Richard Carvajal, MD presents Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape at the 2017 CURE OM Patient & Caregiver Symposium.
Targeted Therapy for Uveal Melanoma - Richard Carvajal, MD
1. Targeted Therapy for Uveal Melanoma and the
Uveal Melanoma Clinical Research Landscape
Richard D. Carvajal, M.D.
Director, Experimental Therapeutics
Director, Melanoma Service
Associate Professor of Medicine
Columbia University Medical Center
2. Critical Gaps in the UM Field
Epidemiology Primary Therapy
Adjuvant
Therapy
Surveillance
Management of
Advanced
Disease
Surveillance
strategies
Risk
stratification
Liver-directed
& systemic tx
Risk
factors
International Uveal Melanoma Natural History Study
Specific Aim 1: To document clinical outcomes of patients with uveal melanoma,
adjusting for known prognostic risk factors as well as other baseline demographic and
clinical factors, including therapies, in order to provide benchmark endpoints for the
development of novel therapies for this disease.
Specific Aim 2: To inform critical outstanding questions in the field unlikely to be
answered by well-designed prospective clinical trials regarding risk stratification,
radiographic surveillance, and optimal patient selection for liver-directed as opposed to
systemic therapies.
Specific Aim 3: To develop a virtual uveal melanoma tumor repository that can be
utilized by investigators to develop or confirm hypotheses related to tumor biology and to
facilitate drug development.
3. Participating Centers:
Cleveland Clinic Foundation
Columbia University Medical Center
Dana-Farber Cancer Institute
Duke University Medical Center
Emory University
Ohio State University
Massachusetts Eye and Ear
Massachusetts General Hospital
Memorial Sloan Kettering Cancer Center
Mt. Sinai Medical Center
NYU Medical Center
Northwestern University
Oregon Health Sciences University
University of California San Francisco
University of Cincinnati
University of Miami Medical Center
University of North Carolina
University of Texas Houston
Thomas Jefferson University
Vanderbilt University
CUMC UM Natural History Program: Participating Centers
4. • US National Cancer Institute
• European Organization for Research and Treatment of Cancer
• Cancer Research UK
• National Institute for Health Research Cancer Research Network
• Institut National Du Cancer
• National Cancer Institute of Canada Clinical Trials Group
5. Parallel International Natural History Efforts
UK/Europe Australia
Lead Investigator Joseph Sacco Anthony Joshua
Coordinating
Organization
Liverpool Clinical Trials Unit
Garvan Institute of Medical
Research
Platform MACRO Save Sight Registry
Number of Centers 10 TBD
6. Critical Gaps in the UM Field
Epidemiology Primary Therapy
Adjuvant
Therapy
Surveillance
Management of
Advanced
Disease
Vision preserving
therapy for
primary disease
Surveillance
strategies
Risk
stratification
Effective tx in
adjuvant setting
Effective tx in
metastatic setting
Liver-directed
& systemic tx
Risk
factors
7. Compartmentalization of Biomedical Research
http://www.urmc.rochester.edu/ctsi/information/what-we-do.cfm
Bench to Bedside
Translation: Laboratory
to Human
8. cMET and HGF is Overexpressed in Uveal Melanoma
• Uveal melanomas overexpress c-MET in 60% - 86% of cases
• Activating mutations or genetic amplifications of c-MET are uncommon
• HGF/c-MET pathway activation is associated with inferior clinical outcomes
Surriga et al. Mol Cancer Ther 2013.
9. cMET Inhibition with Crizotinib Results in Decreased Cell Migration
Surriga et al. Mol Cancer Ther 2013.
B.
D.
D.
11. Phase II Trial of Adjuvant Crizotinib in High-Risk Uveal Melanoma
Following Definitive Therapy
Active Therapy Observation Follow-up
o 48 weeks (12 four-week cycles)
of crizotinib 250 mg PO BID
o Routine bloodwork and physical
examination every 4 weeks
o Imaging studies every 12 weeks.
o Patients who have distant disease
recurrence during follow-up will
then be contacted every 3
months (+/-2 weeks) to obtain
vital status for at least 32 months
from the start of active therapy.
o Imaging studies every 12
weeks until distant disease
recurrence, withdrawal of
patient consent, or study
closure.
Primary Endpoint
o Distant relapse free survival
Secondary Endpoints
o Overall survival, Disease specific survival
o Quality of life
12. Adjuvant Trials for Uveal Melanoma
Agent(s) Phase Sponsor/Lead Center Clinicaltrials.gov ID
DTIC + Interferon* II Cleveland Clinic NCT01100528
Ipilimumab* I/II MDACC NCT01585194
Cisplatin, Tamoxifen + Sunitinib II San Diego Pacific Oncology NCT00489944
Fotemustine IV vs Observation III Institut Curie
EudraCT Number 2008-
005691-27
Dendritic Cell Vaccination * I/II Radboud University NCT00929019
Crizotinib II CUMC NCT02223819
Sunitinib vs Valproic Acid II Jefferson NCT02068586
Prophylactic Liver RT * II UCLA NCT02336763
(as of 1/27/2017)
(* - accrual held/complete)
13. Oncogenic Drivers In Melanoma Subtypes
Cutaneous
TCGA
(n = 333)
Conjunctival
Greiwank et al
(n = 78)
Mucosal
Sheng et al
(n = 284)
Uveal
(Primary)
TCGA
(n = 80)
Uveal
(Metastatic)
Piperno-
Neumann et al
(n = 75)
BRAF 52% 29% 13% 0% 1%
NRAS 28% 18% 8% 0% 1%
NF1 14% NR NR 0% 1%
KIT 7% 0 – 7% * 7% 0% NR
GNAQ 2% 0% 5% 50% 63%
GNA11 3% 0% 5% 46% 33%
Akbani et al. Cell 2015; Sheng et al. Eur J Cancer 2016; Omholt et al. Clin Cancer Res 2011;
Piperno-Neumann et al, ASCO 2014; Griewank KG et al. Clin Cancer Res 2013
* Beadline et al, Clin Cancer Res 2008; Wallander et al. Mod Pathol 2011.
14. A Subway Map of Cancer Pathways
http://www.nature.com/nrc/poster/subpathways/index.html
15. MEK Inhibition has Clinical Activity in Uveal Melanoma
Ambrosini et al. Clin Cancer Res, 2012;
Patel et al. CCR 2011; Carvajal et al. JAMA. 2014.
Selumetinib
17. No Improvement Observed with Selumetinib/DTIC vs Placebo/ DTIC
DTIC/Placebo vs DTIC/SelumetinibTMZ vs Selumetinib
PFSRR
Carvajal et al, JAMA 2014
Carvajal et al, SMR 2015
14% Response Rate
(n = 5/49)
3% Response Rate
(n = 3/97)
mPFS: 2.8 vs 1.8 months
18. Strategies to Improve MEK Inhibition Efficacy
2. Vertical Pathway Blockade 3. Dual Pathway Blockade
1. Optimizing Single Agent MEK Inhibition
• Might other MEK inhibitors be more effective?
• Are there alternative dosing schedules that can
improve efficacy?
• Can we block the MAPK pathway
at multiple levels to improve
outcomes?
• Can we block other parallel growth
pathways to improve outcomes?
A A B
MEK Inhibitor
Drug X
MEK Inhibitor
Drug Y
19. Pharmacodynamic activity of selumetinib predicts radiographic
response in advanced uveal melanoma (abstract #8598)
Richard D. Carvajal1, Grazia Ambrosini1, Jedd D. Wolchok1, Paul B. Chapman1, Mark A.
Dickson1, Sandra P. D'Angelo1, Mark J. Bluth2, Daniel Paucar1, Anne Fusco1, David Bohr1,
Ruth Ann Roman1, Mary Montefusco1, L. Austin Doyle5, Brian Marr3, David H. Abramson3,
Joanne F. Chou4, Katherine Panageas4, Gary K. Schwartz1
Departments of Medicine1, Radiology2, Ophthalmic Oncology3 and Epidemiology & Biostatistics4; Memorial Sloan-Kettering Cancer Center ; National Cancer
Institute5
ASCO 2012
Clinical Benefit*
n = 6
No Clinical Benefit
n = 12
p
Median pERK (IQR)
-81.4%
(-58%, -96%)
-26.6%
(11%, -60%)
0.04
Median CyclinD1 (IQR)
-80.5%
(-64%, -92%)
-63.7%
(10%, -82%)
0.38
(* Clinical benefit defined as a RECIST response or SD > 16 weeks)
Sustained pathway inhibition is associated with improved clinical
outcome
20. Multi-Center Phase I Study of Intermittent Dosing of the MEK Inhibitor,
Selumetinib, in Patients with Advanced Uveal Melanoma not Previously
Treated with a MEK Inhibitor
Hypothesis: Intermittent dosing will enhance the tolerability of selumetinib,
permit the use of higher drug doses, achieve greater pERK inhibition, and
lead to greater anti-tumor effects
Specific Aims
• To identify the spectrum of toxicities and the maximum tolerated dose
of selumetinib when administered on an intermittent dosing schedule;
• To assess the efficacy of selumetinib in uveal melanoma when dosed
intermittently; and,
• To use serial tumor biopsies to evaluate for changes in degree of MAPK
pathway inhibition at various dosing time points, and correlate these
results with pharmacokinetic and clinical outcomes.
21. Resistant tumors emerge more rapidly under continuous dosing with vemurafenib
Tumor growth controlled on intermittent schedule with no resistance emerging
Resistance emerged in all
mice
| AACR 2013 | Das Thakur
4 weeks on / 2 weeks
off
- No evidence of resistance
0
200
400
600
800
1,000
1,200
59 79 99 119 139 159 179 199
TumorVolumemm3
Days Post Treatment
Intermittent dosing 15mg/kg Vemurafenib
0
200
400
600
800
1,000
1,200
23 43 63 83 103 123 143 163 183
TumorVolumemm3
Days
Continuous dosing 15mg/kg Vemurafenib
Start dose
Start dose
Stop dose
0 20 40 60 80 100 120 140 160 180 200
0 20 40 60 80 100 120 140 160 180 200
21 Das Thakur et al. Nature. 2013.
22. Phase I Study of Intermittent Dosing of Selumetinib in Metastatic UM
Key Inclusion:
• Metastatic or unresectable UM
• ECOG ≤ 2
• Measurable disease
• No prior MEK, RAS, RAF inhibitor therapy
• Stats: Estimated ~28 subjects enrolled using TITE-CRM method
• Primary endpoint: MTD and RP2D dose of intermittent selumetinib in UM
Dose Level Selumetinib Dose
1 100mg BID
2 125mg BID
3 150mg BID
4 175mg BID
5 200mg BID
6 225mg BID
C1W1 C1W2 C1W3 C1W4
3d ON 3d ON 3d ON 3d ON
Baseline
Biopsy
On Tx Biopsy Off-Tx
Biopsy
POD Biopsy
(optional)
4d OFF 4d OFF 4d OFF 4d OFF
Assess target
inhibition and
Feedback activation
Assess for
reversal of
feedback
Assess for
mechanisms
of resistance
1 cycle = 4 weeks
24. Molecularly Targeted Trials for Uveal Melanoma
Pathway Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
PKC/MEK
AEB071 + BYL719 I CUMC NCT02273219
Intermittent Selumetinib I CUMC NCT02768766
Binimetinib + AEB071 * I/II Novartis NCT01801358
LXS196 I Novartis NCT02601378
Epigenetic
Vorinostat II NCI/CUMC NCT01587352
PLX51107 II CUMC pending
Other
Sorafenib (STREAM Trial) * II Essen, Germany NCT01377025
Cabozantinib versus
TMZ/DTIC
II NCI/Alliance NCT01835145
Liver Directed
Sorafenib +
Radioembolization
I
Centre Hospitalier
Universitaire Vaudois
NCT01893099
(as of 1/27/2017)
(* - accrual held/complete)
25. • A number of abnormally expressed
genes that distinguish between class 1
and 2 are known to be epigenetically
regulated:
– Histone acetylation PHLDA1 , GSTM3,
SPP1, ENDRB, and BTG1
– Micro RNAs PDCD4
– Hypermethylation TIMP3, p16INK3a, 29
LZTS1
• Gene Set Enrichment Analysis and
Connectivity mapping demonstrates
that histone deacetylase inhibitors are
predicted to shift class 21
Genes that Define Class 2 UM are Epigenetically Regulated
Landreville S et al. Clin Cancer Res 2012;18:408-416
26. “Reversal” of BAP1 Phenotype with HDACi
Landreville S et al. Clin Cancer Res 2012;18:408-416
Harbour et al. Science 2010
27. Metastatic Uveal Melanoma
Age ≥ 18
ECOG 0-2
Measurable Disease RESIST 1.1
Any # prior treatments
Tissue for GNAQ/GNA11/BAP1 typing
Adequate End organ Function
Eligibility
Vorinostat
300mg PO BID
3 of 7 days each week
1 cycle = 4 weeks
Pre-Rx Evaluation
10 pts mandatory Bx
Treatment Evaluation
Week 2 paired Bx for 10
patients
-Toxicity by CTCAE 4.0 q 4 wk
-Disease Assessment q 8 wk
(i.e. CT-CAP or MRI)
Phase II Trial of Vorinostat in Uveal Melanoma
Primary Endpoint: ORR (5% vs 20%)
Secondary Endpoints: OS, PFS, Toxicity
Two Stage Design: 1/18 required to expand to 2nd stage; 3/32 to support 20% response rate
(alpha and beta both 0 .1)
28. Conclusions
• Uveal melanoma is a unique biological and clinical subset of melanoma that
require therapeutic considerations distinct from those required for cutaneous
disease
• Emerging insights into the biology of uveal melanoma have led to the
development of a series of novel immunological and targeted therapies which
hold promise for improving the outcomes for patients with advanced disease
• Patient participation in clinical trials, both in the adjuvant and metastatic setting,
remains the standard of care and is critical to the successful development of
effective therapies for this challenging disease
29. Immunotherapy Trials for Uveal Melanoma
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
Pembrolizumab II Vanderbilt NCT02359851
Ipilimumab/Nivolumab II MDACC NCT01585194
Ipilimumab/Nivolumab II
Grupo Español Multidisciplinar de
Melanoma
NCT02626962
Ipilimumab +
Radioembolization *
I Case Comprehensive Cancer Center NCT01730157
Ipilimumab/Nivolumab +
Radioembolization
Feasibility
California Pacific Medical Center
Research Institute
NCT02913417
Glembatumumab Vedotin II NCI/MDACC NCT02363283
Tumor Infiltrating
Lymphocytes
II NCI NCT01814046
IMCgp100 I Immunocore NCT02570308
(* - accrual held/complete)
(as of 1/27/2017)
30. Liver Targeted Trials for Uveal Melanoma
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
SIR-Spheres II Thomas Jefferson NCT01473004
Liver Transplantation * II Oslo University NCT01311466
Isolated Hepatic Perfusion vs Best Alternative
Care (SCANDIUM)
III Sahlgrenska University NCT01785316
Sorafenib + SirSpheres I
Centre Hospitalier Universitaire
Vaudois
NCT01893099
Ipilimumab/Radioembolization * 0
Case Comprehensive Cancer
Center
NCT01730157
SIR-Spheres, Ipilimumab and Nivolumab I
California Pacific Medical Center
Research Institute
NCT02913417
SIR-Spheres vs Chemoembolization II
Charite University, Berlin,
Germany
NCT02936388
Percutaneous Hepatic Perfusion vs Best
Alternative Care (FOCUS)
III Delcath Systems, Inc NCT02678572
(as of 1/27/2017)
(* - accrual held/complete)
31. Bench to Bedside Translational Science
Schwartz Laboratory
• Grazia Ambrosini
MEK targeting
BET targeting
• Oliver Surriga
cMET targeting
• Elgilda Musi
PKC targeting
Clinical Team
Research Manager
• Sarah DeNoble
Regulatory Coordinator
• Danielle Lacey
Research Nurses
• Amanda Carter
• Shahnaz Singh
Research Coordinators
• Latoya Stewart
• Lauren Taiclet