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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*, Li-Xuan 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
SmoothGLI2GLI3
GLI1
Patched
Hedgehog
Hedgehog Pathway
Survival and
Growth
Hedgehog: Embryonic pathway reactivated in cancer
VISMODEGIB
NICDNotch
γ-Secretase
Survival andGrowth
HES1HEY1 Survivin
NICDCSLMAML
Notch: Embryonic pathway reactivated in cancer
Akt P
RO4929097
MPNST
Combination of Cyclopamine (Hedgehog inhibitor) and GSI (Notch Inhibitor)
Cell
Viab
ility
Gary Schwartz lab, unpublished
Hypothesis #1: Combined inhibition of Hedgehog and Notch pathways is a rational therapeutic strategy in patients with
advanced sarcoma.
• GDC-0449 (Vismodegib)
• Hedgehog inhibitor
• FDA approved in metastatic and advanced Basal Cell Carcinoma.
• 150 mg oral, once daily.
• RO4929097
• Notch inhibitor
• Phase 2 dose: < 20 mg oral, 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
-- Age > 18
-- Advanced, metastatic sarcoma
-- measurable disease (RECIST 1.1)
-- 1 – 4 prior therapies.
Key Eligibility Criteria
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
Pre- and post- treatment tumor biopsies confirm inhibition of Notch
Myx
oid
Lipos
arco
ma
Clea
r Cel
l
Lipos
arco
ma
Myx
oid
Chon
dros
arco
ma
Epith
elio
id
Desm
oid
Pre- and Post-treatment biopsy of patients confirms inhibition of Hedgehog pathway
GLI-1 by RT-PCR GLI-1 by RT-PCR
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 Notch + Hedgehog p-value
Number enrolled 34 33
Age 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
Liposarcoma26%
MFH14%
LMS9%
Desmoid6%
Epithelioid 6%
GIST6%
Chondrosarcoma3%
Chordoma6%
Ewing6%
Other20%
HISTOLOGY
TOXICITIESNotch Alone Hedgehog + Notch
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
MPNST
MFH/U
PS
Ewing's
Sarco
ma
Chondrosar
coma
Leiomyo
sarco
ma
Ewing's
Sarco
ma
Liposar
coma
Leiomyo
sarco
ma
Extra
skeletal
myx
oid chondro
Liposar
coma
Liposar
coma
Desmoid Tu
morGIST
Chordoma
Liposar
coma
Leiomyo
sarco
ma
MFH/U
PS
MFH/U
PS
Fibro
sarco
ma
Alveolar
Rhabdomyo
sarco
ma
Chordoma
Epith
elioid sa
rcoma
Liposar
coma
Liposar
coma
PEComa
GIST
Desmoid Tu
mor
liposar
coma
MFH/U
PS
Liposar
coma
Epith
elioid sa
rcoma
Liposar
coma
MFH/U
PS
-20
0
20
40
60
80
100
RESPONSE TIME ON STUDY
20 months
11 months
5 months
Liposar
coma
Liposar
coma
Leiomyo
sarco
ma
Osteosar
coma
Liposar
coma
Extra
skelet
al myx
oid chondro
Epith
elioid sa
rcoma
Liposar
coma
Liposar
coma
GIST
Liposar
coma
Desmoplas
tic Small
Round Cell
Chondrosar
coma
Chondrosar
coma
Liposar
coma
Ewing's
Sarco
ma
Liposar
coma
MFH/U
PS
Chondrosar
coma
solita
ry fibro
us tumor
Chordoma
Chordoma
Desmoid Tu
mor
Desmoid Tu
mor
Epith
elioid sa
rcoma
Liposar
coma
MFH/U
PS
solita
ry fibro
us tumor
Clear C
ell
Chondrosar
coma
Desmoid Tu
mor
Liposar
coma
Desmoid Tu
mor
-10
0
10
20
30
40
50
60
10 months
RESPONSE TIME ON STUDY
Notch and Hedgehog: Best response – Duration on study drug
6 months
Progression Free Survival
Notch + Hedgehog: mPFS: 12 weeks6 week PFS: 60%
Notch alonemPFS: 8.8 wks6 week PFS: 60%
p 0.38
PFS: prior drug vs. study drug
recu
rrent d
x untre
ated
recu
rrent d
x, untre
ated
recu
rrent d
x untre
ated
Tem-IGFR
CDK4 prior
CDK4 prior
aurora
kinase
doxoru
bicin
CDK4 prior
CDK4 prior-S
T
CDK4 prior-W
CDK4 prior
CDK4 prior
CDK4 prior
Gem-Doce
CDK4 prior
CDK4 prior
recu
rrent d
x-chro
ns
CDK4 prior
0
50
100
150
200
250
300
350
400
450
500
Individual Liposarcoma Patients: Prior Drug vs. Study drug
Tim
e on
Prio
r Rx
vs. S
tudy
dru
g STUDY DRUG
3 months
8 months
12 months
PRIOR DRUG
NTRK1 and TET2 mutations
Epithelioid Sarcoma1 20% tumor shrinkage – 5 months SD
2 POD – 1 cycle
3 POD – 1 cycle
4 POD – 1 cycle
Desmoid : Wnt pathway
• -- Cross talk between Wnt, Notch and Hedgehog.
• -- Partial responses with PF-03084014 and OMP54-F28.
Progressive Disease Study Terminated Study Terminated Withdrawal Study TerminatedNotch Notch Hedgehog + Notch Hedgehog + Notch Hedgehog + Notch
0
50
100
150
200
250
300
Series1Series2
Tim
e on
Stu
dyDesmoid Tumor: No Responses
HEDGEHOG + NOTCHNOTCH
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.
AcknowledgementsMSKCC
William Tap Gary Schwartz Mark Dickson Mary Louise Keohan Sandra D’Angelo Richard CarvajalRobert Maki Li-Xuan Qin Joseph Erinjeri Mercedes Condy Yelena UsteyovLanier TannerRita Morales
NCI
Percy IvyNaoko Takebe
FUNDING
Gateway Foundation Siskind Family Fund
Crosstalk between Hedgehog and Notch pathway
SmoothGLI2GLI3
GLI1
Patched
Hedgehog
Hedgehog PathwayNICDNotch
NICDγ-Secretase
MAML CSLNICD
Notch Pathway
Akt Pathway
Akt
mTOR
Hes3
Survival andGrowth
P
P
HistologyHistology 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