Post on 23-Jan-2016
description
Clinical Activity Observed in
a Phase 1 Dose-Escalation Trial of an Oral
MET and ALK Inhibitor, PF-02341066
Clinical Activity Observed in
a Phase 1 Dose-Escalation Trial of an Oral
MET and ALK Inhibitor, PF-02341066
EL Kwak1, DR Camidge2, J Clark1, GI Shapiro3, RG Maki4,
MJ Ratain5, B Solomon6, Y-J Bang7, S-H Ou8, R Salgia5
EL Kwak1, DR Camidge2, J Clark1, GI Shapiro3, RG Maki4,
MJ Ratain5, B Solomon6, Y-J Bang7, S-H Ou8, R Salgia5
1. Massachusetts General Hospital 5. University of Chicago Cancer Center
2. University of Colorado Cancer Center 6. Peter MacCallum Cancer Centre
3. Dana-Farber Cancer Institute 7. Seoul National University4. Memorial Sloan-Kettering Cancer Center 8. University of California at
Irvine
PF-02341066PF-02341066
Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants
Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants
ON
N
Cl
F
Cl
NN
NMETMET ALKALK
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
SEMA
TMTMExtracellular
Intracellular
YYPP
YYPP
Kinase
YYPP
YYPPYYPPYYPP
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
TMTMExtracellular
Intracellular
YYPP
YYPP
Kinase
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
KinaseYY
PP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
Kinase
Cytoplasmic Fusion Variants of
ALK
Cytoplasmic Fusion Variants of
ALK
NPM-ALKNPM-ALK EML4-ALKEML4-ALK
Study Dosing and ObjectivesStudy Dosing and Objectives
PF-02341066 dosing schedule: Continuous oral administration for 28 days per cycle. A single Day -7 dose was administered to establish PK.
1. Phase I dose escalation Determine the safety profile of PF-02341066. Determine recommended phase 2 dose (RP2D). Determine the PK profile after oral dosing.
2. Recommended Phase 2 Dose Cohort (RP2D) Enroll patients with MET or ALK activation into a Molecular Cohort. Focused study on patients with ALK fusion after observing preliminary evidence of dramatic
activity.
PF-02341066 dosing schedule: Continuous oral administration for 28 days per cycle. A single Day -7 dose was administered to establish PK.
1. Phase I dose escalation Determine the safety profile of PF-02341066. Determine recommended phase 2 dose (RP2D). Determine the PK profile after oral dosing.
2. Recommended Phase 2 Dose Cohort (RP2D) Enroll patients with MET or ALK activation into a Molecular Cohort. Focused study on patients with ALK fusion after observing preliminary evidence of dramatic
activity.
PF-02341066: Phase 1 Dose EscalationPF-02341066: Phase 1 Dose Escalation
Key Eligibility
Advanced malignancy (excluding leukemias)
Age ≥ 18 years
Refractory to or no standard care
ECOG PS 0 or 1
Adequate organ function
Stable brain metastases
Key Eligibility
Advanced malignancy (excluding leukemias)
Age ≥ 18 years
Refractory to or no standard care
ECOG PS 0 or 1
Adequate organ function
Stable brain metastases
Patient Characteristics
37 patients entered
Most common tumor types:
CRC (6), Sarcoma (4), NSCLC (3), ASPS (2), IMT (2), Bladder (2), Pancreas (2), Ovarian (2)
Mean age: 49 years
Male% : Female% = 57 : 43
Race: 89% white
ECOG: PS 0 = 43%, PS 1 = 54%
Prior therapies >3: 44%
Patient Characteristics
37 patients entered
Most common tumor types:
CRC (6), Sarcoma (4), NSCLC (3), ASPS (2), IMT (2), Bladder (2), Pancreas (2), Ovarian (2)
Mean age: 49 years
Male% : Female% = 57 : 43
Race: 89% white
ECOG: PS 0 = 43%, PS 1 = 54%
Prior therapies >3: 44%
PF-02341066: Dose EscalationPF-02341066: Dose Escalation
MTD = Maximum Tolerated Dose
RP2D = Recommended Phase 2 Dose
MDZ = Midazolam (In-vitro data indicated that
PF-02341066 is a major substrate and
inhibitor of CYP3A activity).
MTD = Maximum Tolerated Dose
RP2D = Recommended Phase 2 Dose
MDZ = Midazolam (In-vitro data indicated that
PF-02341066 is a major substrate and
inhibitor of CYP3A activity).
Cohort 4Cohort 4
Cohort 1Cohort 1
50 mg QD50 mg QD
Cohort 2Cohort 2
100 mg QD100 mg QDMDZ Sub-StudyMDZ Sub-Study
Cohort 3Cohort 3
200 mg QD200 mg QD
Cohort 4Cohort 4
200 mg BID200 mg BID
Cohort 5Cohort 5
300 mg BID300 mg BID
Cohort 6Cohort 6
250 mg BID250 mg BID
MDZ Sub-StudyMDZ Sub-Study
MTD / RP2DMTD / RP2D
Most Common Treatment-Related Adverse Events (≥ 10%)
Dose Escalation Cohorts (N=37)
Data in the database as of March 9, 2009Data in the database as of March 9, 2009
DLTs are highlighted in red.DLTs are highlighted in red.
Adverse Event
50 mg QD (n=3)
100 mg QD (n=4)
200 mg QD (n=8)
200 mg BID (n=7)
300 mg BID (n=6)
250 mg BID (n=9)
Grade 1-2 1-2 1-2 3 1-2 1-2 3 1-2 3
Nausea 2 3 6 0 3 4 0 4 0
Vomiting 2 2 5 0 2 2 0 3 0
Diarrhea 3 0 1 0 2 0 0 2 0
Fatigue 2 2 0 0 0 0 2 1 1
Headache 0 2 1 0 1 0 0 0 0
Visual Disturbance
0 0 0 0 1 1 0 0 0
ALT Increased 0 0 0 1 1 0 0 0 0
AST Increased 0 0 0 0 1 0 0 0 0
PF-02341066: Overview of Pharmacokinetics
PF-02341066: Overview of Pharmacokinetics
Peak plasma concentration occurred at 4 hr after single doses
Plasma elimination half life ~53 hr (at 250 mg BID)
No evidence of non-linearity in PK at doses between
100 mg QD - 300 mg BID
Moderate inter-subject variability (CV 30-69% for AUC and Cmax)
Moderate CYP3A4 inhibitor (mean 3.6-fold increase in oral MDZ AUC, 90%CI:
2.7-4.9)
Peak plasma concentration occurred at 4 hr after single doses
Plasma elimination half life ~53 hr (at 250 mg BID)
No evidence of non-linearity in PK at doses between
100 mg QD - 300 mg BID
Moderate inter-subject variability (CV 30-69% for AUC and Cmax)
Moderate CYP3A4 inhibitor (mean 3.6-fold increase in oral MDZ AUC, 90%CI:
2.7-4.9)
PF-02341066 Concentrations vs.
Time at Steady State
PF-02341066 Concentrations vs.
Time at Steady State
Cycle 1 Day 15
Time (hr)
PF-0
23
41
06
6 M
edia
n C
once
ntr
ati
on (
ng/m
L)
0 2 4 6 8 10 1201
00
20
03
00
40
05
00
50mg QD100mg QD200mg QD200mg BID250mg BID300mg BID
Cycle 2 Day 1
Time (hr)
0 2 4 6 8 10 1201
00
20
03
00
40
05
00
50mg QD100mg QD200mg QD200mg BID250mg BID300mg BID
Target C trough, c-MET
Target C trough, ALK
Patients of Molecular Interest Enrolled
into the Dose-Escalation Cohort
Patients of Molecular Interest Enrolled
into the Dose-Escalation Cohort
200 mg BID cohort
42 yo male with Sarcoma (2p23 ALK+ Inflammatory
Myofibroblastic Tumor), achieved partial response
by cycle 2
200 mg BID cohort
42 yo male with Sarcoma (2p23 ALK+ Inflammatory
Myofibroblastic Tumor), achieved partial response
by cycle 2 300 mg BID cohort
49 yo male with EML4-ALK fusion NSCLC
Dramatic clinical response within cycle 1,
then limited by LFTs
300 mg BID cohort
49 yo male with EML4-ALK fusion NSCLC
Dramatic clinical response within cycle 1,
then limited by LFTs
42 yo Male with Inflammatory Myofibroblastic Tumor
(ALK Fusion)
Pre-Treatment After 2 Cycles of PF-02341066
Patients of Molecular Interest Enrolled
into the Dose-Escalation Cohort
Patients of Molecular Interest Enrolled
into the Dose-Escalation Cohort
200 mg BID cohort
42 yo male with Sarcoma (2p23 Inflammatory
Myofibroblastic Tumor), achieved partial response
by cycle 2
200 mg BID cohort
42 yo male with Sarcoma (2p23 Inflammatory
Myofibroblastic Tumor), achieved partial response
by cycle 2 300 mg BID cohort
49 yo male with EML4-ALK fusion NSCLC.
Dramatic clinical response within cycle 1,
then limited by LFTs
300 mg BID cohort
49 yo male with EML4-ALK fusion NSCLC.
Dramatic clinical response within cycle 1,
then limited by LFTs
EML4-ALK Fusion in NSCLCEML4-ALK Fusion in NSCLC
Nature 448; 561 (2007)Nature 448; 561 (2007)Nature 448; 561 (2007)Nature 448; 561 (2007)
EML4-ALK Frequency:
Adenocarcinoma = 4% (26/662)
EML4-ALK Frequency:
Adenocarcinoma = 4% (26/662)
At least 7 fusion variantsAt least 7 fusion variants
~250 kb ~300 kb
t(2;5) ALK genebreakpoint region
Chromosome 2p23 region
3’ 5’
Break-Apart FISH Assay for ALK Fusion Genes
Potential Fusion Partners:
• EML4
• KIF5B• TFG
RP2D Molecular Cohort: NSCLC with ALK Fusion, Patient Characteristics
CharacteristicsMedian (Range) Age,
YearsGender (Male:Female)
N=19 50 (28-73)
9:10
ECOG PS 0 4 (21%)
1 12 (63%)
2 3 (16%)Smoking
HistoryCurrent Smoker
0
Former Smoker 5 (26%)
Never Smoker 14 (74%)Histology Adenocarcinoma 17 (90%)
Squamous Cell Carcinoma 1 (5%)
Unknown 1 (5%)Prior
Treatment 1 Regimen 7 (37%)
2 Regimens 4 (21%)
3 Regimens 4 (21%)
> 3 Regimens 4 (21%)
Data in the database as of March 9, 2009Data in the database as of March 9, 2009
Study Status – NSCLC ALK PatientsStudy Status – NSCLC ALK Patients
27 Patients Dosed: Data Collection Ongoing
18 Patients Entered into Safety Database
19 Patients Evaluable for Response
27 Patients Dosed: Data Collection Ongoing
18 Patients Entered into Safety Database
19 Patients Evaluable for Response
Tumor Size Change
Duration of Response (Weeks)
-100
-80
-60
-40
-20
0
20
40
Green - PR Blue - SD Black - PD
% o
f b
est
chan
ge
fro
m
bas
elin
e
Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK
Fusions
Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK
Fusions
8+8+2020
4040
8+8+ 12122+2+ 13
+13
+ 15+
15+
8+8+
23+
23+
15+
15+
2+2+
1616
8+8+
4+4+
One patient had clinical progression and discontinued without radiographic confirmation.
Molecular Cohort: NSCLC ALK FusionMolecular Cohort: NSCLC ALK Fusion
Overall Response Rate = 53% (10/19 pts)
Disease Control Rate at 8 weeks = 79% (15/19 pts)
4 patients had progression at first evaluation
Overall Response Rate = 53% (10/19 pts)
Disease Control Rate at 8 weeks = 79% (15/19 pts)
4 patients had progression at first evaluation
48 yo Female Non-Smoker with NSCLC ALK Fusion
Pre-Treatment Pre-Treatment After 2 Cycles PF-02341066After 2 Cycles PF-02341066
Treatment-Related Adverse Events (≥10%) NSCLC Patients with ALK Fusion (N=18)
Data in the database as of March 9, 2009Data in the database as of March 9, 2009
Treatment-
Related
Adverse Event
Grade 1
n (%)
Grade 2
n (%)
Grade 3
n (%)
Grade 4
n (%)
Total n
(%)
Nausea 11 (61) 0 0 0 11 (61)
Vomiting 7 (39) 0 0 0 7 (39)
Diarrhea 6 (33) 0 0 0 6 (33)
Visual Disturbance
4 (22) 0 0 0 4 (22)
ALT Increased 0 2 (11) 1 (6) 0 3 (17)
Constipation 0 2 (11) 1 (6) 0 3 (17)
Cough 2 (11) 0 0 0 2 (11)
Conclusions
The MTD and RP2D of oral PF-02341066 is 250 mg BID.
The most frequent AEs were mild and moderate GI-related and fatigue. All AEs were manageable and reversible.
Treatment with PF-02341066 resulted in dramatic clinical activity against tumors carrying activating ALK gene fusions.
Results of this trial support the importance of incorporating prospective molecular profiling into early-phase clinical trials for targeted therapies.
The MTD and RP2D of oral PF-02341066 is 250 mg BID.
The most frequent AEs were mild and moderate GI-related and fatigue. All AEs were manageable and reversible.
Treatment with PF-02341066 resulted in dramatic clinical activity against tumors carrying activating ALK gene fusions.
Results of this trial support the importance of incorporating prospective molecular profiling into early-phase clinical trials for targeted therapies.
PF-02341066: Future Directions
For the Molecular Cohort Focus efforts on identifying patients with MET
amplification or mutations Conduct genetic characterization of ALK
fusion partners and EML4-ALK variants in responders
and non-responders Conduct molecular analyses of other determinants of response
Clinical Development of PF-02341066 Conduct a Phase 3 clinical trial in NSCLC
patients harboring ALK fusions
For the Molecular Cohort Focus efforts on identifying patients with MET
amplification or mutations Conduct genetic characterization of ALK
fusion partners and EML4-ALK variants in responders
and non-responders Conduct molecular analyses of other determinants of response
Clinical Development of PF-02341066 Conduct a Phase 3 clinical trial in NSCLC
patients harboring ALK fusions
AcknowledgmentsAcknowledgments
PfizerIsan Chen, James Christensen, Victoria Cohan, Gina Emory, Ray Lu, Sophia Randolph, Weiwei Tan, Greg Wei, Keith Wilner
All The Patients
Funding provided by PfizerFunding provided by Pfizer
Peter MacCallum Cancer Centre
Peter MacCallum Cancer Centre
Massachusetts General HospitalMassachusetts General Hospital
Dana-Farber Cancer InstituteDana-Farber Cancer Institute
Beth Israel Deaconess Medical CenterBeth Israel Deaconess Medical Center
Memorial Sloan KetteringMemorial Sloan Kettering
Seoul National UniversitySeoul National University
University of California - Irvine
University of California - Irvine
University of ChicagoUniversity of Chicago
University of ColoradoUniversity of Colorado
Geoffrey Shapiro, Pasi Janne*, James Butrynski, Leena Gandhi, Andrew Wolanski Suzanne Hitchcock-Bryan, Charles Lee
Geoffrey Shapiro, Pasi Janne*, James Butrynski, Leena Gandhi, Andrew Wolanski Suzanne Hitchcock-Bryan, Charles Lee
Bruce Dezube, Daniel Costa, Myles ClancyBruce Dezube, Daniel Costa, Myles Clancy
Robert Maki, Suresh C. Jhanwar*Linda Ahn, Cory OrnelasRobert Maki, Suresh C. Jhanwar*Linda Ahn, Cory Ornelas
Yung-Jue Bang, Woo-Ho Kim*, Dong-Wan KimSe-Hoon Lee, Do Youn Oh, Sae-Won HanYung-Jue Bang, Woo-Ho Kim*, Dong-Wan KimSe-Hoon Lee, Do Youn Oh, Sae-Won Han
Benjamin Solomon, Alex Dobrovic*, StephenFox*, Hongdo Do*, Toni-Maree Rogers*Benjamin Solomon, Alex Dobrovic*, StephenFox*, Hongdo Do*, Toni-Maree Rogers*
Ross Camidge, Marileila Garcia*, S. GailEckhardt, Wells MessersmithRoss Camidge, Marileila Garcia*, S. GailEckhardt, Wells Messersmith
Sai Hong OuSai Hong Ou
Ravi Salgia, Mark Ratain, David GearyLeonardo Faoro, Rajani KantetiRavi Salgia, Mark Ratain, David GearyLeonardo Faoro, Rajani Kanteti
John Iafrate*, Jeffrey Clark, Eunice Kwak Thomas Lynch, Alice Shaw, Panos Fidias Jeffrey Engelman, Marguerite Parkman
John Iafrate*, Jeffrey Clark, Eunice Kwak Thomas Lynch, Alice Shaw, Panos Fidias Jeffrey Engelman, Marguerite Parkman
* Molecular Profiling Contributor* Molecular Profiling Contributor
All The Research StaffAll The Research Staff
ALK-Related EfficacyEvaluable NSCLC Patients
ALK-Related EfficacyEvaluable NSCLC Patients
* Best response to EGFR inhibitor* Best response to EGFR inhibitor
19 Evaluable: 10 19 Evaluable: 10 (7 Confirmed; 3 Unconfirmed),(7 Confirmed; 3 Unconfirmed), 5 SD; 4 PD 5 SD; 4 PD19 Evaluable: 10 19 Evaluable: 10 (7 Confirmed; 3 Unconfirmed),(7 Confirmed; 3 Unconfirmed), 5 SD; 4 PD 5 SD; 4 PD
Patient ID Previous Treatments
Best Response
PF-1066 Best Response
Duration of Response Status
10021042 1 SD PR 12 wk Discontinued (5 mo)
10081001 2 (erlotinib) PD*,PR* PR 15 wk + Ongoing (8 mo +)
10021038 2 (erlotinib) SD,SD* PR 23 wk + Ongoing (7 mo +)
10021039 1 PD PR 15 wk + Ongoing (7 mo +)
10071016 3 PD,PD,PD PR 8 wk + Ongoing (4 mo +)
10021043 2 PD,SD PR 13 wk + Ongoing (4 mo +)
10071019 7 (gefitinib) PD,SD,PD*,SD,SD,SD,PD PR 8 wk + Ongoing (2 mo +)
10071020 5 (gefitinib) SD,SD,PD*,PR, PR uPR 4 wk + Ongoing (3 mo +)
10021023 3 SD/PD/PD uPR 2 wk + Ongoing (2 mo +)
10081002 3 (erlotinib) SD/PD/*SD uPR 2 wk + Ongoing (2 mo +)
10021045 1 SD SD N/A Ongoing (2 mo +)
10021056 1 SD SD N/A Ongoing (2 mo +)
10021026 3 (erlotinib) SD*,SD,PD SD N/A Discontinued (PD) (10 mo)
10021040 1 (erlotinib) PD* SD N/A Discontinued (PD) (4 mo)
10021014 2 (erlotinib) SD,PD* SD N/A Discontinued (PD) (5 mo)
10021051 1 PD PD N/A Discontinued (<1 mo)
10021058 1 PD PD N/A Discontinued (1 mo)
10071021 3 (erlotinib) SD,SD,PD* PD N/A Discontinued (<1 mo)
10051003 4 (erlotinib) PD*,PR,PR,SD PD N/A Discontinued (1 mo)