Kelly CM et al. JAMA Oncol. 2020 Jan 23. doi: 10.1001/jamaoncol.2019.6152.

ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.

Vidyard Video

During a video roundtable at the meeting, experts discussed some of the CAR T-cell studies presented at ASH and what those findings mean in practice. The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.

Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.

Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.

Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.

In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.

The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.

The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”

“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.

The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).

Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.

[email protected]

ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.

Vidyard Video

During a video roundtable at the meeting, experts discussed some of the CAR T-cell studies presented at ASH and what those findings mean in practice. The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.

Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.

Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.

Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.

In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.

The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.

The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”

“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.

The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).

Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.

[email protected]

ORLANDO – There’s now mature data surrounding the use of chimeric antigen receptor (CAR) T-cell therapy in lymphoma, and the annual meeting of the American Society of Hematology brought forth additional information from real-world studies, insights about what is driving relapse, and promising data on mantle cell lymphoma.

Vidyard Video

During a video roundtable at the meeting, experts discussed some of the CAR T-cell studies presented at ASH and what those findings mean in practice. The roundtable participants included Brian Hill, MD, of the Cleveland Clinic Taussig Cancer Center; Frederick L. Locke, MD, of the Moffit Cancer Center in Tampa, Fla.; and Peter Riedell, MD, of the University of Chicago.

Among the studies highlighted by the panel was the Transcend NHL 001 study (Abstract 241), which looked at third-line use of lisocabtagene maraleucel (liso-cel) in patients with diffuse large B-cell lymphoma, transformed follicular lymphoma, and other indolent non-Hodgkin lymphoma subtypes. More than 300 patients were enrolled, and liso-cel met all primary and secondary efficacy endpoints, with an overall response rate of more than 70%. The notable take-home point from the study was the safety profile, Dr. Riedell noted. Liso-cel was associated with a lower rate of cytokine release syndrome and neurologic toxicity, compared with the currently approved products.

Since patients in the study had a lower incidence and later onset of cytokine release syndrome, liso-cel could be a candidate for outpatient administration, Dr. Locke said. However, doing that would require “significant infrastructure” in hospitals and clinics to properly support patients, especially given that the treatment-related mortality on the study was similar to approved CAR T-cell products at about 3%. “You have to be ready to admit the patient to the hospital very rapidly, and you have to have the providers and the nurses who are vigilant when the patient is not in the hospital,” he said.

Another notable study presented at ASH examined the characteristics and outcomes of patients receiving bridging therapy while awaiting treatment with axicabtagene ciloleucel (Abstract 245). This real-world study adds interesting information to the field because, in some of the studies that were pivotal to the approval of CAR T-cell therapy, bridging therapy was not allowed, Dr. Locke said.

In this analysis, researchers found that the overall survival was worse among patients who received bridging. This finding suggests that patients who received bridging therapy had a different biology or that the therapy itself may have had an effect on the host or tumor microenvironment that affected the efficacy of the CAR T-cell therapy, the researchers reported.

The panel also highlighted the Zuma-2 study, which looked at KTE-X19, an anti-CD19 CAR T-cell therapy, among more than 70 patients with relapsed/refractory mantle cell lymphoma who had failed treatment with a Bruton’s tyrosine kinase inhibitor (Abstract 754). “This was, I thought, kind of a sleeper study at ASH,” said Dr. Hill, who was one of the authors of the study.

The overall response rate was 93% with about two-thirds of patients achieving a complete response. Researchers found that the response was consistent across subgroups, including Ki-67 and patients with prior use of steroids or bridging therapy. Dr. Locke, who was also a study author, said the results are a “game changer.”

“I’m very excited about it,” Dr. Riedell said, noting that these are patients without a lot of treatment options.

The panel also discussed other studies from ASH, including an analysis of tumor tissue samples from patients in the ZUMA-1 trial who had responded and subsequently relapsed (Abstract 203); a multicenter prospective analysis of circulating tumor DNA in diffuse large B-cell lymphoma patients who had relapsed after treatment with axicabtagene ciloleucel (Abstract 884); and the early use of corticosteroids to prevent toxicities in patients in cohort 4 of the ZUMA-1 trial (Abstract 243).

Dr. Hill reported consulting with Juno/Celgene/BMS and Novartis and research and consulting for Kite/Gilead. Dr. Locke reported consulting for Cellular Biomedicine Group and being a scientific adviser to Kite/Gilead, Novartis, Celgene/BMS, GammaDelta Therapeutics, Calibr, and Allogene. Dr. Riedell reported consulting for Bayer and Verastem, consulting for and research funding from Novartis and BMS/Celgene, and consulting for, research funding from, and speaking for Kite.

[email protected]

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Anti-CD5 chimeric antigen receptor (CAR) T cells can produce complete responses (CRs) in patients with relapsed or refractory T-cell malignancies, according to findings from a phase 1 trial.

Jennifer Smith/MDedge News

Three of 11 patients achieved a CR after CAR T-cell therapy, and one patient achieved a mixed response that deepened to a CR after transplant. Three responders, all of whom had T-cell lymphoma, were still alive and in CR at last follow-up.

There were no cases of severe cytokine release syndrome (CRS) or severe neurotoxicity, no serious infectious complications, and no nonhematologic grade 4 adverse events in this trial.

LaQuisa C. Hill, MD, of Baylor College of Medicine, Houston, presented these results at the annual meeting of the American Society of Hematology.

“While CD19 CAR T cells have revolutionized the treatment of relapsed/refractory B-cell malignancies, development of CAR T-cell platforms targeting T-cell-driven malignancies have been hindered by three main factors: CAR T-cell fratricide due to shared expression of target antigens leading to impaired expansion, ablation of normal T cells continuing to cause profound immunodeficiency, and the potential of transduced tumor cells providing a means of tumor escape,” Dr. Hill said.

Researchers have theorized that anti-CD5 CAR T cells can overcome these obstacles. In preclinical studies, anti-CD5 CAR T cells eliminated malignant blasts in vitro and in vivo and resulted in “limited and transient” fratricide (Blood. 2015 Aug 20;126[8]:983-92).

With this in mind, Dr. Hill and her colleagues tested CD5.28z CAR T cells in a phase 1 trial (NCT03081910). Eleven patients have been treated thus far – five with T-cell acute lymphoblastic leukemia (T-ALL), three with peripheral T-cell lymphoma (PTCL), two with angioimmunoblastic T-cell lymphoma (AITL), and one with Sézary syndrome.

The patients’ median age at baseline was 62 years (range, 21-71 years), and 63% were men. They had received a median of 5 prior therapies (range, 3-18). Two patients had relapsed after allogeneic hematopoietic stem cell transplant (HSCT), three had relapsed after autologous HSCT, and five were primary refractory.

Patients underwent lymphodepletion with fludarabine and cyclophosphamide, then received CAR T cells at doses of 1 x 10⁷ or 5 x 10⁷.
 

Response

Three lymphoma patients – two with AITL and one with PTCL – were still alive and in CR at last follow-up. The PTCL patient achieved a CR after CAR T-cell therapy and declined a subsequent HSCT. The patient has not received additional therapy and has retained the CR for 7 months.

One AITL patient achieved a CR and declined transplant as well. He relapsed after 7 months but received subsequent therapy and achieved another CR. The other AITL patient had a mixed response to CAR T-cell therapy but proceeded to allogeneic HSCT and achieved a CR that has lasted 9 months.

The remaining three lymphoma patients – two with PTCL and one with Sézary syndrome – progressed and died.

One T-ALL patient achieved a CR lasting 6 weeks, but the patient died while undergoing transplant workup. Two T-ALL patients did not respond to treatment and died. The remaining two patients progressed, and one of them died. The other patient who progressed is still alive and in CR after receiving subsequent therapy.

Factors associated with response

Dr. Hill said a shortened manufacturing process may be associated with enhanced response, as all responders received CAR T cells produced via a shorter manufacturing process. The shortened process involves freezing cells on day 4-5 post transduction, as opposed to day 7.

“While the numbers are too small to make any definitive conclusions, this seems to correlate with less terminal differentiation, which might improve potency,” Dr. Hill said. “However, additional analyses are ongoing.”

Dr. Hill also pointed out that CAR T-cell expansion was observed in all patients, with higher peak levels observed at the higher dose. In addition, CAR T-cell persistence was durable at both dose levels.

“We have been able to detect the CAR transgene at all follow-up time points, out to 9 months for some patients,” Dr. Hill said. “While limited persistence may play a role in nonresponders, it does not appear to be the only factor.”

Safety

“Surprisingly, no selective ablation of normal T cells has been observed,” Dr. Hill said. “As CAR T cells dwindled [after infusion], we were able to see recovery of normal T cells, all of which expressed normal levels of CD5. This was observed in all patients on study, except for one patient who had prolonged pancytopenia.”

Cytopenias were the most common grade 3/4 adverse events, including neutropenia (n = 8), anemia (n = 7), and thrombocytopenia (n = 5). Other grade 3/4 events included elevated aspartate aminotransferase (n = 2), hypoalbuminemia (n = 1), hyponatremia (n = 1), hypophosphatemia (n = 1), and elevated alanine aminotransferase (n = 1). There were no grade 5 adverse events.

Two patients developed grade 1 CRS, and two had grade 2 CRS. Both patients with grade 2 CRS were treated with tocilizumab, and their symptoms resolved.

One patient developed grade 2 immune effector cell-associated neurotoxicity syndrome, but this resolved with supportive care.

One patient had a central line–associated bloodstream infection (coagulase-negative staphylococci), and one had cytomegalovirus and BK virus reactivation. There were no fungal infections.

“We have demonstrated that CD5 CAR T cells can be manufactured from heavily pretreated patients with T-cell malignancies, and therapy is well tolerated,” Dr. Hill said. “We have seen strong and promising activity in T-cell lymphoma, which we hope to be able to translate to T-ALL as well.”

Dr. Hill said she and her colleagues hope to improve upon these results with a higher dose level of CD5 CAR T cells (1 x 10⁸), which the team plans to start testing soon. The researchers may also investigate other target antigens, such as CD7, as well as the use of donor-derived CAR T cells for patients who have relapsed after allogeneic HSCT.

Dr. Hill said she has no relevant disclosures. Baylor College of Medicine is sponsoring this trial.

[email protected]

SOURCE: Hill L et al. ASH 2019. Abstract 199.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.

Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.

Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.

Study treatment

Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.

Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.

Next, patients received a single CAR T-cell infusion at a dose of 50 x 10⁶ (n = 5), 150 x 10⁶ (n = 3), or 300 x 10⁶ (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.

Safety

“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.

One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.

All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
 

Efficacy

“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”

The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.

The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.

The patient with a CR received the 50 x 10⁶ dose of CAR T cells, and the patients with stringent CRs received the 150 x 10⁶ and 300 x 10⁶ doses.

Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.

Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.

“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”

Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.

This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.

[email protected]

SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.

ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.

Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.

Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.

Study treatment

Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.

Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.

Next, patients received a single CAR T-cell infusion at a dose of 50 x 10⁶ (n = 5), 150 x 10⁶ (n = 3), or 300 x 10⁶ (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.

Safety

“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.

One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.

All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
 

Efficacy

“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”

The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.

The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.

The patient with a CR received the 50 x 10⁶ dose of CAR T cells, and the patients with stringent CRs received the 150 x 10⁶ and 300 x 10⁶ doses.

Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.

Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.

“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”

Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.

This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.

[email protected]

SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.

ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.

Jennifer Smith/MDedge News

The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.

Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.

Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.

Study treatment

Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.

Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.

Next, patients received a single CAR T-cell infusion at a dose of 50 x 10⁶ (n = 5), 150 x 10⁶ (n = 3), or 300 x 10⁶ (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.

Safety

“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.

One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.

All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
 

Efficacy

“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”

The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.

The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.

The patient with a CR received the 50 x 10⁶ dose of CAR T cells, and the patients with stringent CRs received the 150 x 10⁶ and 300 x 10⁶ doses.

Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.

Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.

“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”

Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.

This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.

[email protected]

SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.