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FDA Adcomm to Tackle Complexity of CAR-T for Multiple Myeloma
Mar. 12 2024

Pictured: Concept of FDA meeting collage/Nicole Bean for BioSpace

On March 15, the FDA’s Oncologic Drugs Advisory Committee will meet to discuss two CAR T cell therapies for multiple myeloma—Abecma, from Bristol Myers Squibb and 2seventy bio, and Carvykti, from Johnson & Johnson and Legend Biotech. Both treatments are currently approved for the treatment of adults with relapsed/refractory multiple myeloma (RRMM) after four or more prior lines of therapy, and their makers are seeking to move them into earlier lines of treatment.

As CAR-T therapies have recently come under FDA scrutiny over safety issues, Friday’s meeting is significant, Jack Allen, a senior research analyst with Baird, told BioSpace. “At a high level, this will be an interesting meeting for the CAR-T field as the industry looks to understand how the FDA is thinking about moving these treatments into earlier-line settings,” he said. “I expect many who follow this space to be looking to the FDA’s ‘body language’ here and any read-throughs it may have as it relates to a path forward for broader use of this innovative modality both in oncology settings and beyond.” CAR-T therapy for autoimmune indications has recently been topic of interest as well.  

The morning of the 15th will be devoted to discussing J&J’s CARTITUDE-4 study of Carvykti in lenalidomide-refractory multiple myeloma, while the afternoon will focus on the KarMMa-3 study of Abecma in RRMM. Experts told BioSpace they are optimistic the therapies will gain these additional approvals.

Rahul Banerjee, a physician-researcher specializing in multiple myeloma at the Fred Hutchinson Cancer Center in Seattle, Wash., noted that both Abecma and Carvykti could be poised for approval as earlier lines of treatment in Europe as well. In January, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended greenlighting Abecma for RRMM after at least two prior therapies. A similar CHMP recommendation followed in February for Carvykti, with the committee supporting approval in RRMM after one previous line of treatment.

“I hope the FDA will view the benefits of earlier treatment similarly,” Banerjee told BioSpace.  

A representative for BMS was also optimistic. “During the upcoming ODAC meeting, we look forward to reinforcing the potential of Abecma to deliver significantly improved outcomes for patients in earlier lines of treatment,” the spokesperson wrote in an email to BioSpace. “We remain confident in the safety profile and clinical value of our cell therapies.”

Overall Survival Isn’t Everything
In November 2023, the agency delayed approval of Abecma for earlier treatment and announced an upcoming advisory committee meeting. That same month, the FDA revealed that CAR-T therapies were under review after several reports of secondary blood cancers in treated patients, and in January, the agency added a class warning to all six currently approved CAR-T therapies.

The FDA’s announcement of the upcoming adcomm for Abecma and Carvykti noted that the survival benefits of both therapies will be reviewed. This was confirmed in a February press release from BMS and 2seventy bio, which stated that the companies “anticipate that the ODAC will review data related to the secondary endpoint of overall survival” from the KarMMa-3 study.

At first glance, the survival benefit data in KarMMa-3 can be confusing. Abecma met its primary endpoint, with a statistically significant improvement in progression-free survival (PFS) compared to standard treatment, impacting both disease progression and death. It also met a secondary endpoint, slashing patients’ risk of death by 31% in comparison to individuals receiving standard of care.

However, this was a modified crossover trial. More than half of the patients in the control standard-of-care arm were switched to Abecma after their cancers progressed. Data from the KarMMa-3 study presented at the December 2023 American Society of Hematology Annual Meeting and Exposition showed that if the two groups were compared without a statistical adjustment accounting for that change, there was no significant improvement in overall survival.

Banerjee explained that allowing patients to cross over to CAR-T if they have failed standard therapy is fairly typical and also humane. “You can do a study where the moment a patient in the control group experiences any progression, they go straight to CAR-T,” he explained. “That is a statistician’s dream and a perfect study, but it’s not only expensive, it’s tricky because some patients might not have access to CAR-T.” The other extreme, he said, is to forbid any crossover so that patients in the study can never receive CAR-T in their lifetime. “That’s not ethical,” Banerjee said. Most studies leave the decision to move to CAR-T up to the physician based on progression or toxicity of other drugs.  

But he added that survival benefit is not the most important measure of the CAR-T success. While patients may not necessarily live longer, “what we do see is that [they] get a substantial benefit, remission and better quality of life across the board.” Banerjee pointed to the concept of time toxicity in myeloma, where patients in the control arm receiving standard-of-care treatment need to travel to and spend time in the clinic repeatedly in order to receive treatment. “With CAR-T, there’s a one-time infusion and patients are in remission, and by those metrics, CAR-T is a runaway success,” he said.

Gurbakhash Kaur, an oncologist at UT Southwestern Medical Center in Dallas, agreed. “We generally try to give three drugs and patients stay on that for a long time,” she told BioSpace. “They never really get a treatment holiday or a break from therapy.” With CAR-T, following an upfront time investment, patients can be treatment-free “and enjoy a good quality of life,” she said. “We also think the immune system will be less exhausted if they receive CAR-T earlier when T cell responses are more robust.”

Reassessing the Lines of Therapy Concept
J&J and Legend Biotech are basing their supplemental Biologics License Application (sBLA) on the results of the CARTITUDE-4 trial, where treatment with Carvykti led to a 74% reduction in disease progression or death in patients who had received at least one previous line of therapy with an immunomodulatory agent or a proteasome inhibitor. The trial also tested Carvykti in patients refractory to Revlimid, a first-line immunomodulatory treatment for multiple myeloma.

But according to Banerjee, when it comes to CAR-T therapy, the lines of therapy concept may be outdated. Whether or not the approach makes sense is a topic of conversation at meetings and conferences, he said, noting that a line of therapy can be different from a treatment regimen. For example, “if the dose of a medication is lowered, it is not considered a new line,” he explained. “It’s a little bit arbitrary.”

In the KarMMa-3 trial, some patients were triple-class refractory, meaning “the therapies simply failed the patient.” Banerjee added that the first relapse is significant, but that CAR-T prognosis depends more on what therapies patients failed and how long they had worked for than the total number of treatments they had.

Even if earlier treatment is approved, it will not be available to everybody, Kaur noted. “Access remains a big issue. . . . [G]iving CAR-T requires a lot of collaboration, and not all transplant centers can deliver it.” Nonetheless, she is hopeful that moving therapies like Abecma and Carvykti to an earlier line of treatment will allow more patients to access them.

Jill Neimark is a freelance science writer based in Macon, Georgia.

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