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1、Results of the Phase 3, placebo-controlled trial (SUCCEED) evaluating the mTOR inhibitor ridaforolimus as maintenance therapyin advanced sarcoma patientsfollowing clinical benefit fromprior standard cytotoxic chemotherapy,S. P. Chawla, J. Y. Blay, I. Ray-Coquard, A. Le Cesne, A. P. Staddon, M. M. Mi
2、lhem, N. Penel, R. F. Riedel, B. Bui Nguyen, L. D. Cranmer, P. Reichardt, E. Bompas, Y. Song, R. M. Lee, J. E. Eid, J. Loewy, F. G. Haluska, P. F. Dodion, G. D. Demetri, on behalf of all SUCCEED investigators,mTOR signaling dysregulated in multiple sarcomas Ridaforolimus: a rapamycin analog and pote
3、nt mTOR inhibitor Clinical activity in sarcomas in Phase 1 and 2 studies,The PI3K-AKT-mTOR pathway regulates cell growth, proliferation and metabolism in sarcoma,Ridaforolimus: antitumor activity in sarcoma,Ridaforolimus: previous activity demonstrated in sarcomas,Clinical benefit rate: CR+PR+SD 4 m
4、onths,PD,Metastatic sarcoma after 1-3 lines CT, per SOC,Ineligible,Ridaforolimus Placebo (40 mg QD x 5 per week),SOC watchful waiting,IRC,CR, PR, SD,randomization,Sarcoma standard care and the SUCCEED pivotal Phase III trial design,SUCCEED study endpoints,Primary endpoint Improvement in PFS by indep
5、endent radiology review Secondary endpoints Overall survival Best target lesion response Cancer-related symptoms Safety and tolerability,Pivotal Phase III trial design statistics and key features,Statistical design: 650 patients with 90% power to detect 33% improvement in PFS (516 PFS events, =0.025
6、, one-sided) Stratified for line of therapy, histology, and geography Two interim analyses 711 patients enrolled between Oct 07 and Jan 10; 702 patients received either ridaforolimus or placebo Largest randomized study ever in the soft tissue and bone sarcoma population,Patient characteristics were
7、balanced at study entry,PFS per independent radiology review,Independent Radiology Review (HR=0.72, p=0.0001),Weeks,(Data cut-off date 10-25-2010),PFS rate Median PFS 3 mon 6 mon Ridaforolimus 17.7 weeks 70% 34% Placebo 14.6 weeks 54% 23%,PFS per investigator assessment,Weeks,Investigator Assessment
8、 (HR=0.69, p0.0001),(Data cut-off date 10-25-2010),PFS rate Median PFS 3 mon 6 mon Ridaforolimus 22.4 weeks 72% 37% Placebo 14.7 weeks 55% 23%,Consistent progression free survival improvement across multiple subgroup analyses,favor rida,favor placebo,SUCCEED: trend in Overall Survival (OS),386 death
9、 events based on data cut-off date 4-30-2011 (6 months after PFS data cut-off date),HR 0.88, p=0.2256 Median OS ridaforolimus: 21.4 months Placebo: 19.2 months,Tumor response: Clinical Benefit Rate (CBR) 4 months,Exploratory analysis of cancer-related symptoms,Questionnaires completed by the patient
10、s periodically in 3 categories: pain, cough and shortness of breath Vast majority (90%) of patients who stayed on therapy were free of severe symptoms in both treatment groups Small numerical imbalances favoring placebo at some time points Large amount of missing information mainly due to treatment
11、discontinuation Greater in placebo patients over time Analysis is inconclusive due to large amount of missing information Following disease progression, no information about cancer-related progression was collected,SUCCEED: ridaforolimus inhibited tumor growth,Waterfall plots,Best target lesion resp
12、onse (mean) Ridaforolimus -1.3% Placebo +10.3% (p0.0001),Survival following disease progression was similar for the ridaforolimus and placebo groups,Post-progression survival = duration from disease progression to death,HR=0.94 (95% CI 0.76, 1.18, p=0.6152),Ridaforolimus Placebo,Weeks,Adverse events
13、 noted during SUCCEED trial,Adverse events reported with the class of mTOR inhibitors,6 deaths due to “pulmonary disorders” with ridaforolimus vs. none in placebo. 1 drug-related pneumonitis, 2 pleural effusion , 1 pulmonary embolism, 2 respiratory distress,Summary: Ridaforolimus improves disease co
14、ntrol to maintain benefit of prior therapy,Study met the primary endpoint in PFS improvement (HR 0.72, p=0.0001) Trend toward OS benefit (HR 0.88, p=0.2256) Better tumor growth control No adverse impact on survival following disease progression No major unexpected AEs, and toxicities similar to othe
15、r mTOR inhibitors,Acknowledgements,All of the sarcoma patients and their families who made this trial SUCCEED All of the worldwide investigators and study team members The study sponsors, Merck and Ariad Pharmaceuticals,Backup slides,Comparison of Independent radiology review and investigator assess
16、ment (concordance rate 80%),Weeks,Investigator Assessment (HR=0.69, p0.0001),Ridaforolimus Placebo,Independent Radiology Review (HR=0.72, p=0.0001),Ridaforolimus Placebo,Efficacy result of pediatric populations,Ridaforolimus group 7 patients enrolled 64% tumor size reduction in one osteosarcoma patient 1 PR, 4 SD, 2 PD CBR 4mos: 5/7 = 71% PFS durations: 59, 48, 23, 20, 19, 16, and 8 weeks,Placebo group 5 patients enroll
