In aphase III trial reported in The Lancet and at the recent American Society of Hematology Annual Meeting and Exposition, Martin Dreyling, MD, of the European Mantle Cell Lymphoma Network, and colleagues found that ibrutinib (Imbruvica) was associated with improved progression-free survival vs temsirolimus (Torisel) in patients with relapsed or refractory mantle cell lymphoma.¹

Study Details

In this open-label trial, 280 patients from 21 countries who had received at least one rituximab (Rituxan)-containing treatment were randomly assigned between December 2012 and November 2013 to receive oral ibrutinib at 560 mg daily (n = 139) or intravenous temsirolimus at 175 mg on days 1, 8, and 15 of cycle 1 and 75 mg on days 1, 8, and 15 of subsequent 21-day cycles (n = 141). The primary endpoint was progression-free survival assessed by masked independent review committee. The trial is ongoing.

For the ibrutinib and temsirolimus groups: median age was 67 and 68 years; 72% and 77% of patients were male; 83% and 91% were white, and 12% and 4% were Asian. Almost all patients (99% in both groups) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Disease stage was III in 12% and 10% and IV in 81% and 85%; histology was nonblastoid in 88% in both; and the risk group was low in 32% and 30%, intermediate in 47% and 49%, and high in 22% and 21%. The median number of previous lines of therapy was two in both groups, with 68% and 66% having one or two prior treatments; 74% and 67% had relapsed disease, and 26% and 33% had refractory disease.

Progression-Free Survival

Median treatment duration was 14.4 months in the ibrutinib group vs 3.0 months in the temsirolimus group. After median follow-up of 20 months, median progression-free survival was 14.6 months (95% confidence interval [CI] = 10.4 months to not estimable) in the ibrutinib group vs 6.2 months (95% CI = 4.2–7.9 months) in the temsirolimus group (hazard ratio [HR] = 0.43, P < .0001). Hazard ratios consistently favored ibrutinib in subgroup analyses, although less of a benefit was observed among the 33 patients with blastoid histology. Two-year progression-free survival was 41% vs 7%.

Response Rate, Overall Survival

Overall response rate on independent review was 72% vs 40% (P < .0001), including complete response in 19% vs 1%. At the time of data cutoff, median duration of response was not reached in the ibrutinib group vs 7.0 months in the temsirolimus group; response was ongoing in 59% of responders in the ibrutinib group.

Median overall survival was not reached in the ibrutinib group vs 21.3 months in the temsirolimus group (HR = 0.76, P = .1324). A total of 23% of patients in the temsirolimus group crossed over to ibrutinib at progression. Overall, subsequent therapy was received by 32% of the ibrutinib group, with the most common treatments being rituximab (15%), bendamustine (Bendeka, Treanda; 11%), and cyclophosphamide (9%), and by 58% of patients in the temsirolimus group, with the most common being rituximab (26%), ibrutinib, bendamustine (16%), and cyclophosphamide (13%). One-year survival was 68% vs 61%.

As assessed by the Functional Assessment of Cancer Therapy-Lymphoma questionnaire, clinically meaningful improvement in lymphoma symptoms was reported in 62% vs 35% of patients, with median time to improvement of 6.3 vs 57.3 weeks (P < .0001), and clinically meaningful worsening occurred in 27% vs 52%, with median time to worsening of not reached vs 9.7 weeks (P < .0001).

Adverse Events

The most common adverse events of any grade in the ibrutinib group were diarrhea (29% vs 31%), cough (22% vs 22%), and fatigue (22% vs 29%), and the most common in the temsirolimus group were thrombocytopenia (56% vs 18%), anemia (43% vs 18%), diarrhea, fatigue, neutropenia (26% vs 16%), epistaxis (24% vs 9%), cough, peripheral edema (22% vs 13%), nausea (22% vs 14%), pyrexia (21% vs 17%), and stomatitis (21% vs 3%). Grade ≥ 3 adverse events occurred in 68% of the ibrutinib group vs 87% of the temsirolimus group, including neutropenia in 13% vs 17%, thrombocytopenia in 9% vs 42%, anemia in 8% vs 20%, atrial fibrillation in 4% vs 1%, fatigue in 4% vs 7%, and diarrhea in 3% vs 4%.

Major bleeding occurred in 10% vs 6%. New malignancies were observed in 4% vs 3%. Adverse events led to discontinuation of treatment in 6% vs 26%. During the first 6 months of treatment, 6% of patients in the ibrutinib group and 8% in the temsirolimus group had a treatment-emergent adverse event leading to death.

The investigators concluded: “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.” ■

Disclosure: The study was funded by Janssen Research & Development, LLC. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Dreyling M, Jurczak W, Jerkeman M, et al: Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: An international, randomised, open-label, phase 3 study. Lancet. December 7, 2015 (early release online).

See commentary by Mitchell R. Smith, MD, PhD, here.