Supportive Efficacy Analyses for the Phase 3 Study of Temsirolimus Versus Investigator’s Choice Therapy for the Treatment of Patients with Relapsed or Refractory Mantle Cell Lymphoma.

Abstract Temsirolimus (Torisel®) is a specific inhibitor of the mTOR kinase with antitumor activity in patients with relapsed or refractory mantle cell lymphoma. In a phase 3, randomized, open-label study, patients treated with temsirolimus 175 mg weekly 3 times followed by 75 mg weekly (175/75-mg) had significantly longer progression-free survival (PFS) than those treated with investigator’s choice therapy (p-value temsirolimus: investigator’s choice = 0.0009; hazard ratio = 0.44; 97.5% CI = 0.25, 0.78; Hess et al. J Clin Oncol.2008, 28:abs 8513). Patients treated with temsirolimus 175 mg weekly 3 times followed by 25 mg weekly (175/25-mg) showed a trend towards longer PFS than those treated with investigator’s choice therapy (p-value = 0.0618; hazard ratio = 0.65; 97.5% CI = 0.39, 1.10). Patients treated with temsirolimus 175/75-mg and 175/25-mg had 22% and 6% objective response rates, respectively, compared with a 2% rate for patients treated with investigator’s choice therapy (p=0.0019 and 0.6179). These results were obtained for the intent-to-treat population, which included all randomized patients (n=54 for both temsirolimus groups and the investigator’s choice group). We now report the results of sensitivity and subgroup analyses for the recommended temsirolimus dose, 175/75-mg, compared with those for investigator’s choice therapy. The primary endpoint of the study was PFS, the time from the date of randomization to the earlier date of either progressive disease (PD) or death from any cause, if within 4 months of the last valid tumor assessment (per FDA guidance), censored at that assessment. Progression was assessed by independent review of radiographic and clinical data. Progression-free survival was analyzed by Kaplan-Meier estimates and an unstratified Cox proportional hazards model. Sensitivity analyses for PFS included: evaluable population: those who remained on treatment for at least 8 weeks and did not discontinue early for PD or death, had no major protocol violations, and had at least 1 screening tumor assessment and at least 1 postbaseline independent tumor assessment to which an overall response was assigned all deaths: those patients who had PD or died at any time during the study all deaths + withdrawal from therapy + initiation of anticancer therapy: those patients who had PD, died, or stopped treatment because of withdrawal from therapy or initiation of other anticancer therapy; and all deaths, excluding patients with blastoid histology. The latter analysis was performed because 0 patients in the 175/75-mg group and 4 patients in the investigator’s choice group had blastoid histology. The characteristics of PFS for the 4 sensitivity analyses are shown (Table). In each analysis, PFS was significantly longer for the patients treated with temsirolimus 175/75-mg than for those treated with investigator’s choice therapy, consistent with the PFS results for the intent-to-treat population. Thus, based on several analyses, temsirolimus 175/75-mg benefits patients with relapsed or refractory mantle cell lymphoma. Additional exploratory analyses will be presented. PFS Analysis Temsirolimus 175/75-mg Investigator’s Choice p-Value Hazard Ratio (95% CI) n Median PFS, Mo n Median PFS, Mo Evaluable population 29 5.2 26 1.9 0.0002 0.29 (0.15, 0.57) All deaths 54 5.2 54 2.0 0.0007 0.46 (0.29, 0.72) All deaths + withdrawal from therapy + initiation of anticancer therapy 54 2.6 54 0.8 <0.0001 0.43 (0.28, 0.65) All deaths, excluding pts with blastoid histology 54 5.2 50 2.1 0.0020 0.48 (0.30, 0.77)

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