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)