Desmoid tumor trial using a gamma secretase inhibitor PF ... · Desmoid tumor trial using a gamma...
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Desmoid tumor trial using a gamma secretase inhibitor PF-03084014 Victor M. Villalobos, M.D., Ph.D. Assistant Professor Director, Sarcoma Medical Oncology Division of Medical Oncology
Transcript of Desmoid tumor trial using a gamma secretase inhibitor PF ... · Desmoid tumor trial using a gamma...
Desmoidtumortrialusingagammasecretaseinhibitor
PF-03084014
VictorM.Villalobos,M.D.,Ph.D.AssistantProfessor
Director,SarcomaMedicalOncologyDivisionofMedicalOncology
Disclosures
• Advisorycapacity:• Lilly,Novartis,Janssen
Gammasecretaseinhibitionindesmoid• Gammasecretaseisanintegralmembraneproteinthatcleavesmultipledifferenttransmembraneproteincomplexesincluding:• NOTCH• E-CADHERIN• AmyloidPrecursorProtein• others
• PF-03084014isanoncompetitive,reversible,targetedagentthatselectivelyinhibitsgammasecretase• ActivationofWNTpathwaythroughB-CatorAPCmutationsappearstobeprimarydriverindesmoidtumors• HypothesisthatcooperativityexistsbetweenWNTpathwayactivationandactiveNOTCHsignaling.• InhibitionofNOTCHmayreverseactivationofB-cateninduetomutationsinBcatorAPC. Hughes,D.P.M.etal.,ClinicalCancerResearch21,7–9(2015).
APhaseI,Dose-FindingStudyinPatientswithAdvancedSolidMalignanciesoftheOralg-SecretaseInhibitorPF-03084014
• 64patients(solidtumors)enrolledin3+3doseescalationdesign.•MTD:220mgBIDorally(n=16)• RP2Dwas150BIDorally(n=23)• Atotalof9desmoidpatientswereenrolled(7atUCDenver)
Messersmith,W.A.etal.ClinicalCancerResearch21,60–67(2015).
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RESPONSESONGAMMASECRETASEINHIBITORPF03084014INDESMOID
TUMORS(months)
Known germlineAPCmutation
Spontaneousdesmoid� 80 mgBID
� 100mgBID� 130mgBID
● 150mgBID
◼ 220mgBID
Arrows:Patientsstoppedtherapy,maintaineddiseasestabilitydespite nofurtherintervention
Patientwasbiopsiedatendofstudyandpathologyshowedpaucicellulartissuewithprominentcollagenousfibrosis
PF-03084014inDesmoidtumors
• 7desmoidsaccruedatUCD(9total)• OverallRECISTresponserateof71.4%• MedianTTP– Notmet• MedianDOR– 49.8+mo.(47.9-67+mo.)• Meantimetoresponse-8.7mo.• Effectiveevenatlowdoses(80mgBID)
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RESPONSESONGAMMASECRETASEINHIBITORPF03084014INDESMOIDTUMORS(months)
� 80 mgBID� 100mgBID� 130mgBID● 150mgBID◼ 220mgBID
Treatmenteffects
• EveninabsenceofRECISTresponse,therewereconsiderabletreatmenteffects• Arrow– cameoffstudyat42monthsduetopatientpreference
2monthsPretreatment 4months
6months 10months 14months
36months 48months 54months
OffTherapy
2012Biopsypriortotreatment 2015Endoftreatmentbiopsy
Pathologicresponsetotherapy
Paucicellularfibroconnectivetissuewithprominentcollagenousfibrosis
Desmoidfibromatosis
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Timetotreatmentfailureineachpatientinchronologicorder(weeks)
Treatmentduration(years)
PF-03084014 (GSI)OffRx FreeofProgressionTamoxifen/SulindacSurgeryMethotrexate/VinblastineVinorelbineImatinibIndomethacinLiposomal Doxorubicin
Timetotreatmentfailureoftherapies(chronologic)42
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53 13
78
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Timetotreatmentfailureineachpatientinchronologicorder(weeks)
Treatmentduration(years)
PF-03084014 (GSI)OffRx FreeofProgressionTamoxifen/SulindacSurgeryMethotrexate/VinblastineVinorelbineImatinibIndomethacinLiposomal Doxorubicin
Timetotreatmentfailureoftherapies(chronologic)42
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4/28/11baseline
Week63Takenoffstudyforpatientprotocolviolation
10/8/14Week142
5/12/16Week262
RECIST17cm%Change----WHO171.7cm2%Change-----
RECIST11.7cm%Change-31%WHO34.6cm2%Change-80%
RECIST12cm%Change-30%WHO24.7cm2%Change-85%
RECIST12.3cm%Change+5%WHO27.1cm2%Change+10%
Conclusions– PF-03084014gammasecretaseinhibitor
• Excitingpotentialforuseindesmoidpatients• 72%RECISTresponserate• Activeatevenlowdoses(aslowas80mgBID)• Tolerablesideeffectprofile(primarilydiarrhea,hypophosphatemia)• Clinicalbenefitin100%ofpatients(onlypatientwithprogressionhadmildregressionlasting12months)• Evenifnoresponsebysizecriteria,evidenceoftumoractivityonpathology• Workingonfurtherclinicaldevelopment
Acknowledgements
• PhaseIteam• WellsMessersmithMD• AntonioJimenoMD,PhD• LiaGoreMD
• SarcomaTeam• AnthonyEliasMD• BriannaHoffnerNP
• Pfizer
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