Janssen and Legend Biotech’s Carvykti to be Put in Front of FDA AdComm Regarding Multiple Myeloma Expanded Use BLA

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The European Medicines Agency Committee for Advanced Therapies will likewise hold a SAG-O meeting regarding the Type II variation application for the CAR-T in the EU.

Janssen’s and Legend Biotech's ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti), which is an FDA-approved BCMA-directed autologous chimeric antigen receptor T-cell (CAR-T), will be put in front of the FDA’s Oncologic Drugs Advisory Committee (AdComm) as part of the review process for its biologics license application (BLA) for an expanded indication in adult patients with relapsed and lenalidomide-refractory multiple myeloma (MM) who have been treated with at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent.1 This information was revealed in a United States Securities and Exchange Commission (SEC) filing dated to January 23, 2024.

The date for the AdComm meeting has not yet been announced, but according to the SEC filing will be revealed in the Federal Register. Alongside the announcement of the FDA AdComm meeting, Legend also noted in the SEC filing that the European Medicines Agency Committee for Advanced Therapies will likewise hold a Scientific Advisory Group Oncology (SAG-O) meeting regarding the Type II variation application that the company has submitted for an expended indication in patients with relapsed and lenalidomide-refractory MM who have been treated with 1 to 3 previous lines of therapy.

The SEC filing additionally 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, 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 CARVYKTI.”2

“Since ciltacabtagene autoleucel (CARVYKTI) was approved, we have become aware of the risk of T-cell malignancies, with serious outcomes, including hospitalization and death, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies,” Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, the signed author of the letter, wrote.2 “FDA identified postmarketing adverse event and clinical trial reports describing [the] occurrence of mature T-cell malignancies, including CAR-positive tumors, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies... Furthermore, we consider the serious risk of T-cell malignancy to be applicable to all BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies.”

Key Takeaways

  • Janssen’s and Legend Biotech's ciltacabtageneautoleucel (cilta-cel; marketed as Carvykti), which is an FDA-approved BCMA-directed autologous chimeric antigen receptor T-cell (CAR-T), will be put in front of the FDA’s Oncologic Drugs Advisory Committee (AdComm) as part of the review process for its biologics license application (BLA) for an expanded indication in adult patients with relapsed and lenalidomide-refractory multiple myeloma (MM) who have been treated with at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent.
  • Alongside the announcement of the FDA AdComm meeting, Legend also noted in the SEC filing that the European Medicines Agency Committee for Advanced Therapies will likewise hold a Scientific Advisory Group Oncology (SAG-O) meeting regarding the Type II variation application that the company has submitted for an expended indication in patients with relapsed and lenalidomide-refractory MM who have been treated with 1 to 3 previous lines of therapy.
  • The SEC filing additionally 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, currently approved by the agency for use in the United States.

Both the BLA and Type II variation application, which were submitted to the agencies in June 2023 and May 2023, respectively, are supported by data from the phase 3 CARTITUDE-4 clinical trial (NCT04181827).1,3-4 Leaked data from the study reported by STAT News in April 2023 indicated that cilta-cel had outperformed expectations compared with standard chemotherapy regimens—such as pomalidomide, bortezomib and dexamethasone; or daratumumab, pomalidomide and dexamethasone—in patients with relapsed and lenalidomide-refractory MM.5 Based on the data that were obtained, those treated with the CAR-T therapy showed a 74% reduction in the risk of disease progression compared with standard regimens. Additionally, cilta-cel is reported to have cut the mortality risk by 22% relative to standard chemotherapy, though this effect appears to have been deemed not statistically significant.

Cilta-cel was originally approved by the FDA in February 2022 for the treatment of adult patients with relapsed/refractory MM following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.6 Recently, at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California, CGTLivespoke with Piers Blombery, MBBS, PhD, associate professor, Peter MacCallum Cancer Centre, and head, Wilson Centre for Blood Cancer Genomics, to learn more about a case of CAR+ lymphoma reported in a patient in CARTITUDE-4 who had received treatment with cilta-cel.7

“It looks there’s a contribution of possibly where the CAR's inserted, into a... premalignant T-cell, in a patient with a potential germline mutation predisposition to developing this malignancy and that appears together to have caused a CAR-T uncontrolled lymphoproliferation,” Blomberry said in the interview. “There’s always a lot of work to be done and a lot of work we’re doing at the moment to further understand the contribution of all 3 parts, but that's where we are at the moment.”

REFERENCES
1. Legend Biotech provides update on US FDA and EMA applications for expanded use of CARVYKTI® (ciltacabtagene autoleucel) in earlier lines of treatment for relapsed/refractory multiple myeloma; FDA label update for CAR-T cell immunotherapies. United States SEC Form 6-K. January 23, 2024. Accessed January 25, 2024. https://investors.legendbiotech.com/static-files/0e1a1a5f-2b96-4cf7-9003-e188fa6fba79
2. Safety Labeling Change Notification Letter - CARVYKTI (ciltacabtageneautoleucel). News release. FDA. January 19, 2024. Accessed January 25, 2024. https://www.fda.gov/media/175624/download?attachment
3. Legend Biotech announces submission of supplemental application to the U.S. FDA for expanded use of CARVYKTI® (ciltacabtagene autoleucel). News release. Legend Biotech Corporation. June 6, 2023. Accessed January 25, 2024. https://legendbiotech.com/legend-news/legend-biotech-announces-submission-of-supplemental-application-to-the-u-s-fda-for-expanded-use-of-carvykti-ciltacabtagene-autoleucel-2/
4. Legend biotech announces submission to the European Medicines Agency for expanded use of CARVYKTI® (ciltacabtagene autoleucel). News release. Legend Biotech Corporation. May 25, 2023. Accessed January 25, 2024.https://legendbiotech.com/legend-news/legend-biotech-announces-submission-to-the-european-medicines-agency-for-expanded-use-of-carvykti-ciltacabtagene-autoleucel/
5. Feuerstein A. Leaked study results show a CAR-T from J&J providing big benefit for patients with multiple myeloma. STAT. April 19, 2023. Accessed January 25, 2024. https://www.statnews.com/2023/04/19/leaked-study-results-show-a-car-t-from-jj-providing-big-benefit-for-patients-with-multiple-myeloma/
6. U.S. FDA approves CARVYKTI™ (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. February 28, 2022. Accessed January 25, 2024. https://bit.ly/35yWwjv
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