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Experts Back FDA Approval of Janssen and BMS CAR T-Cell Therapies in Early-Line Multiple Myeloma


NEW YORK – Advisers to the US Food and Drug Administration on Friday voted in favor of the agency approving two CAR T-cell therapies, Janssen's Carvykti (ciltacabtagene autoleucel) and Bristol Myers Squibb's Abecma (idecabtagene vicleucel), in early-line multiple myeloma, but still stressed the need for additional research clarifying the treatments' overall survival benefit and the best approach to bridging therapy regimens in multiple myeloma.

In an all-day meeting Friday, the FDA's Oncologic Drugs Advisory Committee discussed whether the progression-free survival benefits seen with Carvykti and Abecma in two randomized trials, Janssen's CARTITUDE-4 and BMS's KarMMa-3, were significant enough to warrant approving them as second- and third-line treatments for multiple myeloma, even though both studies showed an increased risk of early death among patients on the cell therapies versus those on the standard-of-care treatment arms.

For Janssen's Carvykti, ODAC members voted unanimously — 11 to 0 — in favor of approving it, and for BMS's Abecma, the votes were slightly more divided — 8 to 3 — though still in favor of approving the cell therapy.

The FDA isn't required to follow its committee members' recommendations, though it usually does.

Parsing causes of early deaths in CARTITUDE-4

The FDA first approved Janssen and Legend Biotech's B-cell maturation antigen (BCMA)-directed CAR T-cell therapy in 2022 for relapsed or refractory multiple myeloma patients after at least four prior treatments, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Now, Janssen is hoping to score approval for Carvykti in relapsed or refractory multiple myeloma patients who've received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and who are refractory to BMS's Revlimid (lenalidomide).

During the ODAC's discussion on Friday morning, experts reviewed data from Janssen's Phase III CARTITUDE-4 trial in which patients who received Carvykti experienced a statistically significant improvement in progression-free survival compared to those who received either BMS's Pomalyst (pomalidomide) plus bortezomib and dexamethasone or Janssen's Darzalex (daratumumab) plus Pomalyst and dexamethasone.

In CARTITUDE-4, the median progression-free survival was not yet reached at the time of the data cutoff for patients who received Carvykti and was 11.8 months for those who received the standard-of-care regimens. The overall survival analysis also wasn't mature at the time of the data cutoff, but after two years, 79 patients on the Carvykti arm were still alive, versus 66 percent of patients on the control arm.

However, FDA reviewers also noted an increased risk of death within the first 10 months of patients receiving Carvykti and convened the ODAC to gather experts' views on how to interpret the risk-benefit profile of the cell therapy in light of this data. In this early period in the trial, 14 percent of patients who received Carvykti died, versus 12 percent on the standard of care.

Because these early Carvykti deaths were the FDA's chief concern, presenters, advisers, and reviewers on Friday spent considerable time homing in on their specific timing and causes. Helkha Peredo-Pinto, a clinical reviewer in the malignant hematology branch at the agency's Center for Biologics Evaluation and Research (CBER), noted in a presentation of the data that 4.8 percent of patients on the Carvykti arm died due to their cancers progressing before they had actually had a chance to receive the CAR T-cell therapy. Meanwhile, 9.1 percent of patients on the Carvykti arm died after their CAR T-cell therapy infusions. Further narrowing down that data, 1.4 percent of patients who died on the Carvykti arm died of progressive disease after their infusions, and 7.7 percent died of adverse events after their infusions.

In the standard-of-care arm, meanwhile, just 0.5 percent of patients died before they received their treatment regimen, whereas 11.3 percent died within 10 months of receiving their standard therapy. In the control arm, 7.1 percent of patients died early due to progressive disease, and 4.2 percent died from adverse events.

Throughout the presentations and ensuing discussions, ODAC members raised questions as to whether the type and duration of bridging therapy allowed in the CARTITUDE-4 trial contributed to these early deaths. Indeed, patients randomized to the Carvykti arm received at least a cycle of one of the same treatments included in the standard-of-care arm. When ODAC members voted on whether the FDA should approve Carvykti in this early-line setting, almost all of them stressed the need for better bridging therapy strategies.

"While the risk of early death, often prior to therapy, is not ignored in this discussion or this vote, it does seem to be outweighed by potential benefits here," said Ravi Madan, chair of the ODAC and a senior clinician at the National Cancer Institute. "Ideally, emphasis in the further development of this therapy could be placed in understanding how to better optimize bridging therapy."

"I remain unconvinced that the upfront risk is directly attributable to the therapy itself," echoed William Gradishar, an ODAC member and oncologist at Northwestern Feinberg School of Medicine. "There are other factors that are likely contributing rather than the therapy in question."

In addition to discussing the potential cause of early deaths, ODAC members as well as patients who shared their experience on Carvykti stressed that they felt the cell therapy's benefit went beyond what the study data could show. Because Carvykti is a one-time infusion and results in long-lasting responses for many patients, they get to spend that time "off treatment." Patients consider this time invaluable, even if their cancers ultimately recur. With other types of therapies, patients often receive consecutive doses over long periods of time.

"The opportunity for off-treatment time is incredibly compelling for patients and families," said Susan Lattimore, an oncology research nurse at Oregon Health & Science University. "Improving access to this treatment will improve overall outcomes for all individuals."

Now that the ODAC has voted, the FDA is expected to decide by April 5 if it will act in accordance with its advisers and approve Carvykti in the earlier-line multiple myeloma treatment setting.

Abecma Risk-Benefit Discussion

After the morning session focusing on the Carvykti application, ODAC members shifted their attention to BMS's BCMA-directed CAR T-cell therapy Abecma.

In 2022, the FDA approved Abecma for patients with relapsed or refractory multiple myeloma who'd previously received at least four lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Now, BMS, together with its collaborator 2seventy Bio, is seeking FDA approval for Abecma for treating patients who have received at least two prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

BMS's application contains data from the randomized, Phase III KarMMa-3 trial in which the CAR T-cell therapy led to a statistically significant improvement in progression-free survival versus standard of care. Patients randomized to receive Abecma lived for a median of 13.3 months without their cancers progressing, versus 4.4 months for those on a standard regimen. Standard treatments could include Darzalex, Pomalyst, and dexamethasone; Darzalex, bortezomib, and dexamethasone; BMS's Empliciti (elotuzumab), Pomalyst, and dexamethasone; Takeda's Ninlaro (ixazomib), Revlimid, and dexamethasone; or Amgen's Kyprolis (carfilzomib) plus dexamethasone.

Abecma did not significantly improve overall survival as of the most recent analysis from KarMMa-3. Patients on the cell therapy lived for a median of 41.4 months, versus 37.9 months in the comparator arm. However, at the ODAC meeting, Eric Bleickardt, who heads up late-stage clinical development of cell therapies at BMS, attributed the overall survival outcomes in KarMMa-3 to its crossover design, which allowed patients in the control arm to receive Abecma upon disease progression. More than half of the patients crossed over from the control arm, making Abecma's overall survival benefit relative to standard treatments challenging for FDA reviewers and ODAC members to interpret.

Additionally, similar to the concerns raised for Carvykti, FDA reviewers sought committee members' input on the increased risk of early deaths in KarMMa-3. Within the first nine months of randomization, 45 out of 254 patients in the Abecma arm died, versus 15 out of 132 patients in the control arm.

Here, again, advisers turned to the allowance of bridging therapy in KarMMa-3 as a potential explanation for these early deaths. Within six months, "more than half the patients who died early … never crossed the bridge to receive ide-cel," Bleickardt said. "This is not a direct ide-cel-related mortality; it is [attributable to] patients who did not receive ide-cel."

In contrast to the unanimous support among committee members for the approval of Carvykti, several experts weren't convinced that the benefits of earlier-line Abecma outweighed its risks when it came time to vote whether the agency should approve this cell therapy.

"I know there's a lot of optimism about moving these therapies earlier in the disease states for multiple myeloma, but for me, these data at this level of maturity really didn't provide convincing evidence that ide-cel earlier had a favorable risk-benefit assessment in the proposed indication," said Madan, who was among the three ODAC members who voted "no" to the question about Abecma's approval. "It seems like the bridging therapy strategies really need to be optimized further, [and] while the [progression-free survival] is quite remarkable, the ultimate readouts of similar overall survival question whether earlier is truly better in this setting."

Those who voted in favor of Abecma, including Ranjana Advani, an oncologist at Stanford Medicine, shared these same concerns but still supported approving the agent. "We have problems with bridging. … We don't know what the ideal bridging is across almost any indication, [but] once it's available, physicians know how to manipulate bridging better than when it's on a trial where you get restricted to one versus the other," Advani said. "And we do know that early deaths were related to patients who had rapidly progressive disease and did not get the product."

With Abecma, committee members also pointed out that it can give patients prolonged time off treatment that is so important to patients and their families. "Even if the overall outcomes are similar to standard-of-care treatment, this opportunity for people to have the time off treatment … certainly has a higher benefit in my mind," Lattimore said, adding that "a really transparent disclosure" of the risk-benefit with patients and families is ultimately important.

The FDA was originally expected to decide on BMS's application for Abecma in earlier-line multiple myeloma by Dec. 16 but didn't meet that deadline, choosing to take the KarMMa-3 data before the ODAC. BMS hasn't announced a new FDA decision date for this Abecma application.