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Clinical Trials Panel Discussion: 2019 CURE OM Symposium

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Dr. Richard Carvajal discusses ocular melanoma clinical trials at the 2019 CURE OM Symposium.

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Clinical Trials Panel Discussion: 2019 CURE OM Symposium

  1. 1. Navigating the Treatment Landscape of Uveal Melanoma: Focus on Immunotherapeutic Strategies Richard D. Carvajal, M.D. Director, Experimental Therapeutics Director, Melanoma Service Associate Professor of Medicine Columbia University Medical Center
  2. 2. Consulting: Array, BMS, Castle Biosciences, Compugen, Foundation Medicine, Immunocore, I- Mab, Incyte, Merck, Roche/Genentech, PureTech Health, Sanofi Genzyme, Sorrento Therapeutics Clinical/Scientific Advisory Boards: Aura Biosciences, Chimeron, Rgenix Research Funding to Columbia University: Amgen, Astellis, AstraZeneca, Bayer, Bellicum, BMS, Corvus, Eli Lilly, Immunocore, Incyte, Macrogenics, Merck, Mirati, Novartis, Pfizer, Plexxikon, Roche/Genentech Disclosures
  3. 3. Factors in Decision Making Resources • Available expertise • Clinical trials You • Your health status • Your preferences • HLA status Your Disease • Tumor growth pattern • Sites of involvement • Molecular characteristics • PRAME status Treatment Recommendations
  4. 4. Broad Therapeutic Categories Treatment Recommendations Locoregional Therapies Systemic Therapies Supportive Care Concurrent Strategies
  5. 5. Systemic Treatment Strategies for Uveal Melanoma Hanahan and Weinberg. Cell 2000. Jones et al. Nat Rev Genetics 2016. Genetic Targeting Epigenetic Targeting Immunological Targeting
  6. 6. T cell Tumor cell MHC TCR PD-L1PD-1 - - - T cell Dendritic cell MHC TCR CD28 B7 CTLA-4 - - - Activation (cytokines, lysis, proliferation, migration to tumor) B7 +++ +++ CTLA-4 Blockade PD1/PDL1 Blockade anti-CTLA-4 anti-PD-1 Tumor Microenvironment +++ PD-L2PD-1 anti-PD-1 - - - Antigen Presentation Blocking CTLA-4 versus Blocking PD1/PDL1
  7. 7. Ipilimumab and Nivolumab Week 12 Nivolumab Baseline Immunological Checkpoint Blockade in Cutaneous Melanoma
  8. 8. PD1 Blockade can be Effective in Uveal Melanoma Rodriguez M et al. Nature Communications 2018. 76 yo female with left choroidal melanoma (monosomy 3, GNAQ Q209L mut, BAP1 mut) s/p enucleation who developed metastases to the liver, lungs and bones. She was treated in the frontline setting with pembrolizumab.
  9. 9. Why Doesn’t Checkpoint Blockade Work as Well in UM? Yarchoan M et al. N Engl J Med 2017. Javed A et al. Immunotherapy 2017. Tumor Mutation Burden Tumor PDL1 (SP142) Expression* * SP142 PDL1 Positive: ≥ 5% membranous staining of tumor detected with 2+/3+ intensity
  10. 10. Response to Combined Checkpoint Blockade Baseline 10 months 52 year old female with Decision DX Class 2, GNA11 Q209L mutant, right ciliary body melanoma s/p enucleation with the development of metastatic disease 26 months later to the liver, lung, bone and soft tissue 3 months Ipi/Nivo Observation
  11. 11. Phase II Trial of Adjuvant Ipilimumab and Nivolumab (n = 50) Primary Endpoint o RFS at 3 years Secondary Endpoints o RFS, OS High Risk Definition o GEP Class 2 o Impact Genetics 3 yr recurrence risk > 50% o Monosomy 3 with tumor ht > 8mm Participating Centers: Georgetown, Columbia University, MD Anderson Cancer Center, UCSF, Washington University
  12. 12. Immune Related Adverse Events (irAEs) Postow MA et al. N Engl J Med 2018;378:158-168 • Checkpoint inhibition can lead to varied toxicities caused by an augmented immune response and decrease in immune self-tolerance • Toxicities can be organ-specific – Skin – GI tract – Lungs – Endocrine system – Heart – Neurologic system • Toxicities can also be generalized – Fatigue – Fever – Infusion reactions
  13. 13. Adoptive T Cell Therapy Rosenberg et al. Science 2015.
  14. 14. Phase II Trial of Adoptive T Cell Therapy in Uveal Melanoma Chandran SS et al. Lancet Oncol. 2017. 35% Response Rate (n = 7/20) Response Duration: 3-21+ Months • 3 of 7 responses occurred in patients who progressed on prior CPB • 6 of 27 patients enrolled were excluded from treatment due to insufficient TILs or ineligibility for protocol treatment
  15. 15. Targeting gp100 in Uveal Melanoma TCR affinity increased 3,500,000 fold from 85μM to 24 pM KD ~24 pM Residence T½ ~24 hrs at 37ºC KD nM Residence T½ mins Targeting TCRend Effector scFvend RNAseq data generated from The Cancer Genome Atlas Program Cutaneous Melanoma Uveal Melanoma
  16. 16. IMCgp100 Program Registration Strategy Accelerated approval strategy: Single arm trial approval strategy is based on either ORR or OS with RWE as comparator IMCgp100-102: Second or third line in the metastatic setting IMCgp100 at RP2D from Ph I N ~ approx 150 Interim Analysis Final Analysis Real World Evidence (ORR, OS via one of three platforms: Meta- analysis, global patient registry or Flatiron derived comparator) Opportunities for approval IMCgp100-202: First line metastatic setting R Investigator Choice (dacarbazine, pembrolizumab or ipilimumab) N = approx 109 Sample size Interim Analysis Final Analysis re-estimation Primary endpoint: Median OS Traditional approval strategy: Randomized study of IMCgp100 v. Investigator choice with OS as endpoint IMCgp100 at RP2D from Ph I N = approx 218 Opportunities for approval
  17. 17. Conversion of Tumor from “Cold” to “Hot” with IMCgp100 Baseline C1D2 C1D16 CD8 (green) X PD-1 (magenta) X PD-L1 (red) Baseline C1D16 Patient 1 Patient 2 C1D16 MHC Class I (yellow) X gp100 (orange) Sato T et al. ASCO Annual Meeting. June 2018.
  18. 18. Response to Combined Checkpoint Blockade 12/2017 09/2018 52 year old female with Decision DX Class 2, GNA11 Q209L mutant, right ciliary body melanoma s/p enucleation with the development of metastatic disease 26 months later to the liver, lung, bone and soft tissue 03/2018 Ipi/Nivo Observation Dev mets to liver, bone, lung, soft tissue and received: • Ipilimumab x 4 • Pembrolizumab + radioembolization x 7 months • IMCgp100 x 20 months • Ipi/Nivo
  19. 19. (* - accrual held/complete) Mechanism Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID Checkpoint Blockade Adjuvant Ipilimumab/Nivolumab II Hoosiers NCT02359851 Ipilimumab/Nivolumab * II MDACC NCT01585194 Pembolizumab + Entinostat (PEMDAC) II Vastra Gotaland Region, Sweden NCT02697630 Ipi/Nivo + Immunoembolization * II Thomas Jefferson NCT03472586 Ipi/Nivo + Radioembolization 0 CPMC NCT02913417 CVA21 + Ipilimumab (CLEVER) * I Viralytics NCT03408587 ADV/HSV-tk + SBRT + Nivolumab (ENSIGN) II Methodist Hospital NCT02831933 Vaccination Dendritic Cell Vaccine II University Hospital Erlangen NCT01983748 TILS Adoptive T Cell Therapy II UPMC NCT03467516 Cellular Adoptive Immunotherapy + Ipilimumab I MDACC NCT03068624 T Cell Redirection IMCgp100 * I Immunocore NCT02570308 IMCgp100 II Immunocore NCT03070392 Immunotherapy Trials for Uveal Melanoma (as of 03/27/2019)(* - accrual held/trial complete)
  20. 20. • Our understanding of the biology of uveal melanoma introduces new opportunities and challenges for the successful development of effective treatments • Progress is being made in the translational and clinical development of molecularly targeted, epigenetic and immunological therapies • Combinatorial treatment strategies may be necessary for optimal results • Collaboration within the academic community (laboratory, ocular oncology, medical oncology, pathology, radiation oncology) and with the patient community is critical for us to rapidly and successfully move the field forward Concluding Thoughts

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