Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study

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Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a reported median overall survival (OS) of 3-5 years [1]. Most patients relapse after first-line therapy and have a poor prognosis [1]. Regulatory approval of ibrutinib has provided a much needed therapeutic option for patients with relapsed or refractory (R/R) MCL [2], with ibrutinib becoming a preferred standard of care in current guidelines [3,4]. The randomized, open-label phase 3 RAY study (NCT01646021) was key in confirming the efficacy and safety of ibrutinib, with ibrutinib (N = 139) showing significantly improved progression-free survival (PFS) versus temsirolimus (N = 141) (primary analysis [20-month followup]: 14.6 vs. 6.2 months, hazard ratio [HR] 0.43, 95% confidence interval [CI]: 0.32-0.58) [5]. Here, we report extended follow-up data from the final analysis of the RAY study.
At this final analysis, after an almost doubled median study follow-up of 38.7 months, 33 patients (24%) in the ibrutinib group and no patients in the temsirolimus group remained on initially randomized treatment. Crossover to ibrutinib from the temsirolimus group was permitted for patients who had confirmed disease progression. Fifty-five patients in the temsirolimus group (39%) received subsequent ibrutinib (42 were included in the formal study crossover; 13 received ibrutinib outside of the study). Disease progression or relapse was the most common reason for discontinuing treatment for both groups ( Overall response rate (ORR) in the final analysis was consistent with the primary analysis (77% for ibrutinib vs. 47% for temsirolimus; odds ratio 4.27 [95% CI 2.47-7.39]; P < 0.0001), with a higher proportion of patients achieving a complete response (CR) with ibrutinib (23%) than with temsirolimus (3%). ORR results for ibrutinib were similar regardless of extent of prior treatment (75 vs. 78% for 1 prior line and >1 prior line, respectively). However, the CR rate was two-fold higher in patients treated with ibrutinib who received 1 prior line of therapy than those who received >1 prior line: 33 and 16%, respectively. Overall median duration of response (DOR) was 23.  10.0 months [N = 51], respectively, for those who had received 1 vs. >1 prior line of therapy). Therefore, DOR for complete responders with only 1 prior line was more than three times longer than for partial responders with >1 prior line of therapy.
Consistent with the primary analysis, the most common treatment-emergent AEs (TEAEs) of any grade were diarrhea (33%), fatigue (24%), and cough (23%) in the ibrutinib group, and thrombocytopenia (56%), anemia (44%), and diarrhea (31%) in the temsirolimus group. Despite longer treatment exposure in the ibrutinib group versus the temsirolimus group, the frequency of grade ≥3 TEAEs (75 vs. 87%), serious AEs of any grade (57 vs. 60%) and AEs leading to discontinuation (17 vs. 32%) were lower in the ibrutinib group than in the temsirolimus group, respectively. The most common grade ≥3 TEAEs for both groups were hematological in nature and were less frequently reported in the ibrutinib group than the temsirolimus group, respectively: neutropenia (13 vs. 17%), thrombocytopenia (9 vs. 43%) and anemia (9 vs. 20%) ( Table 1). The rate of any grade bleeding was 40 and 33% in the ibrutinib and temsirolimus groups, respectively. The rate of grade ≥3 bleeding was 9% in the ibrutinib group and 5% in the temsirolimus group, with exposure-adjusted rates being lower in the ibrutinib group (0.455 events per 100 patient-months) versus  Fig. 1d).
In conclusion, longer-term follow-up from the final analysis of the RAY study supports the initial report, demonstrating significant improvement in ORR and PFS with ibrutinib over temsirolimus in patients with R/R MCL. At the final analysis, OS showed a trend in favor of ibrutinib versus temsirolimus (30.3 vs. 23.5 months; HR 0.74 [95% CI 0.54-1.02], P = 0.0621). In the initial analysis, number of previous lines of therapy was identified as a prognostic factor [5]. With longer follow-up this was evident, with patients who had received 1 prior line of therapy benefiting the most from the use of ibrutinib. More patients were able to achieve a CR (33 vs. 16%), and those achieving a PR had a longer DOR (22.3 vs. 10.0 months) when using ibrutinib after 1 versus >1 prior line of therapy. In ibrutinib patients with 1 prior line of therapy, this resulted in a doubling of PFS versus ibrutinib patients with >1 prior line of therapy (25.4 vs. 12.1 months) and an almost 15-month improvement of OS versus temsirolimus patients with 1 prior line of therapy (42.1 vs. 27.0 months). These data from the RAY study, irrespective of the number of prior lines of therapy, compare favorably to the results from pivotal clinical trials of other single agents in R/R MCL (e.g., bortezomib, lenalidomide, and temsirolimus), the use of which was associated with median PFS of 4-5 months, median OS of 13-19 months, and ORRs of 22-33% [6][7][8][9]. Given that these findings support earlier use of ibrutinib in the relapsed/refractory setting, a relevant clinical question is whether patients can be successfully treated after progression on ibrutinib. Here, we show that patients could be successfully rescued post ibrutinib therapy with rituximab-based chemotherapy (ORR = 41%), including bendamustine-rituximab (ORR = 53%). Importantly, longer follow-up revealed no new late or cumulative toxicities, supporting the overall well-tolerated safety profile for ibrutinib [5]. The significant improvements in PFS2 provide further evidence that ibrutinib benefit is maintained beyond subsequent lines of treatment. Collectively, these results support the role of ibrutinib in the treatment of previously treated MCL. Emerging data suggest that ibrutinib may also have a role in treatment-naïve MCL [10] Acknowledgements This study was funded by Janssen Research & Development. Writing assistance was provided by Juan Sanchez-Cortes, PhD (PAREXEL, Hackensack, NJ, USA) and Natalie Dennis (PAREXEL, Worthing, UK) and was funded by Janssen Global Services, LLC. The authors would like to thank the contribution of Mark Wildgust and Lori Parisi for their support in the long-term reporting for this study. We also thank the patients who participated in this trial, their families and the investigators and coordinators at each of the clinical sites.
Author contributions All authors conceived and/or designed the work that lead to this submission, acquired data and/or played an important role in interpreting the results. All authors were involved in drafting or reviewing the manuscript, and all authors approved the final version of the manuscript.

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Conflict of interest Conflicts of interestSR has served as an advisor for Janssen, Pharmacyclics and Napp, and has received research funding from Janssen. WJ has received research funding from Janssen and Pharmacyclics. MJ has received research funding from Janssen, Celgene, Abbvie and Gilead. CR has served as an advisor for Italfarmaco, Teva, Janssen, Takeda and Roche. MT has served as an advisor and received research funding from Janssen. CJ has served as an advisor for Celgene, Janssen, Takeda, Amgen and Roche. MW-H has served as an advisor and received honoraria from Janssen. GH has served as an advisor and received honoraria from Roche, Pfizer, Janssen, CTI and Celgene, and received research support from Roche, Pfizer, Mundipharma, Celgene and CTI. CT has served as an advisor for Bayer, Celgene, Janssen and Roche, and received research funding from Roche. MD has served as an advisor and received research funding from Janssen and Pfizer, and has received honoraria from Janssen. WZ is a contractor of Janssen. TH, JG and JV are employees of Janssen and own stocks in Johnson & Johnson. The remaining authors declare that they have no conflict of interest.
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