New paradigms for treating metastatic melanoma

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

2 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

3 Objective response rates of 20 th Century treatments for metastatic melanoma Response rates DTIC, temozolomide 10-15% IL-2 16% Nitrosoureas 10-18% Cisplatin 14-29% Interferon-α 14% Paclitaxel, nabpaclitaxel 14-21% Vincristine 12%

4 20 th Century combination chemotherapy - Minimal interpretable OS data Regimen Phase II RR Phase III OS results DTIC/bleo/HU RR- 29% (N=386; no OS data) CVD 40-44% Negative vs. DTIC (abst only) DTIC/cDDP/BCNU/Tam 39-55% Negative vs. DTIC (N= 226) Myeloablative chemo with autotransplant rescue Carboplatin/Taxol 11%, 18% (phase III trials) 60% Short PFS. No randomized trials

5 I m dealing with medievalism here. Chemotherapy, fundoscopic examinations

6 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

7 Inhibition of the ERK pathway RTK RAS 40-60% of melanomas Trametinib Cobimentinib ATP ATP BRAF V600E MEK ERK Vemurafenib Dabrafenib Cellular Proliferation

8 Treatment with vemurafenib Pretreatment Week 10

9 Treatment with Dabrafeninb Baseline Week 32

10 Progression-free Survival. Chapman PB et al. N Engl J Med 2011;364:

11 Overall Survival. Chapman PB et al. N Engl J Med 2011;364:

12 Final ITT analysis of BRIM3 data Presented at SMR, 2015

13 Comparing RAF inhibitors Vemurafenib Dabrafenib Chapman PB et al. N Engl J Med 2011;364: Hauschild et al. Lancet 2012; 380:

14 Dabrafenib ± trametinib: Overall Survival From Long et al. Lancet 386: , 2015

15 Vemurafenib ± Cobimetinib : OS Larkin et al. NEJM 2014;371:1867

16 Blockade of PD-1 or CTLA-4 Signaling in Tumor Immunotherapy. Ribas A. N Engl J Med 2012;366:

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 Pre-treatment Week 12 (10/06) 4 blinded doses ipilimumab No drug 12/06 5/ mg/kg doses ipilimumab

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

20 Primary analysis of pooled overall survival (OS) data. Schadendorf D et al. JCO doi: /jco by American Society of Clinical Oncology

21 Colitis

22 Hypophysitis

23 Alive (%) # of patients at risk 0 OS: Randomized Patients IPI 10 mg/kg IPI 3 mg/kg 54% 48% IPI 10 OS mg/kg n = 365 IPI 3 mg/kg n = 362 Events (%) 262 (72) 279 (77) Median (95% CI), mo 15.7 (11.6, 17.8) 11.5 (9.9, 13.3) HR (95% CI) 0.84 (0.70, 0.99) Log-rank P value % 31% Time (Months) 31% 23% IPI 10 mg/kg IPI 3 mg/kg Minimum OS follow-up: ~43 mo Ascierto et all,

24 PFS, ORR, DCR by mwho: Randomized Patients PFS (%) IPI 10 mg/kg n = 365 IPI 3 mg/kg n = 362 PFS Events (%) 328 (90) 330 (91) Median (95% CI), mo 2.8 (2.8, 3.0) 2.8 (2.8, 2.8) HR (95% CI) 0.89 (0.76, 1.04) Log-rank P value 0.16 ORR % (95% CI) 15 (12, 20) 12 (9, 16) DCR % (95% CI) 32 (27, 37) 28 (23, 33) Number of patients at risk 0 IPI 10 mg/kg IPI 3 mg/kg Time (Months) IPI 10 mg/kg IPI 3 mg/kg Ascierto et all,

25 Safety Summary: Treated Patients AEs during initial treatment phase IPI 10 mg/kg n = 364 Any grade Grades 3-5 IPI 3 mg/kg n = 362 Any grade Grades 3-5 AEs, % Treatment-related AEs, % Serious AEs, % AEs leading to discontinuation, % Immune-related AEs, % During the entire study period, study-drug toxicity led to death in 4 patients (1%) in the 10 mg/kg arm Diarrhea leading to general deterioration, fulminant colitis, multiorgan failure, bowel perforation 2 patients (<1%) in the 3 mg/kg arm Multifocal colon perforation, myocardial infarction from complications of diarrhea and colitis Ascierto et all,

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

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

28 Pneumonitis from nivolumab

29 Ipilimumab vs. nivolumab vs. both: Progression-free Survival Larkin J et al. N Engl J Med 2015;373:23-34

30 Ipilimumab vs. Ipilimumab + nivolumag: Change in Tumor Burden, Durability of Tumor Regressions, and Progressionfree Survival. Postow MA et al. N Engl J Med 2015;372:

31 Chest wall melanoma metastasis Pre-treatment 3 weeks (1 treatment with Ipi/nivo) 17 weeks (3 treatments with Ipi/nivo)

32 Patient Demographics 64 patients treated Age, median 56 (22 82) (range) Male:Female 1:01 Elevated LDH 20 (31%) ECOG 0 51 (81%) 1 13 (19%) Stage (Cutaneous or Uveal) III 11 (17%) M1a 9 (14%) M1b 12 (19%) M1c 32 (50%) Presented by:

Early Discontinuation of Ipi+Nivo 60% of patients discontinued Ipi+Nivo before receiving all 4 doses Number of Patients 30 25 20 15 10 5 0 Number of Doses of Ipi+Nivo Administered 8

33 Early Discontinuation of Ipi+Nivo 60% of patients discontinued Ipi+Nivo before receiving all 4 doses Number of Patients Number of Doses of Ipi+Nivo Administered Number of Doses of Ipi + Nivo 25 3% POD Reasons for Stopping Ipi+Nivo Early 18% Other 79% Toxicity Toxicity (n=31) POD (n=7) Death due to other causes (n=1) Presented by:

34 Adverse events on Ipi/Nivo 91% had significant irae 72% required steroids 22% received infliximab 50% seen in ER 36% admitted

35 Overall survival in stage IV melanoma: Progress so far Ipi Nivo Ipi +Nivo Dab Vem Dab/Tram Vem +Cobi Balch C M et al. JCO 2009;27: by American Society of Clinical Oncology

37 Kaplan Meier Estimates of Relapse-free Survival with adjuvant Ipilimumab. Eggermont AM et al. N Engl J Med DOI: /NEJMoa

38 Kaplan Meier Estimates of Overall Survival with adjuvant Ipilimumab. Eggermont AM et al. N Engl J Med DOI: /NEJMoa

39 Checkpoint inhibitor treatments given at relapse Treatments Ipilimumab cohort N=264 Placebo cohort N=323 Ipilimumab 24 (9%) 76 (24%) Anti-PD1 24 (9%) 30 (9%) Adapted from Eggermont AM et al. N Engl J Med DOI: /NEJMoa

40 Serious or permanent AEs with ipilimumab Ipilimumab-related Severe Adverse event # of patients Hypophysitis 77 Grade 3 or 4 Neurotoxicity 9 GI perforation 7 Death 5 Total 98 (21%) Adapted from Eggermont AM et al. N Engl J Med DOI: /NEJMoa

41 MSKCC Melanoma Team

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

Treatment and management of advanced melanoma: 2018 Paul B. Chapman, MD Melanoma Clinical Director, Melanoma and Immunotherapeutics Service MSKCC Disclosure Paul B. Chapman, MD Nothing to disclose. Off