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Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy

In association with Translational Research in Oncology. Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy. Antoni Ribas, MD Professor Department of Medicine and Hematology-Oncology University of California, Los Angeles Los Angeles, California.

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Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy

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  1. In association with Translational Research in Oncology Evolving Treatment Options in Melanoma: Utilizing Genetic Features to Optimize Therapy Antoni Ribas, MDProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California This program is supported by educational grants from

  2. About These Slides • Our thanks to the presenters who gave permission to include their original data • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Program Faculty Program Director Dennis J. Slamon, MD, PhD TRIO ChairmanChief, Division of Hematology/OncologyDavid Geffen School of Medicine at UCLALos Angeles, California Faculty Antoni Ribas, MD ProfessorDepartment of Medicine and Hematology-OncologyUniversity of California, Los AngelesLos Angeles, California

  4. Faculty Disclosures AntoniRibas, MD, has disclosed that he has received consulting fees from Amgen, Celgene, Genentech/Roche, GlaxoSmithKline, Millennium, Novartis, and Prometheus. Dennis J. Slamon, MD, PhD, has disclosed that he has received consulting fees from Genentech, GlaxoSmithKline, and Roche.

  5. > 3000 Trials Between 1970 and 2010 Had No Real Clinical Impact Total number of clinical trial publications*: 3337 250 200 150 Clinical Trial Publications (n)* 100 50 0 1970 1975 1980 1985 1990 1995 2000 2005 2010 Publication Yr *Data collected using PubMed; search criteria: “melanoma clinical trial.” US National Library of Medicine and National Institutes of Health.

  6. Improved OS in Melanoma With Ipilimumab and Vemurafenib 100 100 Vemurafenib (n = 336) 80 80 Dacarbazine(n = 336) 60 60 OS (%) OS (%) 40 40 HR: 0.37 (95% CI: 0.26-0.55; P < .001) 20 20 0 0 0 8 16 24 32 40 48 56 0 1 2 3 4 5 6 7 8 9 10 11 12 Mos Mos Immunotherapy Targeted Therapy Percent Alive Percent Alive 0 1 2 3 0 1 2 3 Yrs Yrs 1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

  7. cKIT, NRAS, BRAF mutated in ~ 70% of melanomas, usually mutually exclusive[1] < 5% melanomas (mucosal, acral) KIT inhibitors: imatinib, nilotinib, dasatinib[4] cKIT ~ 20% melanomas (> age)[2,3] NRAS ~ 50% melanomas (< age)[2,3] BRAF BRAF inhibitors: vemurafenib, dabrafenib[4] MEK MEK inhibitors: trematenib, TAK733[4] ERK MAP Kinase Pathway Targeting in Melanoma Oncogenic cell proliferation and survival 1. Sosman JA, et al. ASCO 2011 Educational Book. 2. Arkenau HT, et al. Br J Cancer. 2011;104:392-398. 3. Thomas N, et al. Cancer Epidemiol Biomarkers Prev. 2007;16:991-997. 4. Nikolaou VA, et al. J Invest Dermatol. 2012;132:854-863.

  8. Day 15 Vemurafenib Vemurafenib Inhibition of MAPK Signaling in BRAF V600 Melanoma Biopsies[1] GF Baseline[2] Ras GTP RTK BRAFV600 pERK Y-P Y-P MEK P Cyclin D ERK P Cyclin D Ki67 Cell cycle (Ki67) 1. Ribas A. HemOnc Today: Melanoma. 2012. 2. Flaherty KT, et al. N Engl J Med. 2010;363:809-819.

  9. Tumor Response to Vemurafenib Cycle 4 Day 1, 6/8/2011 Baseline, 3/15/2011 PLX4032 = RG7204 = vemurafenib

  10. Vemurafenib: Tumor Response by Metastatic Stage Sosman 2012 [2] Flaherty 2010[1] Chapman 2011[3] 1. Flaherty KT, et al. N Engl J Med. 2010;363:809-819. 2. Sosman JA, et al. N Engl J Med. 2012;366:707-714. 3. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

  11. BRIM2: Toxicities With Vemurafenib Includes AEs reported in ≥ 20 patients *1 patient with 2 grade 4 AEs. †Cases of cuSCC/KA were generally managed with simple excision and did not generally require dose modification. ‡Managed with dose reduction; 1 removed from study. §Led to discontinuation of therapy. Ribas A, et al. ASCO 2011. Abstract 8509.

  12. BRIM2: cuSCC/KA Development With Vemurafenib • cuSCC/KAs • Incidence: 26% • Median time: 8 wks (range: 2-36) • Median number of cuSCC/KAs per patient: 1 (range: 1-7) • Each dot represents wks to development of first cuSCC/KA lesion Median 0 5 10 15 20 25 30 35 40 Wks on Vemurafenib Ribas A, et al. ASCO 2011. Abstract 8509.

  13. BRAFi RAS RAS BRAFi CRAF BRAFV600 BRAF CRAF BRAF CRAF MEK1/2 MEK1/2 MEK1/2 P P P ERK ERK ERK P P P MAPK signaling[1-3] MAPK signaling MAPK signaling[1-3] BRAF Inhibition: Differential Effects in BRAF V600 and BRAF Wild-Type Cells BRAF Wild-Type Cells BRAF V600 Mutant Melanoma BRAFV600 CRAF MEK1/2 P ERK P MAPK signaling 1. Hatzivassiliou G, et al. Nature. 2010;464:431-435.2. Heidorn SJ, et al. Cell. 2010;140:209-221. 3. Poulikakos PI, et al. Nature. 2010;464:427-430.

  14. RAS BRAF CRAF MEK1/2 P ERK P MAPK signaling Paradoxical MAPK Activation by BRAF Inhibitors in HRAS-Mutated cuSCC/KAs BRAF Wild-Type Cells BRAF V600 Mutant Melanoma BRAFi HRASQ61 BRAFi BRAFV600 CRAF CRAF BRAFV600 BRAF CRAF MEK1/2 MEK1/2 MEK1/2 P P P ERK ERK ERK P P P MAPK signaling MAPK signaling MAPK signaling Paradoxical MAPK activation with RAF inhibitors Su F, et al. N Engl J Med. 2012;366:207-215.

  15. Acquired Resistance to Vemurafenib: Time to Response, Progression in BRIM2 Time on study Time to response Progressive disease Continued response Median duration of response: 6.7 mos (range: 1.3-12.7; 95% CI: 5.6-9.8) 0 2 4 6 8 10 12 14 16 Mos Approx timing CT assessments Ribas A, et al. ASCO 2011. Abstract 8509.

  16. 02/20/09 (4+ mos) Pt #43, UCLA Melanoma Stroma Response and Relapse With Vemurafenib 10/02/08 (Pre) 11/26/08 (2+ mos) Nazarian R, et al. Nature. 2010;468:973-977.

  17. NRASQ61 [1] PDGFRβ or IGF1R or EGFR BRAF inhibitor COT CRAF PI3K PI3Ki or AKTi BRAFV600E [2] [3,4] [4,6,9-11] AKT MEK MEK-independent progression P MEK-dependent progression [5] ERK [1,6-8] P Survival Mechanisms of Acquired Resistance to BRAF Inhibitors MEKi 6. Villanueva J, et al. Cancer Cell. 2010. 7. Prahallad A, et al. Nature. 2012. 8. Corcoran RB, et al. Cancer Discov. 2012. 9. Jiang CC, et al. Clin Cancer Res. 2011. 10. Atefi M, et al. PLoS One. 2011. 11. Su F, et al. Cancer Res. 2012. 1. Nazarian R, et al. Nature 2010. 2. Johannessen CM, et al. Nature. 2010. 3. Poulikakos, et al. Nature 2011. 4. Shi H, et al. Cancer Discov. 2012. 5. Wagle N, et al. J ClinOncol. 2011.

  18. Occasional prolonged responses[1] Local Tx + BRAFi No activity[2] BRAFi MEKi BRAFi BRAFi ORR 19%[3] MEKi BRAFi ORR 50% to 74%,[4] increased PFS? MEKi Treating Resistance to BRAFi BRAFi BRAFi: vemurafenib, dabrafenib MEKi: trametinib Progression of melanoma 1. Kim KB, et al. ASCO 2011. Abstract 8519. 2. Kim KB. SMR 2011. Abstract.3. Flaherty K, et al. SMR 2011. Abstract 12. 4. Infante JR, ASCO 2011. Abstract CRA8503.

  19. Metastatic Melanoma: Treatment Advances Immunotherapy Targeted Therapy Target tumor Target host

  20. < 5% melanomas, RR 15% KIT inhibitors cKit NRAS 50% melanomas, RR 55% BRAF BRAF inhibitors < 5% melanomas, RR 30% MEK MEK inhibitors IL-2 IFN-α Anti-CD40 Anti-CD137 Anti-OX40 ERK Antitumor immune response Anti-CTLA4 Anti–PD-1 Immunotherapy for Melanoma: Response Oncogenic cell proliferation and survival RR ~ 10%, but many are durable

  21. Ipilimumab Induces Durable Tumor Responses in a Subset of Patients: OS Median OS, Mos 95% CI Est 1, 2, 3-Yr Survival, % MedianOS, Mos 95% CI HR P Value HR P Value < .001 < .001 .003 11.2 9.1 9.4-13.6 7.8-10.5 0.72 47.3, 28.5, 20.8 36.3, 17.9, 12.2 Ipi + gp100 Ipi gp100 10.0 10.1 6.4 8.5-11.5 8.0-13.8 5.5-8.7 0.68 0.66 Ipi + D Placebo + D 100 100 80 80 Censored Censored 60 60 OS (%) Patients Survival (%) 40 40 Ipilimumab-dacarbazine 20 20 Placebo-dacarbazine 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Mos Mos Patients at Risk, nIpi + gp 100Ipigp100 Patients at Risk, nIpi + DPlacebo + D 250252 230229 199190 181160 157136 131116 11489 10478 9172 8564 7956 7447 6844 6142 5942 5637 5634 5231 4126 3119 1711 107 45 23 00 403137136 29710693 2237958 1635632 1153823 813017 542416 42187 33135 24135 1783 751 620 410 000 Ipilimumab vs Placebo[2] Ipilimumab + gp100 vs gp100[1] 1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Robert C, et al. N Engl J Med. 2011;364:2517-2526.

  22. Before Ipilimumab 04/22/11 After Ipilimumab 08/05/11 Ribas A. SMR 2011. Abstract 72.

  23. “Miracle Survivors”: Reproducible but Low Frequency With CTLA4 Blocking MAbs CTLA4 Response Since 2003[1] CTLA4 Response Since 2004[2] 1. Forbes. March 2, 2009. 2. Forbes. October 15, 2007.

  24. Anti-PD1 Anti-PD1 antibodies may be more relevant to unleash an anti-melanoma immune response than anti-CTLA4 antibodies Ribas, NEJM June 2, epub ahead of print

  25. ACT With Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma • Durable complete responses with autologous TILs[2] • Similar efficacy regardless of prior therapy Adoptive Cell Transfer[1] Survival of Patients With Metastatic Melanoma Treated With Autologous TILs and IL-2 1.0 Median follow-up: 62 mos 0.8 0.6 TBI 1200 (n = 25) Proportions Surviving TBI 200 (n = 25) 0.4 All patients (n = 93) 0.2 No TBI (n = 43) 0 0 12 24 36 48 60 72 84 96 Survival Time (Mos) 1. Restifo NP, et al. Nat Rev Immunol. 2012;12:269-281. 2. Rosenberg SA, et al. Clin Cancer Res. 2011;17:4550-4557.

  26. Melanoma-specific lymphocyte Human melanoma KVPRNQDWL HLA TCR-redirected lymphocyte TCR Engineering: Adoptive Cell Transfer 2010 2005 CD8 IHC Take TCR genes from one patient who beat melanoma and use them to engineer a melanoma-fighting immune system in other patients

  27. Immunotherapy for Melanoma • Active immunotherapy • Cytokines • IL-2 • Antibodies • Anti-CTLA4 • Low frequency of tumor responses • Highly durable • IL-2: limited by short-term toxicities • Anti-CTLA4: limited by midterm autoimmune toxicities • High frequency of tumor responses • Variable durability • Limited by requirements of preparative conditioning and IL-2 • Adoptive cell transfer • T-cell cloning • From blood • From tumors: TIL • T-cell genetic engineering • T-cell receptors • Chimeric antigen receptors General clinical effects

  28. Combination Immunotherapy Targeted Therapy Percent Alive Percent Alive Percent Alive ? 0 1 2 3 0 1 2 3 0 1 2 3 Yrs Yrs Yrs Combining Immunotherapy and Targeted Therapy for Melanoma? 100 100 Vemurafenib (n = 336) 80 80 Dacarbazine(n = 336) 60 60 OS (%) OS (%) 40 40 HR: 0.37 (95% CI: 0.26-0.55; P < 0.001) 20 20 0 0 0 8 16 24 32 40 48 56 0 1 2 3 4 5 6 7 8 9 10 11 12 Mos Mos 1. Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

  29. Anti-PD1 Novel BRAFi + MEKi Anti-PD1 TIL ACT TIL ACT • Open questions: • Immunotherapy vs BRAFi for first line? • Immunotherapy + BRAFi? • Treatment of BRAFi resistance? • Prevention of BRAFi resistance? • Role of MTKi? • Role of chemotherapy? • Special considerations: • Uncommon BRAF mutations • NRAS mutants with MAPK dependency Treatment of Advanced Melanoma in 2012 BRAF V600 Positive BRAF V600 Negative Experimental SOC SOC Experimental Ipilimumab Vemurafenib Ipilimumab HD IL-2 HD IL-2

  30. Conclusions • “2011: The year of melanoma” • George Sledge, MD, President of ASCO • Scientific advances translate into improved patient care • The mechanism of resistance to BRAF inhibitors predicts sensitivity to the addition of secondary treatments • MEK inhibitors • PI3K/AKT/mTOR inhibitors • Combining immunotherapy and BRAF-targeted therapy in the clinic is warranted

  31. Go Online for More CCO Coverage of Chicago 2012! Capsule Summariesof all the key data, plusCME-certified Slidesetsexploring the clinical implications of these findings Downloadable slides: for use as a study resource or in your noncommericial presentations clinicaloptions.com/oncology

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