Jenna Goldberg

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

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.

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B‐cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression‐free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non‐blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0–1, non‐bulky disease and non‐blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.

Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus

Abstract Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.

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

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 follow-up]: 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 (ibrutinib, 78 patients [56%]; temsirolimus, 66 patients [47%]). Fewer patients in the ibrutinib group (12 [9%]) than in the temsirolimus group (39 [28%]) discontinued treatment due to adverse events (AEs); eight patients in each arm discontinued due to death. Other reasons for discontinuation included refusing further treatment. Median duration of

IBRUTINIB VS TEMSIROLIMUS: THREE‐YEAR FOLLOW‐UP OF PATIENTS WITH PREVIOUSLY TREATED MANTLE CELL LYMPHOMA FROM THE PHASE 3, INTERNATIONAL, RANDOMIZED, OPEN‐LABEL RAY STUDY

Introduction: The ibrutinib–rituximab combination produced durable responses in 88% of relapsed/refractory mantle cell lymphoma (MCL) patients, providing a “Window” of opportunity to use chemotherapy‐ free induction with ibrutinib‐rituximab followed by fewer cycles of chemo‐immunotherapy in young, fit patients with newly diagnosed MCL. Methods: Enrollment began in June 2015 for a Phase II single‐center clinical trial consisting of a chemotherapy‐free phase of ibrutinib‐rituximab treatment (Part 1) until best response, followed by a shortened intense chemo‐immunotherapy course (Part 2) among newly diagnosed MCL patients of ≤65 years. We previously presented the initial results of this trial with ibrutinib‐rituximab and consolidation (Wang et al., ASH 2016). Here, we report updated data with a longer follow‐ up duration. The primary objective was to evaluate the response rate. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3‐12. Intense chemo‐immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD); alternating every 28 days with rituximab plus high‐dose methotrexate‐Ara C. If in complete remission (CR) after ibrutinib‐rituximab treatment, only 4 cycles of intense chemo‐immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo‐immunotherapy, a total of 2 cycles of chemo‐immunotherapy therapy are administered beyond achievement of CR. Results: As of March 3, 2017, 50 patients were evaluable for response. Of the evaluable patients, overall response rate (ORR) to chemotherapy‐free therapy alone was 100% (50), with CR in 80% (40) and PR in 20% (10). Thirty‐three (33) patients have completed both Parts 1 and 2 and all have achieved CR (i.e., ORR =100%). In Part 1, the most common grade 1‐2 non‐haematological (non‐heme) adverse effects (AEs) were fatigue (50), diarrhea (28), rash (29), myalgia (41), oral mucositis (52), peripheral neuropathy (19), nausea (25), blurred vision (19), edema (23), constipation (18), dry eyes (18), and dizziness (22). Grade 3 non‐heme AEs included fatigue (4), nausea (2), infection (3) and dyspnea (2). No grade 4‐5 non‐heme toxicities were observed in Part 1. Grade 3‐4 heme AEs included lymphocytosis (22), thrombocytopenia (13) and leukopenia (15). Conclusions: These updated data indicate that ibrutinib‐rituximab induction in newly diagnosed, young MCL patients was efficacious and well‐tolerated, providing a window of opportunity for less chemo‐immunotherapy needed for consolidation.