ODAC Meeting: Cilta-Cel Gets Unanimous Vote, Ide-Cel Wins Majority Vote for Benefit-Risk Profile

The FDA’s Oncologic Drugs Advisory Committee (ODAC) Meeting has unanimously voted (11 yes, 0 no, 0 abstain) in favor of ciltacabtagene autoleucel's (cilta-cel; Janssen, Legend Biotech) benefit-risk profile for patients with relapsed and lenalidomide-refractory multiple myeloma (MM) after at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent.¹

ODAC also voted in favor of idecabtagene vicleucel's (ide-cel; Bristol Myers Squibb, 2seventybio) sBLA for patients with triple-class exposed relapsed or refractory (r/r) MM, with 8 yes votes, 3 no votes, and 0 abstains.

"I felt that the lack of the tail of the curve for PFS and the lack of effects on OS outweighed the benefits and led me to conclude that it is not better to get ide-cel now versus later," Neil Vasan, MD, PhD, Assistant Professor of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University, said about his "no" vote on ide-cel.

Cilta-cel is currently FDA-approved under the name Carvykti for the treatment of adult patients with relapsed or refractory MM, after 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and a supplemental biologics application (sBLA) is seeking the expansion to the earlier line of therapy.² The Prescription Drug User Fee Act (PDUFA) date is scheduled for April 5, 2024.³

Ide-cel is currently FDA-approved under the name Abecma for the treatment of patients with r/r MM after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. An sBLA is seeking the expanded indication with a PDUFA date originally scheduled for December 16, 2023, that has been pushed back to an as yet unspecified later date.⁴

Discussion questions were the same for each therapy and included, 1; Discuss whether the results of CARTITUDE-4/KarMMA-3 are sufficient to support a positive risk-benefit assessment of cilta-cel/ide-cel for the proposed indication, and 2; Is the risk of early death associated with cilta-cel/ide-cel treatment acceptable in the context of the PFS benefit?

"I feel strongly that it is important to improve Carvykti sooner instead of later, waiting for patients to receive 5,6, 7 lines of therapy...this is the longest i have been in remission since being diagnosed... because of Carvykti," Deb Holstein, retired oncology nurse who received cilta-cel after 7 lines of treatment, said during the open public hearing. "It's given me a normal life again. i know there is a day in the future when myeloma may come back, but today is not that day, and has not been for over 2 years."

The FDA’s concerns around cilta-cel revolved around overall survival (OS), as there was an increased rate of early deaths in patients treated with cilta-cel compared with standard of care which appears to be inherent to autologous car t therapy. It acknowledged that the increased hazard rate upfront is similar to that seen with other treatments including HCT, but since data are immature, cannot yet definitively say that survival will overall be better with cilta-cel. It also said that part of the concern was that the early deaths seen are due to causes not fully understood.

The sponsor rebutted by providing a restricted mean survival time analysis on PFS which showed a difference of 4.7 months (95% CI, 3.1-6.1) and a difference of 2.3 months (95% CI, 0.1-4.5), and stated that early deaths are due to disease progression before cilta-cel, covid-19, and cilta-cel as subsequent therapy.

"Bringing Carvykti early on is an important consideration... one, it's an effective therapy; sometimes it takes a lot of creativity getting to 4 therapies. I also recognize the importance of a one and done treatment," Mary Kwok, MD, Clinical Associate Professor, Division of Hematology and Oncology, Fred Hutch Cancer Center, University of Washington School of Medicine, said.

FDA’s concern’s turned out to go beyond cilta-cel and were related to the whole CAR-T pathway, in which patients may die or progress while awaiting manufacturing of CAR-T. Janssen noted that bridging therapy is more effective now than it was during the pivotal CARTITUDE-4 trial (NCT04181827).

"We expect the problem of delays to go down. we heard some comments from the FDA that you can't analyze the survival curves... but those curves are pretty wide. they don't look like they'll cross again, so i really think that this is a case of front-loaded risk. i think that as long as the patients understand the magnitude of the front-loaded risk, that these risks are acceptable," Jorge Nieva, MD, associate professor, clinical medicine, Keck School of Medicine, University of Southern California, said.

Concerns were largely the same during the later discussion on ide-cel, with a statistically significant PFS benefit but OS detriment for the first 15 months after treatment. OS curves with ide-cel have not shown quite as much of a benefit compared with standard of care as they did with cilta-cel. Unlike with cilta-cel, a prominent topic of discussion was how the crossover between cohorts may have affected the early death risk.

"Bridging therapy is problematic, we see that now across a couple of studies. Whether its related to the drug or not, it almost doesn't matter. It's part of the treatment regimen, patients are accruing this risk, whether it's due to the treatment itself or the bridging therapy," ODAC member Christopher Lieu, MD, Associate Professor, Medical Oncology, Anschutz School of Medicine, Colorado University, said during the ide-cel discussion questions. "These are wide curves but they come together at the end and maybe it's not as durable as some may hope."

Notably, there was disagreement between ODAC members on the degree of separation between the curves at the end of the interim analyses, with some noting that they were "uninterpretable".

The most recent data from CARTITUDE-4 were presented by Binod Dhakal, MD, associate professor, Medical College of Wisconsin, at the American Society of Clinical Oncology (ASCO) 2023 Annual Meeting, held June 2-6, in Chicago, Illinois.⁴

The data demonstrated that cilta-cel yielded higher rates of progression-free survival (PFS) compared with SOC in patients with MM. Patients in the cilta-cel arm had a 12-month PFS rate of 76% compared with 49% in the SOC arm. In the intent-to-treat population, cilta-cel yielded an 84.6% overall response rate compared with 67.3% with SOC and an 84.7% (95% CI, 78.1-89.4) 12-month duration of response (DOR) rate compared with a 63.0% DOR rate.⁴

The ODAC meeting calls attention to the FDA’s recent request that black box warnings related to secondary cancer risks be added to all 6 of the CAR-T therapy products, including cilta-cel and ide-cel, currently approved by the agency for use in the United States. According to the FDA’s January 19, 2024, letter, the text of the boxed warning to be added to cilta-cel specifically reads: “T-cell malignancies have occurred following treatment with BCMA- and CD19- directed genetically modified autologous T-cell immunotherapies, including [product name]."

REFERENCES

1. March 15, 2024: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. News release. FDA. March 15, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/march-15-2024-meeting-oncologic-drugs-advisory-committee-meeting-announcement-03152024
2. Legend Biotech announces submission of supplemental application to the U.S. FDA for expanded use of CARVYKTI® (ciltacabtagene autoleucel). News release. Legend Biotech. June 6, 2023. https://www.businesswire.com/news/home/20230606005760/en/Legend-Biotech-Announces-Submission-of-Supplemental-Application-to-the-U.S.-FDA-for-Expanded-Use-of-CARVYKTI%C2%AE-ciltacabtagene-autoleucel
3. Second Quarter 2023 Financial Results & Corporate Update. Presentation. Legend Biotech. August 15, 2023. https://investors.legendbiotech.com/static-files/5b7311b2-8681-4b76-bbec-2c9c5fc3b81e
4. Bristol Myers Squibb and 2seventy bio Provide Update on U.S. FDA Review of sBLA for Abecma (idecabtagene vicleucel) in Earlier Lines of Therapy for Triple-Class Exposed Relapsed or Refractory Multiple Myeloma. News release. 2seventy bio, Inc. November 20, 2023. Accessed November 20, 2023. https://ir.2seventybio.com/news-releases/news-release-details/bristol-myers-squibb-and-2seventy-bio-provide-update-us-fda
4. Hillengass J, Cohen AD, Agha ME, et al. The phase 2 CARTITUDE-2 trial: updated efficacy and safety of ciltacabtagene autoleucel in patients with multiple myeloma and 1–3 prior lines of therapy (cohort A) and with early relapse after first line treatment (cohort B). Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas. Abstract #42