Locally Advanced and Metastatic Melanoma Abel D. Jarell, MD, FAAD Adjunct Dartmouth School of Medicine, Hanover, NH Northeast Dermatology Associates, Portsmouth, NH Relevant disclosures What is the median survival of metastatic melanoma? A. Less than 1 year B. Less than 5 years C. 5-10 years D. Greater than 10 years 1
What is the median survival of metastatic melanoma? A. Less than 1 year B. Less than 5 years C. 5-10 years D. Greater than 10 years What is the 5-year survival rate of metastatic melanoma? A. < 1% B. < 5 % C. 5-10 % D. 15-20 % What is the 5-year survival rate of metastatic melanoma? A. < 1% B. < 5 % C. 5-10 % D. 15-20 % 2
Locally Advanced and Metastatic Melanoma Diagnosis Manageable melanoma Role of the sentinel lymph node Metastatic melanoma What happens to your patient when you refer them? 3
Manageable 4
Wide local excision with 1-cm margins 5
Surgical Oncology Medical Hematology Oncology Then what? Surgical Oncology To Lymph node or Not to Lymph node? 6
Indication for SLN in MM Benefit exceeds risk Complication rate of SLN is less than 10% Bleeding, infection, seroma, rarely DVT or lymphedema Greater than 5% risk of SLN positivity AJCC 8 th ed pt1b Any depth with ulceration >0.8mm without ulceration What is a Sentinel? A node upon which a lymph vessel originating in the tumor drains directly Predicts additional LN basin involvement 7
Tracer Injection Intradermal injection 0.1-1 cm from scar or tumor margin 2 wheals on extremities 4 wheals on H&N or trunk Left Mid Back 8
Variables Type and dose of tracer (size of particles) Volume of tracer injected Timing of imaging Gamma probes vary General or local anesthesia 9
What Can Go Wrong? SN can be missed True SN may not be radioactive or blue Tumor obstructs lymph flow Not every radioactive or blue node is a SN First node visualized may not be the only SN Nearest node is not always the node that drains the tumor Initial wide excision alters lymph flow What Can Go Wrong? Gamma probe use requires intense training Surgical learning curve FN rate drops from 10% in first 25 cases to 5% for following cases Cautery or crush obscures the subcapsular space 10
METASTATIC MELANOMA Historically has a poor prognosis Median survival ~ 6-9 months 5-year survival < 5% METASTATIC MELANOMA Historically has a poor prognosis Prior to 2011, no FDA-approved therapy shown to prolong survival METASTATIC MELANOMA The pace of progress Ipilimumab 2011 Vemurafenib 2011 Dabrafenib 2013 Trametinib 2013 Pembrolizumab 2014 Nivolumab 2015 Talimogene laherparepvec 2015 Many promising agents in clinical trials 11
FDA-approved medications for advanced melanoma Targeted kinase inhibitors BRAF inhibitors ( vemurafenib, dabrafenib) MEK (trametinib, cobemetinib) Immunotherapy agents Ipilimumab PD-1 inhibitors (nivolumab, pembrolizumab) Talimogene laherparepvec/t-vec Vemurafenib Selective BRAF kinase inhibitor (V600E Mutation) ve = V600E mu = mutation rafenib = RAF inhibitor Approved for treatment of unresectable or metastatic melanoma with BRAF V600E mutation August 2011 N Engl J Med 2014; 370:e22 12
BRAF mutation 50-60% of all melanomas harbor mutations at codon 600 Valine (V) to glutamic acid (E) substitution most common mutation at position 600 = V600E (90%) 2 nd most common mutation is V600K (valine lysine) Mutation results in constitutive activation of MAP kinase signaling pathway = dysregulated tumor growth V600E mutations confer increased sensitivity to BRAF inhibitors (vemurafenib, dabrafenib) 13
Vemurafenib 80% of patients with BRAF V600E will have at least a partial response within weeks The majority of patients will experience relapse Secondary mutations will develop within melanomas in response to therapy Median time to progression 6-7 months Few long term responders How is BRAF testing performed? PCR-based V600E mutation test Used on formalin-fixed, paraffin-embedded tissue Sensitive detection of the BRAF V600E mutation May also detect other mutations, such as V600D, V600K, and V600R Additional options for BRAF testing Targeted next generation sequencing panels Used on formalin-fixed, paraffin-embedded tissue 14
Vemurafenib Side effects 40% of patients require dose reduction Systemic manifestations Fatigue, arthralgias common 15
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FDA Approved medications for advanced melanoma Targeted kinase inhibitors BRAF inhibitors (vemurafenib, dabrafenib) MEK (trametinib, cobimetinib) Immunotherapy agents Ipilimumab PD-1 inhibitors (nivolumab, pembrolizumab) Talimogene laherparepvec (T-VEC) 17
Ipilimumab 4 IV doses, 3 weeks apart Effect often seen toward the end of dosing 10-15 % of patients will respond But many of these patients will have a durable response Ipilimumab Toxic side effects General activation of the immune system, leading to immune-related issues Diarrhea Hypophysitis Skin manifestations Morbilliform eruption Pruritus Vitiligo 18
Nivolumab and Pembrolizumab IV dosing, indefinitely (?) Higher response rate than ipilimumab 30% will have objective response More rapid response Fewer side effects 10% discontinued pembrolizumab in clinical trials 19
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Prognosis and GEP Established use in uveal MM 31 gene assay in cutaneous MM Stage I and II 23
Combined SLN and GEP Metastatic melanoma with a V600E mutation could successfully be treated with: A. Ipilimumab B. Vemurafenib C. Nivolumab D. TVEC 24
Metastatic melanoma with a V600E mutation could successfully be treated with: A. Ipilimumab B. Vemurafenib C. Nivolumab D. TVEC Questions? 25