Current Trends in Melanoma Theresa Medina, MD UCD Cutaneous Oncology

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1 Current Trends in Melanoma Theresa Medina, MD UCD Cutaneous Oncology Overview Melanoma incidence and prevention Approach to surgical management of early melanoma Landscape of Advanced Melanoma Therapy in 2017 Targeted therapies: BRAF and MEK Inhibition Immunotherapies: Anti PD-1, ipilimumab, and more Adjuvant therapy Cancer statistics, 2017 CA: A Cancer Journal for Clinicians

2 Cancer statistics, 2017 CA: A Cancer Journal for Clinicians Trends in incidence rates, Melanoma of the skin, by sex Per 100,000, age adjusted to the 2000 US standard population. Data sources: Surveillance, Epidemiology, and End Results (SEER) 9 registries, National Cancer Institute, 2017 Who s at risk for melanoma? Anyone can develop melanoma at any age Lifetime risk for melanoma in the US 1 in 40 among Caucasians 1 in 200 for Hispanics 1 in 1000 for African Americans The risk of melanoma increases with age Average age at diagnosis is 63 Among young adults with cancer, melanoma is one of the most common cancers American Cancer Society, 2017

3 Who should be screened? Fair skin, blue or green eyes, blond or red hair Congenital nevi Increased number of nevi (100+) History of atypical (dysplastic) nevi History of heavy sun exposure, prior tanning bed use Personal history of melanoma Family history of melanoma Immunosuppressed: Hematologic malignancies, organ transplant, chronic immunosuppression, HIV/AIDS The Problem Melanoma is the tumor that gives cancer a bad name. George Canellos, Dana-Farber Cancer Institute Overall Survival based on stage

4 Breslow depth Can we make a difference? Australia: Deemed melanoma (and skin cancer, in general) a national public health issue. Instituted mandates and national campaign in 1981: Slip! Slop! Slap! Surgical management for early stage melanoma

5 Surgical management for early stage Melanoma (I-II) Wide Excision to appropriate margins SNLBx (consider for melanoma >0.75mm) Monitoring Risk reduction Systemic treatment for advanced melanoma Dabrafenib plus Trametinib Isolated limb perfusion Adjuvant IFN Ipilimumab Vemurafenib Pembrolizumab Nivolumab Adjuvant ipilimiumab DTIC HD IL Dabrafenib Trametinib Ipilimumab plus Nivolumab Vemurafenib plus Cobimetinib 2016 Talimogene laherparepvec

6 Systemic treatment for advanced melanoma Targeted therapy BRAF and MEK inhibitors Vemurafenib plus cobimetinib Dabrafenib plus trametinib Immunotherapy Ipilimumab Pembrolizumab Nivolumab Ipilimumab plus nivolumab Talimogene laherparepvec (T-VEC) first oncolytic virus The Targets J. Clin. Invest. 115(4): (2005) Melanoma and the immune system

7 Vitiligo of Metastatic Melanoma Mutational load and immunotherapy response More sensitive Less sensitive Mutated proteins represent potential antigens targets for immune recognition or destruction Lawrence, Nature, 2013;499:214 T cells and cancer immunity checkpoint inhibitors Ribas A. N Engl J Med. 2012;366:

8 T cell receptor signaling Adjuvant Therapy finally moving beyond IFN Ipilimumab 10mg/kg approved in 2015 First adjuvant therapy to demonstrate an OS benefit FDA approval expected soon Nivolumab (anti PD-1) Dabrafenib plus trametinib Adjuvant Ipilimumab 10mg/kg q3w x4 Then q3m x 3 years

9 Eggermont AM et al. N Engl J Med 2016;375: Eggermont AM et al. N Engl J Med 2016;375:

10 Checkmate 238 adjuvant nivolumab vs ipilimumab Weber J et al. N Engl J Med Weber J et al. N Engl J Med Combi-AD: adjuvant dabrafenib plus trametinib for BRAF V600E/K mutation Long GV et al. N Engl J Med 2017.

11 Systemic treatment for metastatic melanoma targeted agents BRIM 2 (vemurafenib) response rate cobrim vemurafenib plus cobimetinib Ascierto, P, Lancet Oncology 2016

12 Getting smarter with targeting tumor cells? 5 year OS update from phase II dabrafenib plus trametinib

13 The first approved checkpoint inhibitor - Ipilimumab Comparison HR p-value Arms A vs C Arms B vs C A = Ipilimumab + gp100 B = Ipilimumab alone C = gp100 alone C A B Hodi FS, et al. N Engl J Med. 2010;363(8): Pseudoprogession Screening Week 12: Swelling & progression Week 14: Improved mobile Week 16: Continued improvement Week 72: Complete remission Week 108: Complete remission (Memory) Maggon Available at: Accessed August 26, 2016.

14 Pooled OS Analysis Including EAP Data: 4846 Patients Proportion Alive Median OS (95% CI): 9.5 ( ) 3-year OS Rate (95% CI): 21% (20 22%) Ipilimumab CENSORED Patients at Risk Ipilimumab EAP = expanded access treatment protocol Schadendorf D, et al. J Clin Oncol. 2015;33(17): Months Emerging field of Immuno-oncology This 90 year old had metastatic melanoma with 4 brain metastases and is now without evidence of disease

15 ASCO 2016

16 Checkmate 067- Ipilimumab plus Nivolumab Larkin J et al. N Engl J Med. 2015;373: Ipilimumab + Nivolumab Combination in Melanoma Larkin J et al. N Engl J Med. 2015;373:23-34.

17 Checkmate year OS update NIVO + IPI NIVO IPI Median OS, mos,(95% CI) NR (38.2-NR) 37.6 (29.1-NR) 19.9 ( ) HR (95% CI) vs Ipi 0.55 ( , p<0.001) 0.65 (0.53 to 0.80, p<0.001) HR (95% CI) vs. Nivo 0.85 (0.68 to 1.07) Wolchok JD et al. N Engl J Med 2017;377: Wolchok JD, NEJM 2017

18 Melanoma Brain Metastases At least 40% of patients will have clinically significant brain metastases (BM) Up to 70% of patients may have BM from autopsy studies Typically BM is an exclusion for clinical trials Historical treatment approach is surgical resection and/or stereotactic radiation Whole brain radiation should be avoided ASCO 2017 Ipi/Nivo for untreated brain metastases

19 COMBI-MB: dabrafenib plus trametinib in untreated BM Cancer Immunity Cycle 3 Priming & activation (APCs and T cells) 4 T-cell trafficking to tumours (CTLs) 5 T-cell infiltration into tumours (CTLs, endothelial cells) 2 Antigen presentation (DCs and other APCs) lymph node blood vessel 6 T-cell recognition of cancer cells tumour 1 Antigen release (cancer cell death) 7 Killing of cancer cells Chen DS, Mellman I. Immunity. 2013;39:1 10.

20 Conclusions: Future directions Melanoma is a terrible disease but with the advancements in therapy we are getting closer to achieving our goal in winning the war against melanoma Combination approaches appear to result in greater benefit Optimal combinations and sequencing of therapy is unknown Adjuvant treatment investigations are ongoing Greater understanding of immunotherapy resistance is needed Biomarkers are needed