Transcript A Phase 1b Study of GDC-0449, a hedgehog inhibitor in

A Phase 1b/II Study of Vismodegib, a hedgehog
inhibitor in combination with RO4929097, a notch
(GSI) inhibitor in metastatic sarcomas.
Mrinal Gounder*, Mark Dickson*, Sandra D'Angelo*, Mary Louise Keohan*, LiXuan Qin, Richard Carvajal, Ping Chi, Alexander Shoushtari, Mercedes Condy,
Yelena Ustoyev, Armando Sanchez, Lanier Tanner, Rita Morales, Joseph Erinjeri,
Nian Wu, Cristina Antonescu, Narasimhan Agaram, Samuel Singer, Sam Yoon,
Aimee Crago, Robert Maki, S. Percy Ivy1, Naoko Takebe1, William D. Tap* and Gary
K. Schwartz *.
Sarcoma Medical Oncology Service
Memorial Sloan-Kettering Cancer Center,
New York, NY
Conflict of Interest: None
Rationale for study
Hedgehog: Embryonic pathway reactivated in cancer
Hedgehog Pathway
VISMODEGIB
Survival
and
Growth
GLI1
GLI2
GLI3
Smooth
Patched
Hedgehog
Notch: Embryonic pathway reactivated in cancer
NICD
Notch
MPNST
γ-Secretase
MAML
NICD
CSL
RO4929097
Akt
P
HES1
HEY1
Survivin
Survival and
Growth
Cell Viability
Combination of Cyclopamine (Hedgehog inhibitor) and GSI (Notch Inhibitor)
Gary Schwartz lab, unpublished
Hypothesis #1: Combined inhibition of
Hedgehog and Notch pathways is a
rational therapeutic strategy in
patients with advanced sarcoma.
Question #1: Are the two drugs safe to combine?
• GDC-0449 (Vismodegib)
• RO4929097
• Hedgehog inhibitor
• Notch inhibitor
• FDA approved in
metastatic and
advanced Basal Cell
Carcinoma.
• Phase 2 dose: < 20 mg
oral, daily.
• 150 mg oral, once daily.
A phase I study of RO4929097, a novel gamma secretase inhibitor, in patients with
advanced solid tumors Journal of Clinical Oncology, April 23rd. 2012
Key Eligibility Criteria
-- Age > 18
-- Advanced, metastatic sarcoma
-- measurable disease (RECIST 1.1)
-- 1 – 4 prior therapies.
Phase Ib: Maximum Administered Dose
3 + 3 design
GDC -0449 (HH)
RO4929097 (NCH)
DLT
Dose Level 1
150 mg daily
10 mg daily
None
Dose Level 2
150 mg daily
15 mg daily
None
-- 9 patients enrolled to Phase I: combination well
tolerated.
-- Detailed pharmacokinetic data presented at ASCO 2012
Question #2:
Are the drugs getting into tumor and
inhibiting the pathways?
Pre- and post- treatment tumor biopsies
confirm inhibition of Notch
Pre- and Post-treatment biopsy of patients confirms
inhibition of Hedgehog pathway
GLI-1 by RT-PCR
GLI-1 by RT-PCR
Phase II Study Design
Stratified : Liposarcoma vs. other
Number of prior 1 vs. >1
Primary Endpoint
Progression Free Survival
Sample Size: 90 pts (45 in each arm)
With a 1-sided alpha of 0.1, this sample size allowed to
detect a 75% improvement in the combination arm with a
power of 0.9
In 2013, Roche discontinued further development of the
Notch inhibitor (RO4929097) and ~ 15 studies nationwide in
many solid tumors was prematurely closed.
Sarcoma study was closed in April 2014
67 of the planned 90 pts were enrolled to the study.
Final Phase II results: 67 pts (planned 90)
Notch alone
34
Notch + Hedgehog
33
p-value
56
46
NS
Gender - Male
58%
54%
NS
ECOG PS 0
88%
87%
NS
# Prior therapy
2
3
NS
Liposarcoma
8
9
NS
Other histology
26
24
Number enrolled
Age
HISTOLOGY
Other
20%
Liposarcoma
26%
Ewing
6%
Chordoma
6%
Chondrosarcoma
3%
MFH
14%
GIST
6%
LMS
8%
Epithelioid
6%
Desmoid
5%
Notch Alone
Hedgehog + Notch
TOXICITIES
Grade 1 - 2
Grade 3 -4
Grade 1 -2
Grade 3-4
Anemia
21 (6%)
3 (7%)
22 (5%)
5 (13%)
Thrombocytopenia
8 (2%)
0
11 (3%)
0
Diarrhea
22 (6%)
0
56 (13%)
1
Metabolic
193 (56%)
24 (57%)
177 (43%)
10 (27%)
Fatigue
34 (10%)
3 (7%)
51 (12%)
2
Other
10 (3%)
4 (9.5%)
19 (4.6%)
3
Total
343
42
410
37
Response
• No RECIST responses (CR or PR) were seen.
• Minor response and stable disease was seen in
epithelioid sarcoma, liposarcoma and MFH/UPS.
Notch Single Agent:
Best response – Duration on study drug
100
80
TIME ON STUDY
RESPONSE
20 months
60
11 months
40
20
0
-20
5 months
Notch and Hedgehog:
Best response – Duration on study drug
60
RESPONSE
TIME ON STUDY
50
10 months
40
30
6 months
20
10
0
-10
Progression Free Survival
p 0.38
Notch + Hedgehog:
mPFS: 12 weeks
6 week PFS: 60%
Notch alone
mPFS: 8.8 wks
6 week PFS: 60%
What can we learn from this study?
De-differentiated Liposarcoma
March 2012
Nov 2012
Notch Inhibitor – Single agent
Time on Prior Rx vs. Study drug
PFS: prior drug vs. study drug
500
450
PRIOR DRUG
STUDY DRUG
400
12 months
350
300
250
8 months
200
150
100
3 months
50
0
Individual Liposarcoma Patients: Prior Drug vs. Study drug
Epithelioid Sarcoma
1
20% tumor shrinkage – 5 months SD
2
POD – 1 cycle
3
POD – 1 cycle
4
POD – 1 cycle
NTRK1 and TET2 mutations
Desmoid : Wnt pathway
• -- Cross talk between Wnt, Notch and
Hedgehog.
• -- Partial responses with PF-03084014 and
OMP54-F28.
Desmoid Tumor: No Responses
300
Time on Study
250
200
150
Series1
Series2
100
50
0
Progressive Disease
Study Terminated
Study Terminated
Withdrawal
Study Terminated
Notch
Notch
Hedgehog + Notch
Hedgehog + Notch
Hedgehog + Notch
NOTCH
HEDGEHOG + NOTCH
Chondrosarcoma
• Up-regulation of the Hedgehog pathway
• 5 pts enrolled: No responses or stable disease.
Chordoma
• -- gain of 7q – SHH upregulation
4 patients with chordoma enrolled.
No responses or stable disease with the Hedgehog inhibitor or Notch inhibitor.
Conclusions
• The combination of Vismodegib and RO4929097 is well tolerated.
• Notch and Hedgehog was successfully inhibited in tumor tissues.
• The study did not meet its PFS endpoint
• Notch inhibition may have a role in a subset of liposarcoma,
epithelioid sarcoma and MFH.
• Hedgehog/Smoothened inhibitors (GDC-0449 and IPI-926) have
not shown meaningful clinical activity in chondrosarcoma (or
chordoma).
• Despite pathway inhibition, lack of responses in desmoid tumor
cannot be fully explained.
Acknowledgements
MSKCC
NCI
William Tap
Gary Schwartz
Mark Dickson
Mary Louise Keohan
Sandra D’Angelo
Richard Carvajal
Robert Maki
Li-Xuan Qin
Joseph Erinjeri
Mercedes Condy
Yelena Usteyov
Lanier Tanner
Rita Morales
Percy Ivy
Naoko Takebe
FUNDING
Gateway Foundation
Siskind Family Fund
Crosstalk between Hedgehog and Notch pathway
Notch Pathway
Notch
Hedgehog Pathway
NICD
NICD
Hedgehog
γ-Secretase
CSL
MAML
NICD
Akt
P
mTOR P
Hes3
Survival and
Growth
Akt Pathway
Patched
GLI1
GLI2
GLI3
Smooth
Fibrosarcoma – MFH/UPS
Histology
Histology
Notch
Hedgehog + Notch
Liposarcoma
9
10
MFH
5
2
LMS
3
1
Desmoid
2
4
Epithelioid
2
2
GIST
2
1
Chondrosarcoma
1
4
Chordoma
2
2
Ewing
2
1
RMS, Clear cell, DSRCT, Fibrosarcoma, GIST,
MPNST, SFT, Synovial Sarcoma, PEComa,
Osteosarcoma
7
4
STS and Notch-4
Sam S. Yoon et. al Angiogenic Profile of Soft Tissue Sarcomas Based on Analysis of Circulating Factors and
Microarray Gene Expression Journal of Surgical Research, Volume 135, Issue 2, 2006, 282 - 290
MPNST
Notch inhibition in Liposarcoma
Unpublished. Raymond Meng (Schwartz and Singer lab), MSKCC
Notch Inhibition (Ro) and Apoptosis