Ibrutinib versus Temsirolimus: Results from a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients with Previously Treated Mantle-Cell Lymphoma (MCL)
Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton’s tyrosine kinase that is approved for treatment of patients with mantle-cell lymphoma (MCL) who have received at least 1 prior therapy.1 In 2 single-arm phase 2 trials, single-agent ibrutinib treatment resulted in durable antitumor activity in patients with MCL, with an overall response rate (ORR) of 65%, including a complete response (CR) of 20%. In this setting,2 temsirolimus has demonstrated significantly longer progression-free survival (PFS) compared with investigator’s choice.3 RAY (MCL3001) is a phase 3, randomized study that compared ibrutinib versus temsirolimus in patients with relapsed and/or refractory MCL who had received ?1 prior rituximab-containing therapies. Rule and colleagues reported safety and efficacy results of this trial.4 In this trial, 280 eligible patients were randomized to receive oral ibrutinib (560 mg once daily; n = 139) or intravenous temsirolimus (175 mg in cycle 1; 75 mg thereafter; n = 141) until disease progression or unacceptable toxicity. Patients may cross over and receive treatment with ibrutinib on evidence of disease progression (confirmed by an Independent Review Committee [IRC]). Overall, patients had received a median of 2 (1-9) prior lines of therapy, and about two-thirds of the patients had intermediate- or high-risk disease.
At a median follow-up of 20.0 months, ibrutinib showed superiority to temsirolimus in terms of the primary end point of IRC-assessed progression-free survival (PFS), resulting in a statistically significant 57% reduction in the risk of progression or death and a longer median PFS (14.6 months vs 6.2 months; hazard ratio [HR], 0.43; P <.0001), which was consistent with the investigator-assessed PFS. The 2-year PFS rate was significantly higher with ibrutinib therapy (41% vs 7%) versus temsirolimus. Moreover, the ibrutinib arm was associated with significantly longer PFS compared to the temsirolimus arm, indicating that the treatment benefit is maintained after the next line of subsequent therapy (median PFS, 19.1 months vs. 11.3 months; HR, 0.49; P <.0001). The secondary end point of IRC-assessed overall response rate was also significantly higher for ibrutinib compared with temsirolimus therapy (71.9% vs 40.4%, respectively P <.0001), including a higher complete response rate (18.7% vs 1.4%, respectively). The median duration of response was not reached for ibrutinib therapy and was 7.0 months for temsirolimus. A trend toward an overall survival (OS) improvement was observed with ibrutinib therapy versus control, with a median OS not reached versus 21.3 months, respectively, although it did not reach statistical significance. The 1-year survival rates were 68% versus 61%, respectively. It was noted that the OS results may have been confounded by crossover of 23% of patients from the temsirolimus arm to the ibrutinib arm. Subgroup analysis showed that, in contrast to temsirolimus therapy that was associated with lower responses with increasing lines of therapy, ibrutinib therapy resulted in high responses in patients who had received ?3 prior lines of therapy (75% vs 33.3%).
In terms of safety, a higher proportion of patients who received temsirolimus treatment discontinued treatment due to adverse events (29.5% vs 12.9%) compared with ibrutinib therapy. The median treatment duration was more than 4 times longer for the Ibrutinib arm compared with temsirolimus (14.4 months vs 3.0 months). The most common all-grade treatment-related adverse events (TEAEs) with ibrutinib therapy were diarrhea (28.8%), fatigue (22.3%), and cough (22.3%); TEAEs associated with temsirolimus therapy included thrombocytopenia (56%), anemia (43%), neutropenia (25.9%), fatigue (28.8%), and diarrhea (25%). Patients treated with ibrutinib experienced a lower incidence of grade 3/4 TEAEs compared with the temsirolimus cohort. The authors concluded that ibrutinib therapy was associated with superior efficacy as well as a favorable safety profile compared with temsirolimus therapy in patients with previously treated MCL.
- Wang ML, et al. N Engl J Med. 2013;369:507-516.
- Imbruvica (ibrutinib) [Prescribing information]. 2015.
- Hess G, et al. J Clin Oncol. 2009;27(23):3822-3829.
- Rule S, et al. ASH 2015. Abstract 469.