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FDA Wants Expert Input on Benefits, Risks of CAR T Therapy in Earlier-Line Multiple Myeloma

FDA sign at its headquarters in Washington D.C.

NEW YORK – Do the progression-free survival benefits of Janssen and Bristol Myers Squibbs' autologous CAR T-cell therapies outweigh the risk they pose to multiple myeloma patients in an earlier-line treatment setting?

The US Food and Drug Administration's Oncologic Drugs Advisory Committee (ODAC) will convene on Friday to debate the risk-benefit profiles of Janssen's Carvykti (ciltacabtagene autoleucel) and BMS's Abecma (idecabtagene vicleucel). Both drugmakers are seeking supplemental FDA approvals for their respective CAR T-cell therapies, which are designed to target the B-cell maturation antigen (BCMA) on the surface of multiple myeloma cells.

Janssen, together with its collaborator Legend Biotech, first netted FDA approval for Carvykti in March 2022. At that time, the FDA approved the treatment for relapsed or refractory multiple myeloma patients who'd previously received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Just weeks after Carvykti's approval, the agency approved Abecma for the same fifth-line indication.

Since 2022, these drugmakers have been pursuing earlier-line approvals.

On Feb. 15, 2023, BMS filed a supplemental biologics licensing application with the FDA seeking Abecma's approval as a third-line multiple myeloma option after an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Then, last June, Janssen filed a supplemental application seeking Carvykti's approval for patients who have received at least one prior therapy comprising a proteasome inhibitor and an immunomodulatory agent and are refractory to BMS's Revlimid (lenalidomide).

Drugmakers have referred to these indications as second- or third-line therapies, since the prior regimens patients typically receive — proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies — are often combined into one regimen. Indeed, as the FDA noted in briefing materials posted ahead of Friday's ODAC meeting, multiple myeloma patients whose cancers relapse following first-line lenalidomide often receive triplet regimens.

Squaring PFS benefit with early deaths

The agency is holding the ODAC meeting to hear the expert panel's views on the risk-benefit profile of these drugs based on the clinical data sponsors have submitted in their supplemental applications.

In BMS's randomized Phase III KarMMa-3 trial, there was a statistically significant median progression-free survival benefit among Abecma-treated patients compared to those on standard of care, but a higher proportion of patients died within the first nine months of receiving the cell therapy than in the comparator arm. Similarly, in Janssen's Phase III CARTITUDE-4 trial, median progression-free survival was statistically significantly better with Carvykti versus standard of care, but patients died early on at higher rates with CAR T-cell therapy than in the comparator arm.

Although both trials met their primary endpoints, the FDA has found it difficult to weigh the overall improvement in median progression-free survival associated with these CAR T-cell therapies against the increased risks of early death after treatment.

"FDA has granted approval to drugs that demonstrate a statistically significant and clinically meaningful effect on progression-free survival in the context of an acceptable risk profile," the FDA wrote in its briefing materials. "Because of the higher rate of early deaths in the [Carvykti] arm, it is unclear whether the overall benefit-risk assessment is favorable; specifically, whether additional data is needed to support such an assessment." The agency expressed the same concern in the Abecma briefing materials. 

Mixed KarMMa-3, CARTITUDE-4 data

In KarMMa-3, the median progression-free survival was 13.3 months for patients who received Abecma and 4.4 months for patients who received standard of care. Although the overall survival analysis wasn't complete when BMS submitted its application to the FDA, the median overall survival for patients who received Abecma was 32.8 months but was not yet reached for patients in the standard-of-care arm.

Within the first nine months following randomization, 45 patients out of 254 treated with Abecma died, whereas 15 out of 132 patients treated with standard of care died. In the first 90 days of treatment, the rate of deaths from adverse events was 2.7 percent among patients who received Abecma and 1.6 percent among patients who received standard regimens. Standard regimens in the KarMMa-3 trial could include a number of FDA-approved doublet and triplet therapies such as Janssen's Darzalex (daratumumab), BMS's Pomalyst (pomalidomide), and dexamethasone; Darzalex, bortezomib, and dexamethasone; BMS's Empliciti (elotuzumab), Pomalyst, and dexamethasone; Takeda's Ninlaro (ixazomib), Revlimid, dexamethasone; or Amgen's Kyprolis (carfilzomib) and dexamethasone.

In CARTITUDE-4, the median progression-free survival for patients on Carvykti was not yet reached at the time of the data cutoff versus 12 months for patients treated with standard of care. The overall survival analysis was not yet complete at the time Janssen submitted its application, but the most current data showed that the median overall survival was not yet reached for patients on Carvykti and was 26.7 months for those on the standard of care.

Within the first 10 months of randomization, though, 29 patients died out of 208 on Carvykti, whereas the same was true of 25 patients out of 211 on standard therapy. Within the first 90 days of treatment, 5 percent of patients on Carvykti died versus none of the patients on standard regimens. In CARTITUDE-4, the standard treatments could include Pomalyst, bortezomib, and dexamethasone; or Darzalex, Pomalyst, and dexamethasone.

In its briefing materials, the FDA flagged subgroup analyses researchers conducted in these trials that, though limited and hypothesis-generating only, could help identify patients at risk for early death and potentially mitigate those risks.

On Friday, the FDA will ask the independent experts on the advisory committee to review these data and vote on whether they find the risk-benefit assessment favorable for these BCMA-directed CAR T-cell therapies for the proposed indications. Though the FDA isn't required to take the advice of its advisory committees, it often does.

Meanwhile, across the Atlantic Ocean, the European Medicine Agency's Committee for Medicinal Products for Human Use (CHMP) last month recommended that regulators approve Carvykti as second-line treatment for relapsed or refractory multiple myeloma in the EU. One month earlier, CHMP also recommended European approval for Abecma in its earlier-line setting.