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Update on Systemic Therapy for Melanoma
Melanoma and Cutaneous Oncology Primer
October 14, 2017
Sekwon Jang, MD Director, Melanoma and Cutaneous Oncology Therapeutics and Research
Inova Schar Cancer Institute
Disclosures
• Advisory Board: Bristol-Meyers Squibb
Melanoma Key Statistics
• Estimated New Cases in 2017: 87,110 • Estimated Deaths in 2017: 9,730
www.cancer.gov 2017
Unresectable Stage III or Stage IV melanoma
• 3-year Overall Survival
10%
Unresectable Stage III or Stage IV melanoma
• 3-year Overall Survival
10% ~50%
Systemic therapies approved since 2011 for advanced-stage melanoma
Luke JJ, et al. Nat Rev Clin Oncol. 2017;14(8):463-482
Key clinical trials in advanced melanoma
Luke JJ, et al. Nat Rev Clin Oncol. 2017;14(8):463-482
Ipilimumab superior to gp100 (CA184-002)
Hodi FS, et al. N Engl J Med. 2010;363:711-723.
Pembrolizumab superior to ipilimumab (KEYNOTE 006)
Robert C, et al. ASCO 2017. Abstract 9504.
Ipilimumab and Nivolumab or Nivolumab superior to Iplimumab (CheckMate 067)
Wolchok JD, et al. N Engl J Med. 2017 Online
CheckMate 067: Treatment-Related AEs
Select Treatment-Related AEs, %
Nivo + Ipi (n = 313)
Nivo (n = 313)
Ipi (n = 311)
All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Any select AE 96 59 86 21 86 28
Skin Pruritus Rash Maculopapular rash
35 30 12
2 3 2
21 23 5
<1 <1 1
36 22 12
<1 2 1
Gastrointestinal Diarrhea Colitis
45 13
9 8
21 2
3 1
34 11
6 8
Hepatic ALT increase AST increase
19 16
9 6
4 4
1 1
4 4
2 1
Endocrine Hypothyroidism Hypophysitis
17 7
< 1 2
11 1
0
<1
5 4
0 2
Pulmonary Pneumonitis
7
1
2
< 1
2
< 1
Treatment-related AE leading to discontinuation 39 30 12 8 16 14
Wolchok JD, et al. N Engl J Med. 2017 Online
Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.
Vemurafenib superior to Dacarbazine (BRIM3)
cuSCC/KA Development With Vemurafenib
• cuSCC/KAs – Incidence: 26%
– Median time: 8 wks (range: 2-36)
– Median number of cuSCC/KAs per patient: 1 (range: 1-7)
– Each dot represents wks to development of first cuSCC/KA lesion
0 5 10 15 20 25 35 30 40 Wks on Vemurafenib
Median
Ribas A, et al. ASCO 2011. Abstract 8509.
BRAFi/MEKi combination is superior to BRAFi
RR (%)
mPFS (mo)
3-yr PFS (%)
mOS (mo)
3-yr OS (%)
Reference
COMBI-d ASCO 2016 Dabrafenib + Trametinib
69 11.0 22 25.1 44
Dabrafenib 53 8.8 12 18.7 32 COMBI-v ESMO 2016 Dabrafenib + Trametinib
67 25 45
Vemurafenib 53 11 32 COBRIM Lancet 2016 Vemurafenib + Cobimetinib
68 12.3 22.3
Vemurafenib 45 7.2 17.4
Summary of Overall Survival in Advanced Melanoma
Luke JJ, et al. Nat Rev Clin Oncol. 2017;14(8):463-482
Resected Stage III Melanoma
• 3-year Recurrence-free Survival
35~40%
Resected Stage III Melanoma
• 3-year Recurrence-free Survival
35~40% 55~60%
Adjuvant Ipilimumab is superior to Placebo
Eggermont AM, et al. N Engl J Med. 2016;375:1845-55.
Stage IIIA (LN met > 1mm), IIIB, IIIC Treatment duration: 3 year
Adjuvant Nivolumab is superior to Ipilimumab
Weber J, et al. N Engl J Med. 2017 Online.
Stage IIIB, IIIC, IV Treatment duration: 1 year
Adjuvant Dabrafenib/Trametinib is superior to placebo
Long GV, et al. N Engl J Med. 2017 Online.
Stage IIIA (LN met > 1mm), IIIB, IIIC Treatment duration: 1 year
1. New immunotherapy targets - OX40, GITR, Lag-3, Tim-3, TIGIT, VISTA, IDO, etc 2. Combination strategies - Targeted therapy + immunotherapy - Multiple immunotherapeutic agents 3. Patient selection using clinical and biological biomarker 4. Optimization of timing and sequence of therapies
Future Directions
Clinical trials at Inova
• Advanced Melanoma Phase 3, Epacadostat + Pembrolizumab vs Pembrolizumab + placebo (completed) Phase 1b/2, SD-101 injection + Pembrolizumab (enrolling) Phase 1b, TAK-202 + Nivolumab or vedolizumab + Ipilimumab/nivolumab (enrolling) Phase 1/2, NKTR-214 + Nivolumab (upcoming) • Adjuvant Melanoma Phase 3, Nivolumab + Ipilimumab vs Nivolumab + placebo (enrolling)