肉瘤化疗SUCCEED-ASCO-2011.ppt

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.Milhem,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 investigatorsmTOR signaling dysregulated in multiple sarcomasRidaforolimus:a rapamycin analog and potent mTOR inhibitorClinical activity in sarcomas in Phase 1 and 2 studiesThe PI3K-AKT-mTOR pathway regulates cell growth,proliferation and metabolism in sarcomaPI3K4E-BP1TSCRidaforolimusmTORFKBPPTENPI3KAKTRidaforolimus:antitumor activity in sarcomaCTPETBaselineDay 5(53%)Day 54(85%)Ridaforolimus:previous activity demonstrated in sarcomasRoute of ridaforolimusNumber and diagnosisClinical benefit rateRate ofPFS 6 monthsPhase 1/2oral147 all tumors(85 sarcomas)27%23%Phase 2IV212 sarcomas29%23%EORTC historical review of sarcoma database for“active”agents (Glabbeke,European Journal of Cancer 38(2002)54354914%Clinical benefit rate:CR+PR+SD 4 monthsPDMetastatic sarcoma after 1-3 lines CT,per SOCIneligibleRidaforolimus Placebo(40 mg QD x 5 per week)SOC watchful waitingIRCCR,PR,SDrandomizationSarcoma standard care and the SUCCEED pivotal Phase III trial design SUCCEED study endpointslPrimary endpointImprovement in PFS by independent radiology reviewlSecondary endpointsOverall survivalBest target lesion responseCancer-related symptomsSafety and tolerabilityPivotal Phase III trial design statistics and key featureslStatistical design:650 patients with 90%power to detect 33%improvement in PFS(516 PFS events,=0.025,one-sided)lStratified for line of therapy,histology,and geographylTwo interim analysesl711 patients enrolled between Oct 07 and Jan 10;702 patients received either ridaforolimus or placebolLargest randomized study ever in the soft tissue and bone sarcoma populationPatient characteristics were balanced at study entryPlacebo(N=364)Ridaforolimus(N=347)P-Value Age mean(SD)50.6(15.0)52.0(16.0)0.2360 Gender Male/Female(%)43/57 45/55 0.4969 ECOG 0/1 (%)50/5050/501.0000 Histology soft tissue/bone(%)91/989/110.4476 Prior chemo 1st/2nd or 3rd(%)62/38 61/39 0.9386 Sarcoma grade high/low(%)73/6 74/4 0.7152 Metastatic sites lung/liver(%)64/19 67/14 0.5296 PFS per independent radiology reviewIndependent 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 assessmentWeeksInvestigator Assessment(HR=0.69,p90%)of patients who stayed on therapy were free of severe symptoms in both treatment groupsSmall numerical imbalances favoring placebo at some time pointslLarge amount of missing information mainly due to treatment discontinuationGreater in placebo patients over timelAnalysis is inconclusive due to large amount of missing informationFollowing disease progression,no information about cancer-related progression was collected SUCCEED:ridaforolimus inhibited tumor growth Waterfall plotsBest target lesion response(mean)Ridaforolimus -1.3%Placebo +10.3%(p0.0001)Survival following disease progression was similar for the ridaforolimus and placebo groupsPost-progression survival=duration from disease progression to deathHR=0.94(95%CI 0.76,1.18,HR=0.94(95%CI 0.76,1.18,p=0.6152)p=0.6152)RidaforolimusPlacebo WeeksWeeksAdverse events noted during SUCCEED trialMedDRA System Organ Class Preferred TermPlacebo (N=359)Ridaforolimus (N=343)All Grades(%)Grade 3(%)All Grades(%)Grade 3(%)PERCENT of Patients with 1 Adverse Event942610064 Stomatitis 181619 Infections(all sites included)263526 Fatigue 222363 Thrombocytopenia 413410 Diarrhea 180323 Cough 161311 Rash 60281Adverse events reported with the class of mTOR inhibitors MedDRA System Organ Class Preferred TermPlacebo (N=359)Ridaforolimus (N=343)All Grades(%)Grade 3(%)All Grades(%)Grade 3(%)Anemia 103287 Hypertriglyceridemia 91272 Hypercholesterolemia 50211 Hyperglycemia 31147 Renal and other urinary disorders 71163 Pneumonitis 111036 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 control to maintain benefit of prior therapylStudy met the primary endpoint in PFS improvement(HR 0.72,p=0.0001)lTrend toward OS benefit(HR 0.88,p=0.2256)lBetter tumor growth controllNo adverse impact on survival following disease progressionlNo major unexpected AEs,and toxicities similar to other mTOR inhibitorsAcknowledgementslAll of the sarcoma patients and their families who made this trial SUCCEED lAll of the worldwide investigators and study team memberslThe study sponsors,Merck and Ariad PharmaceuticalsBackup slidesComparison of Independent radiology review Comparison of Independent radiology review and investigator assessment(concordance rate and investigator assessment(concordance rate 80%)80%)WeeksInvestigator Assessment(HR=0.69,p0.0001)Ridaforolimus Placebo Independent Radiology Review (HR=0.72,p=0.0001)Ridaforolimus Placebo Efficacy result of pediatric populationsRidaforolimus groupl7 patients enrolled l64%tumor size reduction in one osteosarcoma patientl1 PR,4 SD,2 PDlCBR 4mos:5/7=71%lPFS durations:59,48,23,20,19,16,and 8 weeksPlacebo groupl5 patients enrolledlNo Responderl1 SD,4 PDlCBR 4mos:1/5=20%lPFS durations:20,8,4,4,and 4 weeks