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The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.
ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.
ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.
The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.
Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.
Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.
The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.
But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.
In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.
However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.
ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.
Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.
In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.
“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.
But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.
With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.
In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.
In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.
“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
Describing Risks to Patients
ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.
In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.
In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.
In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.
In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.
ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.
“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.
“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”
ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.
He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.
“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”
The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.
ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.
ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.
The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.
Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.
Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.
The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.
But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.
In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.
However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.
ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.
Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.
In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.
“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.
But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.
With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.
In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.
In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.
“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
Describing Risks to Patients
ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.
In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.
In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.
In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.
In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.
ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.
“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.
“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”
ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.
He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.
“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”
The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.
ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.
ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.
The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.
Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.
Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.
The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.
But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.
In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.
However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.
ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.
Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.
In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.
“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.
But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.
With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.
In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.
In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.
“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
Describing Risks to Patients
ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.
In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.
In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.
In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.
In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.
ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.
“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.
“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”
ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.
He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.
“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”