Abstract
8513 Background: Temsirolimus (TEMSR) is a specific inhibitor of mTOR, a kinase that regulates translation of key cell cycle proteins such as cyclin D1. Mantle cell lymphoma (MCL) is characterized by an 11;14 translocation that results in overexpression of cyclin D1 mRNA. In this phase 3, randomized, open-label study, we compared the antitumor activity of TEMSR with an investigator’s choice of therapy (IC) in patients (pts) with relapsed and/or refractory MCL. Methods: To test the hypothesis that TEMSR would increase progression-free survival (PFS) compared with IC (assuming medians of 6.2 and 3.0 mo, respectively), accrual of 177 pts to achieve 105 PFS events was planned. Power was 80% and α=0.025 comparing TEMSR with IC. Pts must have received 2–7 prior lines of therapy and received an alkylating agent, an anthracycline, and rituximab. Pts were randomly assigned (1:1:1) to 1 of 2 schedules of IV TEMSR, 175 mg 3x weekly followed by either 75 mg (175/75, arm 1) or 25 mg (175/25, arm 2) weekly, or to IC (arm 3) with the single agents gemcitabine (42%); fludarabine (26%); chlorambucil, cladribine, etoposide (6% ea); cyclophosphamide, thalidomide, vinblastine (4% ea); or alemtuzumab, lenalinomide (2% ea). The primary endpoint was PFS based on central independent review of radiologic and clinical data. Results: We report final results for 162 pts (54 pts/arm, median age 67 y, 81% male, 50% >3 prior regimens, 32% prior stem cell transplant) after 105 PFS events. Treatment with TEMSR 175/75 mg resulted in significant improvement in PFS and objective response rate and a trend toward longer overall survival compared with IC (Table). The most frequently occurring adverse events ≥gr 3 were thrombocytopenia (arm 1: arm 2: arm 3, 59%: 52%: 36% pts), anemia (20%: 11%: 17%), neutropenia (15%: 22%: 26%), and asthenia (13%: 19%: 8%). Conclusions: With an acceptable safety profile, TEMSR 175/75 mg significantly increased PFS and objective response rate of pts with relapsed, refractory MCL compared with IC. Parameter TEMSR, 175/75 mg Arm 1 TEMSR, 175/25 mg Arm 2 IC, Arm 3 Progression-free survival, independent assessment Median (97.5% CI), mo 4.8 (3.1, 8.1) 3.4 (1.9, 5.5) 1.9 (1.6, 2.5) Increase in median * 153% 79% Hazard ratio (97.5% CI) * 0.44 (0.25, 0.78) 0.65 (0.39, 1.10) p-value * 0.0009 0.0618 Overall survival Median (95% CI), mo 10.9 (8.1, 14.1) 8.5 (5.8, 14.0) 5.8 (4.8, 12.4) Increase in median * 88% 47% Hazard ratio (95% CI) * 0.62 (0.37, 1.05) 0.80 (0.48, 1.33) p value * 0.0714 0.3876 Obj response rate (95% CI) 22% (11, 33) 6% (0, 12) 2% (0, 5) p-value * 0.0019 0.6179 * Arm 1 or arm 2 : arm 3 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Wyeth Research Wyeth Wyeth Pharmaceuticals Millennium, Wyeth
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