FDA Adcomm Backs J&J’s Carvykti, BMS’s Abecma Early in Multiple Myeloma

2024-03-15

免疫疗法上市批准细胞疗法临床研究

Pictured: FDA sign at the agency's headquarters/iStock, JHVEPhoto The risks of early death in the trials of Johnson & Johnson and Legend Biotech’s Carvykti and Bristol Myers Squibb and 2seventyBio’s Abcema were not a significant concern for the FDA’s Oncologic Drugs Advisory Committee, which voted 11-0 and 8-3 respectively Friday afternoon to support the approvals of the CAR-T therapies as earlier lines of treatment for multiple myeloma. The advisory committee meeting focused on the higher rate of early deaths for Carvykti in its trial. In its briefing document, the FDA noted that the Cartitude-4 trial showed an “early detriment” in the overall survival treatment arm and an increased rate of early death in the Kapan-Meier curves. But the members of the adcomm voted unanimously that the risks did not outweigh the benefits of the treatment—specifically, the improved progression-free survival (PFS) documented in Carvykti’s Cartitude-4 trial. “I felt that the long-term PFS was compelling, the survival is going in that direction. Furthermore, the upfront risk, I remain unconvinced that that’s directly attributable to the therapy itself,” William Gradishar, chief of hematology/oncology at the Robert H. Lurie Comprehensive Cancer Center, said in his vote. “The totality of the data is what motivated me to go yes.” Neil Vasan, an assistant professor at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, said during the meeting that his vote came down to acknowledging the “very real but small risks” of early deaths relative to the large benefits of the therapy. “We are pleased with the advisory committee's support for Carvykti in earlier lines of treatment based on the Cartitude-4 data," Jordan Schecter, vice president and disease area leader for multiple myeloma at J&J, said in a statement. “As a physician and researcher committed to advancing patient care, I believe the potential of Carvykti in earlier lines of therapy represents an important therapeutic option for patients with multiple myeloma.” The FDA briefing document on Abecma's KarMMA-3 trial also noted that there was a higher rate of early deaths in the treatment arm. The document also said that the subgroup analyses did not “adequately characterize” a heterogeneous patient population. For BMS and 2seventy Bio’s Abecma, the adcomm voted in favor 8-3. Several adcomm members expressed some concerns with the data and issues with early deaths, though they saw a benefit in the PFS data. Gradishar said that the “bridging therapy” is “problematic” and that the survival curves were a bit “uninterpretable,” but was still bullishness on the therapy. While Christopher Lieu, the director of the gastrointestinal medical oncology program at the University of Colorado, did vote in the affirmative, he said he struggled with his decision as there were two aspects of the data that were concerning mainly with the trend toward overall survival and a response that may not be as durable. “But having said that, the PFS difference is prolonged; it's significant and offers our patients a chance of significant time off therapy with associated quality of life improvement,” Lieu said. “And given this, I do believe that the risk-benefit pro favorable for this population as a whole, 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 positive benefits with their provider.” Ravi Madan, the chairperson on the adcomm and head of the prostate cancer clinical research section at the National Cancer Institute Cancer Institute, voted no, stating that while there is optimism around these types of treatments, the data at this level of maturity did not provide “convincing evidence.” “While the PFS is quite remarkable, the ultimate readouts of similar overall survival again question whether earlier is truly better in this setting,” Madan said. BMS has been positive on the label extension for the CAR-T therapy and stands by the trial results. “We really feel strongly and confident in the KarMMa-3 dataset. We met both our primary and key secondary ORR endpoint with highly statistically significant clinically meaningful outcomes that was consistent across all the pre specified subgroups,” Rosanna Ricafort, vice president and head of late development hematology and cell therapy at BMS, said earlier this week. “The overall survival data is confounded by the patient-centric design that we employed, which allowed crossover.” Both companies are similarly seeking label expansions as earlier lines of treatment in multiple myeloma. Carvykti and Abecma are already approved for the treatment of adults with relapsed/refractory multiple myeloma after four or more prior lines of therapy. The agency has been launching probes since last year, noting a risk of secondary malignancies from patients receiving CAR-T cell treatment with CD19- or BCMA-directed autologous immunotherapies, and in January, the agency attached boxed warnings to CAR-T therapies, including Carvykti and Abecma. But while the regulators were taking CAR-T to task, oncologists remained bullish on the therapies, noting that the treatment can be lifesaving. David Porter, director of Cell Therapy and Transplantation at Penn Medicine’s Abramson Cancer Center Cancer Center, previously told BioSpace that moving CAR-T therapies into earlier lines of treatment makes a lot of sense. “Historically, in any cancer treatment, earlier therapies always seem to work better than later lines of therapy,” Porter said. “The T cells that are collected from patients have been less exposed to a lot of toxic therapy over time, and they may be healthier and make better CAR T cell products.” Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.