The Immune therapy revolution: how melanoma became a poster child - PowerPoint PPT Presentation

The Immune therapy revolution: how melanoma became a poster child John Haanen

Mechanism of action of immune checkpoint blockade Anti-CTLA4 Ribas & Wolchok Science 2018

First Major steps: 2011 Anti-BRAF for BRAF mutant Anti-CTLA-4 (for BRAF wt melanoma: or mutant): • Response rate: 50% – Reponse rate: 12% • Median PFS: 6-8 months – Median PFS: 3 months • Median OS : 1 year – Median OS: 1 year

Anti-CTLA-4 Ipilimumab: 4 infusions Pre-treated-pts naive-pts +/- gp100 + DTIC HLA-A2 10 mg/kg 3mg/kg Maintenance possible Re-induction possible Hodi et al 2010 NEJM Robert et al NEJM 2011

Tremelimumab vs DTIC Ribas et al., J Clin Oncol 2014

Tremelimumab vs DTIC Ribas et al., J Clin Oncol 2014

Where are we coming from in melanoma? Pooled OS Analysis of ipilimumab treated 4846 melanoma patients Median OS (95% CI): 9.5 (9.0–10.0) 3-year OS rate (95% CI): 21% (20–22%) Schadendorf et al., J Clin Oncol 2015 Adapted from Korn et al J Clin Oncol 2008

Ipilimumab approved for metastatic melanoma • In 2012: In NL reimbursed as 2 nd line treatment • In 2014: In NL reimbursed as 1 st line treatment • All patients needed to be treated in a limited number of centers/hospitals (14 in total) and all patients were to be included in a nation-based registry (Dutch Melanoma Treatment Registry)

Mechanism of action of immune checkpoint blockade Anti-CTLA4 Ribas & Wolchok Science 2018

2014: 2014: Se Secon ond major or steps Anti-BRAF + anti-MEK for Anti-PD1 for BRAF wt or BRAF mutant mutant • Reponse rate: 70% – ORR: 40% • Median PFS: 12 months – Median PFS: 3-5 months • Median OS : 33 months – Median OS: 33 months

Topalian et al., N Engl J Med 2012; Topalian et al., J Clin Oncol 2014

ANALYSIS OF RESPONSE AND SURVIVAL IN PATIENTS WITH IPILIMUMAB- REFRACTORY MELANOMA TREATED WITH PEMBROLIZUMAB IN KEYNOTE-002 A. Daud 1 ; I. Puzanov 2 ; R. Dummer 3 ; D. Schadendorf 4 ; O. Hamid 5 ; C. Robert 6 ; F. S. Hodi 7 ; J. Schachter 8 ; J. A. Sosman 9 ; A. C. Pavlick 10 ; R. Gonzalez 11 ; C. Blank 12 ; L. D. Cranmer 13 ; S. J. O’Day 14 ; A. K.Salama 15 ; K. A. Margolin 16 ; J. Yang 17 ; B. Homet Moreno 17 ; N. Ibrahim 17 ; A. Ribas 18 1 University of California, San Francisco, San Francisco, CA, USA; 2 Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; (currently at Roswell Park Cancer Institute, Buffalo, NY, USA; 3 University of Zürich, Zürich, Switzerland; 4 University Hospital Essen, Essen, Germany; 5 The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 6 Gustave Roussy and Paris-Sud University, Villejuif, France; 7 Dana-Farber Cancer Institute, Boston, MA, USA; 8 Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Tel Hashomer, Israel; 9 Vanderbilt-Ingram Cancer Center, Nashville, TN, USA (currently at Northwestern University Feinberg School of Medicine, Chicago, IL, USA, USA); 10 New York University Cancer Institute, New York, NY, USA; 11 University of Colorado Denver, Aurora, CO, USA; 12 Netherlands Cancer Institute, Amsterdam, Netherlands; 13 currently at University of Washington and Seattle Cancer Care Alliance, Seattle, WA, USA; 14 John Wayne Cancer Institute, Santa Monica, CA, USA; 15 Duke Cancer Institute, Durham, NC, USA; 16 City of Hope, Duarte, CA, USA; 17 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; 18 University of California, Los Angeles, Los Angeles, CA, USA 13

ORR 26% Robert et al., Lancet 2014

PFS AND OS in All Pembrolizumab-Treated Patients and Those With Best Response of CR, PR, or SD Group Events, n Median, mo (95% CI) Group Events, n Median, mo (95% CI) CR 29 41.0 (38.9-NR) CR 29 NR (NR-NR) PR 70 35.8 (27.9 -NR) NR (NR-NR) PR 70 SD 88 7.0 (5.8-9.7) SD 88 16.5 (13.8-20.5) 100 100 All treated 361 4.2 (3.3-5.6) All treated 361 14.0 (11.8-16.2) 90 90 80 80 70 70 60 60 P F S , % % 50 97% 50 O S , 76% 75% 40 24% 40 66% 72% 29% 6% 49% 100% 30 30 21% 1% 96% 16% 71% 93% 20 20 89% 55% 86% 71% 31% 10 10 24% 37% 30% 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 No. at risk Time, months No. at risk Time, months 29 29 29 28 28 27 27 22 21 20 19 17 10 4 2 0 0 29 29 29 29 29 29 28 27 26 25 25 25 25 16 6 1 0 70 70 68 59 51 48 45 41 39 37 31 31 25 6 4 1 0 70 70 70 69 67 65 63 62 59 54 52 50 47 36 16 5 0 88 86 51 36 20 15 8 5 4 3 2 1 1 0 0 0 0 88 87 83 71 59 46 39 31 25 23 20 18 16 14 6 1 0 361 207 151 124 99 90 80 68 64 60 52 49 36 10 6 0 0 361 298 236 236 194 162 162 145 128 115 108 99 99 99 56 15 0 NR, not reached. PFS was assessed by RECIST v1.1 per investigator. Data cut-off: February 3, 2017.

Conclusions • Responses to pembrolizumab are durable and associated with prolonged OS in ipilimumab-refractory melanoma, especially in patients with CR and PR • Even in these heavily pretreated patients, best response can evolve over time, with late conversions from SD to PR/CR and PR to CR observed • No new safety signals with longer term follow-up

CheckMate-066 Robert et al., NEJM 2015

Updated OS results from CheckMate 066 trial in BRAF wt advanced melanoma Decrease of the risk of death 58% vs chemotherapy Atkinson et al. abstract 3774 SMR 2015

KEYNOTE-006 Study Design (NCT01866319) Pembrolizumab n = 279 10 mg/kg IV Q2W for 2 years Patients • Unresectable, stage III or IV melanoma • ≤1 previous therapy, excluding Pembrolizumab anti–CTLA-4, PD-1, or PD-L1 agents n = 277 R (1:1:1) 10 mg/kg IV Q3W • Known BRAF status a N = 834 for 2 years • ECOG PS 0/1 • No active CNS metastases • No serious autoimmune disease Ipilimumab n = 278 3 mg/kg IV Q3W × 4 doses Stratification factors • ECOG PS (0 vs 1) Primary end points: PFS and OS • • Line of therapy (first vs second) • PD-L1 status (positive b vs negative) • Secondary end points: ORR and safety a Prior anti-BRAF therapy was not required for patients with normal LDH levels and no clinically significant tumor-related symptoms or evidence of rapidly progressing disease. b Defined as ≥1% staining in tumor and adjacent immune cells as assessed by IHC using 22C3 antibody.

ORR: 34% ORR: 33% ORR: 12%

Poststudy Drug Therapy a Pembrolizumab Ipilimumab n = 555 n = 256 Therapy, n (%) ≥1 new systemic therapy 259 (47) 144 (56) Immunotherapy b 186 (34) 103 (40) Anti–CTLA-4 142 (26) 20 (8) Anti–PD-1 63 (11) 97 (38) Anti–PD-L1 3 (1) 1 (<1) BRAF inhibitor ± MEK inhibitor 81 (15) 55 (21) MEK inhibitor 57 (10) 32 (13) Chemotherapy c 67 (12) 34 (13) Other d 10 (2) 12 (5) a Summary of new oncologic therapies after discontinuation from study treatment. b Immunotherapy + other, 1 patient in the pembrolizumab combined arm and 1 patient in ipilimumab arm. c Chemotherapy + other, 1 patient in pembrolizumab combined arm and 0 patients in the ipilimumab arm. d Includes Ckit inhibitor, EGFR inhibitor, VEGF/VEGFR inhibitor, and unspecified investigational drug. Data cutoff: Dec 4, 2017.

Overall Survival Treatment-Naive Patients All Patients HR a (95% CI) Median, b mo (95% CI) HR a (95% CI) Median, b mo (95% CI) Events, n Events, n 0.73 (0.61-0.89) 0.73 (0.57-0.93) Pembro 309 32.7 (24.5-41.6) Pembro 193 38.7 (27.3-NR) Ipi 164 - 15.9 (13.3-22.0) Ipi 104 - 17.1 (13.8-26.2) 100 100 41.7% 49.9% 44.3% 52.9% 90 90 39.0% 34.1% 41.5% 36.4% 80 80 Overall Survival, % Overall Survival, % 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 5 10 15 20 25 30 35 40 45 50 55 0 5 10 15 20 25 30 35 40 45 50 55 60 60 Time, months Time, months No. at risk No. at risk 556 481 416 357 317 289 266 250 239 181 0 0 0 0 0 0 368 324 284 248 221 201 186 174 167 124 278 202 158 127 111 102 94 90 85 76 0 0 0 181 140 105 86 76 70 64 63 60 51 0 0 0 Presented at ASCO 2018 by G Long a Based on Cox regression model with treatment as covariate stratified by line of therapy (1st vs 2nd), PD-L1 status (positive vs negative), and ECOG (0 vs 1); if no patients are in one of the treatment groups involved in a comparison for a particular stratum, then that stratum was excluded from treatment comparison. b Derived by the product-limit (Kaplan-Meier) method for censored data. Data cutoff: Dec 4, 2017.