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Complicated regulatory decision-making following inconsistent trial results: the issue with ibrutinib for mantle cell lymphoma

In 2023, a decade after granting Accelerated Approval to the first-in-class BTK inhibitor ibrutinib for the treatment of mantle cell lymphoma, the FDA requested this indication be withdrawn. Herein, we discuss the seemingly inconsistent results from the SHINE and TRIANGLE trials, which relate to the distinct patient populations of these trials, and posit that regulatory approaches should take these nuances into account.

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  1. Gyawali, B., Ross, J. S. & Kesselheim, A. S. Fulfilling the mandate of the US Food and Drug Administration’s Accelerated Approval pathway: the need for reforms. JAMA Intern. Med. 181, 1275–1276 (2021).

    Article  PubMed  Google Scholar 

  2. Gyawali, B., Rome, B. N. & Kesselheim, A. S. Regulatory and clinical consequences of negative confirmatory trials of accelerated approval cancer drugs: retrospective observational study. BMJ 374, n1959 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wang, M. L. et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N. Engl. J. Med. 386, 2482–2494 (2022).

    Article  CAS  PubMed  Google Scholar 

  4. Dreyling, M. et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized TRIANGLE trial by the European MCL Network. Blood 140 (Supplement 1), 1–3 (2022).

    Article  Google Scholar 

  5. AbbVie. Update on IMBRUVICA® (ibrutinib) U.S. Accelerated Approvals for Mantle Cell Lymphoma and Marginal Zone Lymphoma Indications (2023).

  6. Cliff, E. R. S. & Dickinson, M. Treatment of mantle-cell lymphoma. N. Engl. J. Med. 387, 1146–1147 (2022).

    Article  PubMed  Google Scholar 

  7. Merino, M. et al. Irreconcilable differences: the divorce between response rates, progression-free survival, and overall survival. J. Clin. Oncol 41, 2706–2712 (2023).

    Article  PubMed  Google Scholar 

  8. Pro, B. et al. Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T-cell lymphoma. Hematol. Oncol. 35, 914–917 (2017).

    Article  PubMed  Google Scholar 

  9. Bachy, E. et al. Romidepsin plus CHOP versus CHOP in patients with previously untreated peripheral T-cell lymphoma: results of the Ro-CHOP phase III study (conducted by LYSA). J. Clin. Oncol. 40, 242–251 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Mostaghim, S. R., Gagne, J. J. & Kesselheim, A. S. Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study. BMJ 358, j3837 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

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The research of E.R.S.C. and A.S.K. is funded by Arnold Ventures. The funders had no role in the design and conduct of the study, collection, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication. The authors thank N. Mehta-Shah for discussions regarding romidepsin.

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Correspondence to Edward R. Scheffer Cliff.

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A.S.K. reports having served as an expert witness on behalf of the Leukemia and Lymphoma Society in litigation relating to royalties on venetoclax (2021–2022). E.R.S.C. and T.H. have no competing interests to declare.

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Cliff, E.R.S., Hilal, T. & Kesselheim, A.S. Complicated regulatory decision-making following inconsistent trial results: the issue with ibrutinib for mantle cell lymphoma. Nat Rev Clin Oncol (2023).

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