FDA panel supports earlier use of two CAR-Ts for multiple myeloma
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Key takeaways:
- The panel said two CAR T-cell therapies would ultimately benefit patients with multiple myeloma if they could be taken earlier in treatment.
- Bridging therapy served as a concern when discussing early mortality.
An FDA advisory committee voted that a pair of chimeric antigen receptor T-cell therapies should be approved for earlier line treatments in adults with relapsed or refractory multiple myeloma, although one produced far more deliberation.
The committee determined the PFS benefits of ciltacabtagene autoleucel (Carvykti; Janssen, Legend Biotech) and idecabtagene vicleucel (Abecma, Bristol Myers Squibb) both outweigh data regarding risks for early death in treatment.
The panel voted unanimously to recommend earlier use of ciltacabtagene autoleucel, also called cilta-cel, and 8-3 to advise for earlier-line treatment with idecabtagene vicleucel, also called ide-cel.
Cilta-cel and ide-cel, both B-cell maturation antigen (BCMA)-directed CAR T-cell therapies, had been previously approved for use after at least four other lines of treatment, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody.
“The old adage is, ‘Is the run worth the slide?’” Christopher H. Lieu, MD, co-director of gastrointestinal medical oncology at University of Colorado, said while explaining his yes vote on cilta-cel.
“The run here is not trivial. We’re talking about potential increased risk for death in the early months,” he added. “If there’s only a minimal improvement of PFS, the answer here is always no. It’s too short of a slide.”
If CAR-T can potentially provide durable responses while sparing patients further toxic therapies, then the risk tolerance is greater, Lieu said. “I honestly believe the answer will likely be yes for patients who may want just a chance at a longer time off treatment for multiple myeloma,” he added. “Therefore, I believe the benefit risk profile is favorable.”
Lieu also voted yes on ide-cel, but he had concerns as well.
“I struggled with this decision given what I feel are data that are concerning for two reasons — a prolonged trend toward overall survival detriment in that 15 months as well as a lack of durable PFS tail, suggesting a response that’s not quite as durable as one might hope given what we’re asking our patients to go through,” he said.
“Patients have to be aware of the risk associated with the treatment in the early months, whether it’s related to [idecabtagene vicleucel] or just the risk burden that patients are going to carry with them during a bridging period, which is still part of this overall treatment paradigm,” Lieu continued. “Having said that, the PFS difference is prolonged, is significant and offers our patients a chance of significant time off therapy with associated quality-of-life improvement. I do believe that the risk benefit profile is favorable for this population as a whole, but it’s a closer margin than I think we would like.”
Janssen and Legend Biotech are seeking approval to use cilta-cel after one prior line of treatment among adults who previously received a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.
Bristol Myers Squibb seeks approval of ide-cel after an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) convened to discuss whether both treatments had a favorable risk-benefit assessment.
“The opportunity for off-treatment time is incredibly compelling for patients and families,” Susan Lattimore, RN, GCPH, associate director of the hemostasis and thrombosis center at Oregon Health and Science University, said about cilta-cel. She expressed a similar sentiment after voting yes on ide-cel.
“Certainly, improving access to this treatment will improve overall outcomes for all individuals,” Lattimore said.
Myeloma background and current treatment
Multiple myeloma is the second most common hematologic malignancy in the U.S., with 35,730 new diagnoses and 12,590 deaths in 2023, according to background information provided by the FDA. The 5-year survival rate is roughly 50% and the median age of diagnosis is 69 years.
Nearly 160,000 individuals are living with multiple myeloma or are in remission, according to a presentation from Sham Mailankody, MBBS, clinical director of the cellular therapy service and research director of the myeloma service at Memorial Sloan Kettering Cancer Center.
For transplant-eligible patients, front-line treatment for multiple myeloma begins with induction therapy, which works best with three drugs over two, followed by autologous transplant consolidation and maintenance. Transplant ineligible patients start with initial therapy and are followed by maintenance treatment.
The median PFS for first-line therapy is between 4 and 7 years; however, attrition occurs in the number of individuals who receive subsequent treatments. Only 8% of nontransplant patients and 22% of transplant patients get fifth-line therapy, where the CAR-T treatments have been approved to begin. Possible reasons include adverse events, access to therapies, and death, Mailankody said.
The FDA approved cilta-cel for its current use in February 2022 based on results from the CARTITUDE-1 trial.
In CARTITUDE-4, the trial arm did not reach a median PFS, while the standard care arm had a PFS of 12 months. However, 11% of patients on cilta-cel died compared with 8% in the standard care arm. Additionally, cilta-cel had a higher mortality rate in the first 10 months after randomization compared with standard care (14% vs. 12%).
The FDA made ide-cel the first approved CAR-T for multiple myeloma in March 2021 based on results from the KarMMA study.
In the KarMMA 3 study, the treatment arm had a median PFS of 13.3 months compared with 4.4 months in the standard care arm, but more deaths in the first 9 months occurred among patients who received ide-cel (18% vs. 11%).
Unanimous recommendation of cilta-cel
During discussion for cilta-cel, panelists noted several early deaths had occurred in patients who had not received the treatment.
Mailankody explained during his presentation that the logistics of CAR T cells are “unique.”
The initial screening takes 2-4 weeks, then another few days to go from apheresis to bridging, and then another 4-8 weeks to get to CAR-T infusion.
The delay to treatment, which also included delays in the clinical trial process, the effect of bridging as well as COVID-19 during the trial, all could have played a factor in early deaths.
“When I look at the study, it’s really the maintenance of the patients during bridging that is critically important and maybe something that requires more transparency and education,” Tara Frenkl, MD, MPH, head of oncology development at Bayer Pharmaceuticals, said. “We need to allow the physician and patient to decide what’s best for them based on the heterogeneity of the population and also the emerging treatment landscape.”
The panelists also highlighted oral presenters — doctors and patients — who noted how difficult it can be to reach fifth-line treatment after previous regimens take a toll on the individual. They also noted the impact CAR-T had on a patient getting away from a rigorous treatment schedule and improved quality of life.
“I also recognize the importance of a one-and-done treatment,” Mary Kwok, MD, associate professor at University of Washington, said. “I see patients who come to us from outlying states where they might not have access to clinical trials or more intensive myeloma therapies. To be able to give a one-time treatment without requiring them to come back and forth is a really important treatment option.”
Debate on ide-cel
Although ide-cel ultimately received a comfortable majority recommendation, several yes voters described being torn on the decision.
The issues with bridging therapies continued during the discussion of ide-cel.
However, the data itself also stirred debate, particularly the crossover aspect of the trial, where patients could switch over to ide-cel from standard care. Some panelists believed the two treatment arms did not separate enough and patients do not receive enough benefit to incur the risks.
“Our goal is to help patients experience life better, either quality or quantity of life,” Daniel Spratt, MD, chair of the department of radiation oncology at University Hospitals Seidman Cancer Center Case Western Reserve University, said while his explaining his no vote. “The benefit is clearly PFS is improved. What are the risks right now? The risks are, PFS at the data we have now appears transient and there’s no clear benefit that earlier is better than later. Those that do progress and cross over had favorable OS ... so there’s not a clear benefit of earlier intervention.”
Ultimately, the majority of ODAC members determined the improved PFS of ide-cel should be the deciding factor.
“Even though we have votes for yes and no, there is some agreement on the panel that PFS data here is very encouraging and great for patients, and that the bridging regimen really needs to be optimized” Ravi A. Madan, MD, ODAC chairperson and head of the prostate cancer clinical research section of the Genitourinary Malignancies Branch at NCI’s Center for Cancer Research, said while summarizing the vote.
Madan voted no on recommending ide-cel for earlier use.
“For those people who had concerns and voted no, it was more from a lack of later outcomes, whether it was survival despite the crossover or lack of plateau,” he said. "But that was less of a concern for the people who voted yes who felt that the time off of therapy was valuable and that perhaps in the time down the road, all the bridging issues would be worked out.”
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