Treatment and management of advanced melanoma: Paul B. Chapman, MD Melanoma Clinical Director, Melanoma and Immunotherapeutics Service MSKCC

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1 Treatment and management of advanced melanoma: 2018 Paul B. Chapman, MD Melanoma Clinical Director, Melanoma and Immunotherapeutics Service MSKCC

2 Disclosure Paul B. Chapman, MD Nothing to disclose. Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

3 Melanoma statistics: 2018 Siegel, R. L., Miller, K. D. and Jemal, A. (2018), Cancer statistics, CA: A Cancer Journal for Clinicians

4 Treatment of Melanoma Sentinel lymph node biopsy

5 Treatment of Melanoma Sentinel lymph node biopsy

6 Melanoma Sentinel Lymph node Trial 1: Sentinel lymph node bx followed by Complete lymphadenectomy if positive vs. observation followed by therapeutic lymphadenectomy if needed Morton DL et al. N Engl J Med 2014;370:

7 Melanoma Sentinel Lymph node Trial 2: Role of Complete lymphadenectomy after + Sentinel lymph node biopsy Faries et al. NEJM 376:2211, 2017

9 Sentinel lymph node biopsy is currently standard of care, has prognostic value, but not associated with improved OS Completion lymphadectomy does not improve OS and is no longer standard of care

10 20 th Century Overall survival in stage IV melanoma By site of metastasis Balch C M et al. JCO 2009;27: by American Society of Clinical Oncology

11 FDA-approved drugs/treatments for melanoma since 2011 Drug Target Resp rate Improved OS Vemurafenib RAF kinase 40-50% Yes (vs DTIC) Dabrafenib RAF kinase 40-50% Not tested Trametinib MEK kinase 20% Yes (vs DTIC) Dab/Tram combo RAF/MEK 69% Yes (vs dabrafenib and vemurafenib) Vem/cobimetinib RAF/MEK 68% Yes (vs vemurafenib) Ipilimumab CTLA % Yes (vs vaccine) Pembrolizumab PD % Not tested Nivolumab PD % Yes (vs chemo) Ipi/nivo combo CTLA4/PD % Too early T-VEC (intralesional) Herpes virus 15-60% Not tested

12 Treatment with vemurafenib Pretreatment Week 10

13 Treatment with Dabrafeninb Baseline Week 32

14 Vemurafenib ± Cobimetinib PFS OS Ascierto et al. Lancet Oncol 2016; 17:1248

15 Dabrafenib ± trametinib PFS OS From Long et al. Lancet 386: , 2015

16 Key points BRAFi/MEKi better than BRAFi alone 2 BRAF/MEK inhibitor combinations FDA-approved Vemurafenib/cobimetinib Dabrafenib/trametinib High response rates (50-57%) Responses in brain Resistance usually within 18 months (but not always)

17 FDA-approved checkpoint blocking therapies Antibody Trade name Target Ipilimumab Yervoy CTLA4 Nivolumab Opdivo PD1 Pembrolizumab Keytruda PD1 Ipilimumab + nivolumab combo Yervoy/Keytruda CTLA4 + PD1

18 Ipilimumab vs. vaccine vs. both: Overall Survival and objective response rates Ipi Ipi + vaccine 11 % Resp. rates Vaccine alone 5.7% 1.5% Adapted from Hodi FS et al. N Engl J Med 2010;363:

19 Pooled overall survival from 1861 patients treated with ipilimumab. Schadendorf D et al. JCO doi: /jco by American Society of Clinical Oncology

20 Colitis

21 Hypophysitis

22 Antitumor Activity of Pembrolizumab Hamid O et al. N Engl J Med 2013;369:

23 Pembrolizumab vs Ipilimumab: OS Schachter et al. Lancet 2017; 390:1853

24 Survival End Points: Nivolumab vs. DTIC Robert C et al. N Engl J Med 2015;372:

25 Pneumonitis from nivolumab

26 Ipilimumab vs. nivolumab vs. both: PFS and OS Wolchok et al. N Engl J Med 2017; 377:1345

27 Chest wall melanoma metastasis Pre-treatment 3 weeks (1 treatment with Ipi/nivo) 17 weeks (3 treatments with Ipi/nivo) Chapman et al. NEJM 21:2073, 2015

28 Adverse Events Larkin J et al. N Engl J Med 2015;373:23-34 Larkin J et al. N Engl J Med 2015;373:23-34

29 Number of Ipi/Nivo doses given to patients treated under an EAP at MSKCC 1dose 4 doses 2 doses 3 doses Total=64 Shoushtari, et al. JAMA Oncol 2017

30 Other metrics of toxicity from ipi/nivo experience 91% had irae grade 2 72% required systemic steroids 25% needed infliximab 50% 1 ER visit Shoushtari, et al. JAMA Oncol 2017

31 Intracranial response rate in treatment-naïve brain metastases Ipi/Nivo 1 Nivo 1 Dab/Tram 2 Dab 3 N=20 N=19 N=76 N=74 CR PR (50%) 4 (21%) 44 (58%) 29 (39%) 1 Long et al. ASCO meeting, Davies et al. Lancet, Long et al. Lancet Oncol 2012

32 Key points Checkpoint inhibiting antibodies can shrink large tumors, including brain metastases. Ipilimumab and anti-pd1 (at least nivolumab) antibodies improve overall survival Ipi + nivo higher response rate and toxicity No evidence of better response with more doses Unique and severe AEs No evidence that treatment of iraes impairs response First line for brain metastases

33 Adjuvant nivolumab vs. Ipilimumab (Checkmate 238) 67% 52% Weber et al. NEJM 377:1824, 2017

34 Adjuvant nivolumab (Checkmate 238) No OS data yet Hypophysitis: 1.9% Treated-related AE leading to discontinuation: 11% Adapted from Weber et al. NEJM 377:1824, 2017

35 Adjuvant dabrafenib/trametinib 85% 78% Long et al. NEJM 377:1813, 2017

36 Adjuvant dabrafenib/trametinib Small OS effect 26% who recurred in placebo cohort did not receive treatment Most patients required dose modification or discontinuation

37 Adjvuant therapy for melanoma in 2018 Adjuvant therapies in 2018: Nivolumab and dabrafenib/trametinib Is adjuvant therapy is better than treatment at time of recurrence?

New paradigms for treating metastatic melanoma

New paradigms for treating metastatic melanoma Paul B. Chapman, MD Melanoma Clinical Director Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center, New York 20 th Century Overall