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 survival in stage IV melanoma By site of metastasis Balch C M et al. JCO 2009;27:6199-6206 2009 by American Society of Clinical Oncology
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%
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
I m dealing with medievalism here. Chemotherapy, fundoscopic examinations
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 CTLA4 12-15% Yes (vs vaccine) Pembrolizumab PD1 21-34% Not tested Nivolumab PD1 24-44% Yes (vs chemo) Ipi/nivo combo CTLA4/PD1 58-61% Too early T-VEC (intralesional) Herpes virus 15-60% Not tested
Inhibition of the ERK pathway RTK RAS 40-60% of melanomas Trametinib Cobimentinib ATP ATP BRAF V600E MEK ERK Vemurafenib Dabrafenib Cellular Proliferation
Treatment with vemurafenib Pretreatment Week 10
Treatment with Dabrafeninb Baseline Week 32
Progression-free Survival. Chapman PB et al. N Engl J Med 2011;364:2507-2516
Overall Survival. Chapman PB et al. N Engl J Med 2011;364:2507-2516
Final ITT analysis of BRIM3 data Presented at SMR, 2015
Comparing RAF inhibitors Vemurafenib Dabrafenib Chapman PB et al. N Engl J Med 2011;364:2507-2516 Hauschild et al. Lancet 2012; 380: 2012 358-365
Dabrafenib ± trametinib: Overall Survival From Long et al. Lancet 386:444-451, 2015
Vemurafenib ± Cobimetinib : OS Larkin et al. NEJM 2014;371:1867
Blockade of PD-1 or CTLA-4 Signaling in Tumor Immunotherapy. Ribas A. N Engl J Med 2012;366:2517-2519.
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
Pre-treatment Week 12 (10/06) 4 blinded doses ipilimumab No drug 12/06 5/07 4 10 mg/kg doses ipilimumab
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;363:711-723.
Primary analysis of pooled overall survival (OS) data. Schadendorf D et al. JCO doi:10.1200/jco.2014.56.2736 2015 by American Society of Clinical Oncology
Colitis
Hypophysitis
Alive (%) 100 90 80 70 60 50 40 30 20 10 # 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 0.04 38% 31% 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (Months) 31% 23% IPI 10 mg/kg 365 306 253 217 196 181 161 151 137 126 120 118 111 105 94 16 0 IPI 3 mg/kg 362 310 253 205 168 146 131 118 107 95 87 83 80 76 71 8 0 Minimum OS follow-up: ~43 mo Ascierto et all, 2016 23
PFS, ORR, DCR by mwho: Randomized Patients PFS (%) 100 90 80 70 60 50 40 30 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) 20 10 Number of patients at risk 0 IPI 10 mg/kg IPI 3 mg/kg 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (Months) IPI 10 mg/kg 365 160 89 69 52 46 43 38 38 33 33 31 29 23 11 2 0 IPI 3 mg/kg 362 138 79 60 49 39 35 32 29 27 25 23 22 19 8 0 0 Ascierto et all, 2016 24
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, % 95 59 93 52 Treatment-related AEs, % 79 34 63 19 Serious AEs, % 64 53 51 43 AEs leading to discontinuation, % 31 26 19 16 Immune-related AEs, % 74 30 54 14 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, 2016 25
Antitumor Activity of Pembrolizumab Hamid O et al. N Engl J Med 2013;369:134-144
Survival End Points: Nivolumab vs. DTIC Robert C et al. N Engl J Med 2015;372:320-330
Pneumonitis from nivolumab
Ipilimumab vs. nivolumab vs. both: Progression-free Survival Larkin J et al. N Engl J Med 2015;373:23-34
Ipilimumab vs. Ipilimumab + nivolumag: Change in Tumor Burden, Durability of Tumor Regressions, and Progressionfree Survival. Postow MA et al. N Engl J Med 2015;372:2006-2017.
Chest wall melanoma metastasis Pre-treatment 3 weeks (1 treatment with Ipi/nivo) 17 weeks (3 treatments with Ipi/nivo)
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 20 11 1 2 3 4 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:
Adverse events on Ipi/Nivo 91% had significant irae 72% required steroids 22% received infliximab 50% seen in ER 36% admitted
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;27:6199-6206 2009 by American Society of Clinical Oncology
Kaplan Meier Estimates of Relapse-free Survival with adjuvant Ipilimumab. Eggermont AM et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1611299
Kaplan Meier Estimates of Overall Survival with adjuvant Ipilimumab. Eggermont AM et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1611299
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 2016. DOI: 10.1056/NEJMoa1611299
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 2016. DOI: 10.1056/NEJMoa1611299
MSKCC Melanoma Team