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Targeted Therapy for Uveal Melanoma - Richard Carvajal, MD

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Richard Carvajal, MD presents Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape at the 2017 CURE OM Patient & Caregiver Symposium.

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Targeted Therapy for Uveal Melanoma - Richard Carvajal, MD

  1. 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. 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. 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. 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. 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. 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. 7. Compartmentalization of Biomedical Research http://www.urmc.rochester.edu/ctsi/information/what-we-do.cfm Bench to Bedside Translation: Laboratory to Human
  8. 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. 9. cMET Inhibition with Crizotinib Results in Decreased Cell Migration Surriga et al. Mol Cancer Ther 2013. B. D. D.
  10. 10. Crizotinib Reduces Development of Uveal Melanoma Metastasis Surriga et al. Mol Cancer Ther 2013.
  11. 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. 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. 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. 14. A Subway Map of Cancer Pathways http://www.nature.com/nrc/poster/subpathways/index.html
  15. 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
  16. 16. Carvajal et al, Society for Melanoma Research, 2015.
  17. 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. 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. 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. 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. 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. 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
  23. 23. PIP2 PIP3 mTOR GPCR GDP INACTIVE Ga GTP GNAQ/11 Mutant ACTIVE Ga CELL GROWTH Akt AEB071 MEK P ERK P P PKC P RAF NFkB PLC GSK2141795 P YAP YAP Rho Rac Trio LATS YAP TEAD Inactive Active Amot YAP Amot G-ActinHippo signaling F-Actin The Gα Pathway LXS196 Binimetinib
  24. 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. 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 21 Genes that Define Class 2 UM are Epigenetically Regulated Landreville S et al. Clin Cancer Res 2012;18:408-416
  26. 26. “Reversal” of BAP1 Phenotype with HDACi Landreville S et al. Clin Cancer Res 2012;18:408-416 Harbour et al. Science 2010
  27. 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. 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. 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. 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. 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

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