Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study

• Published in: The Lancet (British edition) Vol. 387; no. 10020; pp. 770 - 778
• Main Authors: Dreyling, Martin, Prof Dr, Jurczak, Wojciech, MD, Jerkeman, Mats, MD, Silva, Rodrigo Santucci, MD, Rusconi, Chiara, MD, Trneny, Marek, Prof, Offner, Fritz, MD, Caballero, Dolores, MD, Joao, Cristina, Prof, Witzens-Harig, Mathias, Prof, Hess, Georg, MD, Bence-Bruckler, Isabelle, MD, Cho, Seok-Goo, Prof, Bothos, John, PhD, Goldberg, Jenna D, MD, Enny, Christopher, BS, Traina, Shana, PhD, Balasubramanian, Sriram, PhD, Bandyopadhyay, Nibedita, PhD, Sun, Steven, PhD, Vermeulen, Jessica, MD, Rizo, Aleksandra, MD, Rule, Simon, Prof
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 20-02-2016; Elsevier Limited
• Subjects: Aged; Aged, 80 and over; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Chemotherapy; Clinical Medicine; Clinical trials; Female; Hematologi; Hematology; Humans; Internal Medicine; Kaplan-Meier Estimate; Klinisk medicin; Lymphoma; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - pathology; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Middle Aged; Neoplasm Staging; Pyrazoles - adverse effects; Pyrazoles - therapeutic use; Pyrimidines - adverse effects; Pyrimidines - therapeutic use; R&D; Recurrence; Research & development; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; Sirolimus - therapeutic use; Survival; Treatment Outcome
• ISSN: 0140-6736; 1474-547X; 1474-547X
• DOI: 10.1016/S0140-6736(15)00667-4

Summary Background Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. Methods This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021 ) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). Findings Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32–0·58]; median progression-free survival 14·6 months [95% CI 10·4–not estimable] vs 6·2 months [4·2–7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). Interpretation Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit–risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. Funding Janssen Research & Development, LLC.