Download Desmoid tumor trial using a gamma secretase inhibitor PF

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