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

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• 作者：Prof Dr Martin Dreyling ; MD^a ; ^&dagger ; ; ^{Martin.Dreyling@med.uni-muenchen.de" class="auth_mail" title="E-mail the corresponding author} ; Wojciech Jurczak ; MD^b ; ^&dagger ; ; Mats Jerkeman ; MD^c ; ^&dagger ; ; Rodrigo Santucci Silva ; MD^d ; Chiara Rusconi ; MD^e ; ^&dagger ; ; Prof Marek Trneny ; MD^f ; ^&dagger ; ; Fritz Offner ; MD^g ; ^&dagger ; ; Dolores Caballero ; MD^h ; ^&dagger ; ; Prof Cristina Joao ; MDⁱ ; ^r ; ^&dagger ; ; Prof Mathias Witzens-Harig ; MD^j ; ^&dagger ; ; Georg Hess ; MD^k ; ^&dagger ; ; Isabelle Bence-Bruckler ; MD^l ; Prof Seok-Goo Cho ; MD^m ; John Bothos ; PhDⁿ ; Jenna D Goldberg ; MDⁿ ; Christopher Enny ; BSⁿ ; Shana Traina ; PhDⁿ ; Sriram Balasubramanian ; PhD^o ; Nibedita Bandyopadhyay ; PhDⁿ ; Steven Sun ; PhDⁿ ; Jessica Vermeulen ; MD^p ; Aleksandra Rizo ; MDⁿ ; Prof Simon Rule ; MD^q ; ^&dagger ;
• 刊名：The Lancet
• 出版年：2016
• 出版时间：20-26 February 2016
• 年：2016
• 卷：387
• 期：10020
• 页码：770-778
• 全文大小：527 K

文摘

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&middot;0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0&middot;43 [95% CI 0&middot;32–0&middot;58]; median progression-free survival 14&middot;6 months [95% CI 10&middot;4–not estimable] m>vsm> 6&middot;2 months [4&middot;2–7&middot;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%] m>vsm> 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.