EC Approves Ibrutinib Plus Chemoimmunotherapy +/- ASCT in Untreated MCL

Results from the phase 3 TRIANGLE trial showed prolonged failure-free survival and overall survival with ibrutinib and CIT vs CIT plus ASCT alone.

The European Commission has expanded the approved indication for ibrutinib (Imbruvica) in patients with previously treated mantle cell lymphoma (MCL) who would be eligible for autologous stem cell transplant (ASCT), according to a press release from the developer, Johnson & Johnson.1

The approval is for ibrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) alternating with rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) or rituximab, dexamethasone, high-dose cytarabine, and oxaliplatin (R-DHAOx) without ibrutinib, followed by ibrutinib monotherapy.

Previously, in June 2025, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended approval for the expansion of the indication.2

Supporting results came from the open-label, randomized phase 3 TRIANGLE trial (NCT02858258) that evaluated whether ibrutinib plus chemoimmunotherapy with or without ASCT improved outcomes vs chemoimmunotherapy plus ASCT alone in patients with MCL.

With a median follow-up of 55 months, the failure-free survival (FFS), at 54 months, was 77% with ibrutinib plus chemoimmunotherapy without ASCT vs 68% with ibrutinib plus chemoimmunotherapy with ASCT (HR, 0.639; 98% CI, 0.428-0.953; P = .0068). The overall survival (OS) with ibrutinib plus chemoimmunotherapy, at 54 months, was 88% vs 78% with chemoimmunotherapy plus ASCT alone (HR, 0.522; 95% CI, 0.341-0.799; P = .0023).

“MCL is still an aggressive, incurable disease and patients suffer under the burden associated with transplant,” stated Martin Dreyling, MD, PhD, professor of medicine, head of the lymphoma program in the Department of Medicine III at the Ludwig Maximilian University of Munich, and lead investigator of TRIANGLE, in the press release.1 “As a targeted therapy, ibrutinib represents an opportunity to improve long-term outcomes earlier in the treatment pathway. Patients now have a new standard of care in first-line treatment that not only offers prolonged survival but also avoids short and long-term toxicities associated with high-dose chemotherapy and ASCT.”

TRIANGLE enrolled a total of 870 patients, all of whom were randomly assigned, in a 1:1:1 ratio, to receive 1 of 3 treatment combinations: in group 1, patients received 6 alternating cycles of R-CHOP and R-DHAP or R-DHAOx followed by ASCT (n = 288); in group 2, 560 mg of oral ibrutinib was added on days 1 to 19 of R-CHOP cycles and as fixed-duration maintenance after ASCT (n = 292); in group 3, treatment was the same as in group 2, but without ASCT (n = 290).3

Eligible patients were 18 to 65 years old with a histologically confirmed diagnosis of previously untreated Ann Arbor stage II to IV MCL that is suitable for ASCT; additional enrollment criteria include an ECOG performance status of 2 or less and at least 1 measurable lesion.

Those with a history of intracranial hemorrhage within 6 months of randomization, known central nervous system involvement of MCL, and a requirement for anticoagulation with warfarin or equivalent vitamin K antagonists or treatment with strong CYP3A4 or CYP3A5 antagonists or treatment with strong CYP3A4 or CYP3A5 inhibitors were excluded from the trial.

The trial’s primary end point was investigator-assessed FFS, defined as the time from randomization to stable disease at the end of induction chemoimmunotherapy, progressive disease, or death. Secondary end points include OS, progression-free survival, duration of remission, and overall and complete remission rates.

Regarding safety, the safety profile of the ibrutinib plus chemoimmunotherapy regimen was consistent with previously reported data of ibrutinib; the most common grade 3 to 5 adverse effects in the ibrutinib plus chemoimmunotherapy arm vs the chemoimmunotherapy plus ASCT arm were blood and lymphatic system disorders (64.9% and 75.0%, respectively), neutrophil count decreased (24.2% and 23.1%), platelet count decreased (29.4% and 33.2%), and infections and infestations (28.7% and 23.1%).

“Until now, fit patients with MCL have only had the option of frontline treatment with ASCT and chemotherapy. We’re incredibly proud that with this approval, ibrutinib has become the first alternative therapy for this patient population after demonstrating superior outcomes compared to the current standard of care,” Jessica Vermeulen, vice president of Lymphoma & Leukemia Disease Area Stronghold Leader at Johnson & Johnson Innovative Medicine, said in the press release.1 “This approval reinforces our ongoing commitment to haematological malignancies, and the power of our collaborations with academics and researchers to bring cutting-edge science to areas of high unmet need.”

Reference

1. European Commission approves IMBRUVICA® (ibrutinib) as the first targeted therapy for patients with previously untreated mantle cell lymphoma who would be eligible for autologous stem cell transplant. News release. Johnson & Johnson. July 23, 2025. Accessed July 23, 2025. https://tinyurl.com/5yyaksp6
2. IMBRUVICA® (ibrutinib) receives positive CHMP opinion for the treatment of patients with previously untreated mantle cell lymphoma (MCL) who would be eligible for autologous stem cell transplant. News release. Johnson & Johnson. June 20, 2025. Accessed July 23, 2025. https://tinyurl.com/3u3fvax4
3. Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3