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Desmoidtumortrialusinga gammasecretaseinhibitor PF-03084014 VictorM.Villalobos,M.D.,Ph.D. AssistantProfessor Director,SarcomaMedicalOncology DivisionofMedicalOncology Disclosures • Advisorycapacity: • Lilly,Novartis,Janssen Gammasecretaseinhibitionindesmoid • Gammasecretaseisanintegralmembraneprotein thatcleavesmultipledifferenttransmembrane proteincomplexesincluding: • • • • NOTCH E-CADHERIN AmyloidPrecursorProtein others • PF-03084014isanoncompetitive,reversible,targeted agentthatselectivelyinhibitsgammasecretase • ActivationofWNTpathwaythroughB-CatorAPC mutationsappearstobeprimarydriverindesmoid tumors • HypothesisthatcooperativityexistsbetweenWNT pathwayactivationandactiveNOTCHsignaling. • InhibitionofNOTCHmayreverseactivationofBHughes,D.P.M.etal.,ClinicalCancerResearch21,7–9(2015). cateninduetomutationsinBcatorAPC. APhaseI,Dose-FindingStudyinPatientswith AdvancedSolidMalignanciesoftheOral g-SecretaseInhibitorPF-03084014 • 64patients(solidtumors) enrolledin3+3doseescalation design. • MTD:220mgBIDorally(n=16) • RP2Dwas150BIDorally(n=23) • Atotalof9desmoidpatients wereenrolled(7atUCDenver) Messersmith,W.A.etal.ClinicalCancerResearch21,60–67(2015). 1 PF-03084014inDesmoidtumors RESPONSESONGAMMASECRETASEINHIBITORPF03084014INDESMOID TUMORS(months) 0.9 0.8 0.7 Known germlineAPCmutation Spontaneousdesmoid 80 mgBID 100mgBID 130mgBID ● 150mgBID ◼ 220mgBID 0.6 0.5 0.4 0.3 0.2 0.1 0 -0.1 - 12 24 36 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1 Arrows:Patientsstoppedtherapy,maintaineddisease stabilitydespite nofurtherintervention Patientwasbiopsiedatendofstudyandpathologyshowed paucicellulartissuewithprominentcollagenousfibrosis 48 60 72 • 7desmoidsaccruedat UCD(9total) • OverallRECISTresponse rateof71.4% • MedianTTP– Notmet 84 • MedianDOR– 49.8+mo. (47.9-67+mo.) • Meantimetoresponse8.7mo. • Effectiveevenatlow doses(80mgBID) 1 0.9 0.8 Treatmenteffects RESPONSESONGAMMASECRETASEINHIBITORPF03084014INDESMOID TUMORS(months) 0.7 80 mgBID 100mgBID 130mgBID ● 150mgBID ◼ 220mgBID 0.6 0.5 0.4 0.3 0.2 0.1 0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1 12 24 36 48 60 72 • Eveninabsenceof RECISTresponse, therewere considerable 84 treatmenteffects • Arrow– cameoff studyat42 monthsdueto patientpreference Pretreatment 6months 2months 4months 10months 14months 48months OffTherapy 36months 54months Pathologicresponsetotherapy 2012Biopsypriortotreatment Desmoidfibromatosis 2015Endoftreatmentbiopsy Paucicellularfibroconnectivetissuewithprominent collagenousfibrosis Timetotreatmentfailureineachpatientinchronologicorder(weeks) Timetotreatmentfailureoftherapies(chronologic) 42 7 9.5 54 6 PF-03084014 (GSI) OffRx FreeofProgression Tamoxifen/Sulindac Surgery Methotrexate/Vinblastine Vinorelbine Imatinib Indomethacin Liposomal Doxorubicin 15 5 47 15 4 13 53 3 78 2 78 1 0 1 2 3 4 5 6 7 Treatmentduration(years) 8 9 10 11 12 Timetotreatmentfailureoftherapies(chronologic) Timetotreatmentfailureineachpatientinchronologicorder(weeks) 42 7 9.5 54 6 PF-03084014 (GSI) OffRx FreeofProgression Tamoxifen/Sulindac Surgery Methotrexate/Vinblastine Vinorelbine Imatinib Indomethacin Liposomal Doxorubicin 15 5 47 15 4 13 53 3 78 2 78 1 0 1 2 3 4 5 6 7 Treatmentduration(years) 8 9 10 11 12 4/28/11 baseline 10/8/14 Week142 Week63 Takenoffstudy RECIST17cm forpatient %Change---protocol WHO171.7cm2 violation %Change----- RECIST12cm %Change-30% WHO24.7cm2 %Change-85% 5/12/16 Week262 RECIST11.7cm %Change-31% WHO34.6cm2 %Change-80% RECIST12.3cm %Change+5% WHO27.1cm2 %Change+10% Conclusions– PF-03084014 gammasecretaseinhibitor • Excitingpotentialforuseindesmoidpatients • 72%RECISTresponserate • Activeatevenlowdoses(aslowas80mgBID) • Tolerablesideeffectprofile(primarilydiarrhea,hypophosphatemia) • Clinicalbenefitin100%ofpatients(onlypatientwithprogressionhad mildregressionlasting12months) • Evenifnoresponsebysizecriteria,evidenceoftumoractivityon pathology • Workingonfurtherclinicaldevelopment Acknowledgements • PhaseIteam • WellsMessersmithMD • AntonioJimenoMD,PhD • LiaGoreMD • SarcomaTeam • AnthonyEliasMD • BriannaHoffnerNP • Pfizer T1post Pretreatment T1post 6weeksafterstarting T1post 4yearsafterstarting T2pre Pretreatment T2pre 6weeksafterstarting T2pre 4yearsafterstarting