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

Ribas & Wolchok Science 2018

Mechanism of action of immune checkpoint blockade

Anti-CTLA4

First Major steps: 2011

Anti-BRAF for BRAF mutant melanoma:

• Response rate: 50%
• Median PFS: 6-8 months
• Median OS : 1 year

Anti-CTLA-4 (for BRAF wt

• r mutant):

– Reponse rate: 12% – Median PFS: 3 months – Median OS: 1 year

Anti-CTLA-4 Ipilimumab: 4 infusions

Hodi et al 2010 NEJM

Pre-treated-pts +/- gp100 HLA-A2 3mg/kg Re-induction possible

Robert et al NEJM 2011

naive-pts + DTIC 10 mg/kg Maintenance possible

Tremelimumab vs DTIC

Ribas et al., J Clin Oncol 2014

Tremelimumab vs DTIC

Ribas et al., J Clin Oncol 2014

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

Pooled OS Analysis of ipilimumab treated 4846 melanoma patients

Adapted from Korn et al J Clin Oncol 2008

Where are we coming from in melanoma?

Ipilimumab approved for metastatic melanoma

• In 2012: In NL reimbursed as 2nd line treatment
• In 2014: In NL reimbursed as 1st 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)

Ribas & Wolchok Science 2018

Mechanism of action of immune checkpoint blockade

Anti-CTLA4

2014: 2014: Se Secon

• nd major
• r steps

Anti-BRAF + anti-MEK for BRAF mutant

• Reponse rate: 70%
• Median PFS: 12 months
• Median OS : 33 months

Anti-PD1 for BRAF wt or mutant

– ORR: 40% – Median PFS: 3-5 months – Median OS: 33 months

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

13

ANALYSIS OF RESPONSE AND SURVIVAL IN PATIENTS WITH IPILIMUMAB- REFRACTORY MELANOMA TREATED WITH PEMBROLIZUMAB IN KEYNOTE-002

• A. Daud1; I. Puzanov2; R. Dummer3; D. Schadendorf4; O. Hamid5; C. Robert6; F. S. Hodi7; J. Schachter8; J. A. Sosman9;
• A. C. Pavlick10; R. Gonzalez11; C. Blank12; L. D. Cranmer13; S. J. O’Day14; A. K.Salama15; K. A. Margolin16; J. Yang17;
• B. Homet Moreno17; N. Ibrahim17; A. Ribas18

1University of California, San Francisco, San Francisco, CA, USA; 2Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; (currently at Roswell Park Cancer

Institute, Buffalo, NY, USA; 3University of Zürich, Zürich, Switzerland; 4University Hospital Essen, Essen, Germany; 5The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 6Gustave Roussy and Paris-Sud University, Villejuif, France; 7Dana-Farber Cancer Institute, Boston, MA, USA; 8Ella Lemelbaum Institute of Melanoma, Sheba Medical Center, Tel Hashomer, Israel; 9Vanderbilt-Ingram Cancer Center, Nashville, TN, USA (currently at Northwestern University Feinberg School of Medicine, Chicago, IL, USA, USA); 10New York University Cancer Institute, New York, NY, USA; 11University of Colorado Denver, Aurora, CO, USA; 12Netherlands Cancer Institute, Amsterdam, Netherlands; 13currently at University of Washington and Seattle Cancer Care Alliance, Seattle, WA, USA; 14John Wayne Cancer Institute, Santa Monica, CA, USA;

15Duke Cancer Institute, Durham, NC, USA; 16City of Hope, Duarte, CA, USA; 17Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth,

NJ, USA; 18University of California, Los Angeles, Los Angeles, CA, USA

ORR 26%

Robert et al., Lancet 2014

NR, not reached. PFS was assessed by RECIST v1.1 per investigator. Data cut-off: February 3, 2017.

PFS AND OS in All Pembrolizumab-Treated Patients and Those With Best Response of CR, PR, or SD

P F S , %

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 10 20 30 40 50 60 70 80 90 100 Time, months

• No. at risk

29 27 27 22 21 20 19 17 10 4 2 70 48 45 41 39 37 31 31 25 6 4 1 88 15 8 5 4 3 2 1 1 361 29 70 86 207 29 68 51 151 28 59 36 124 28 51 20 99 90 80 68 64 60 52 49 36 10 6

97% 76% 24% 29% 75% 66% 6% 21% 72% 49% 1% 16%

29 70 88 361 41.0 (38.9-NR) 35.8 (27.9 -NR) 7.0 (5.8-9.7) 4.2 (3.3-5.6) CR PR SD All treated Events, n Median, mo (95% CI) Group NR (NR-NR) NR (NR-NR) 16.5 (13.8-20.5) 14.0 (11.8-16.2) Events, n Median, mo (95% CI) Group SD All treated 88 361 PR 70 29 CR O S , % 29 29 28 27 26 25 25 25 25 16 6 70 65 63 62 59 54 52 50 47 36 16 88 46 39 31 25 23 20 18 16 14 6 361 29 70 87 298 29 70 83 236 29 69 71 236 162 162 145 128 115 108 99 99 99 56 100% 96% 71% 55% 93% 86% 31% 37% 89% 71% 24% 30% Time, months

• No. at risk

10 20 30 40 50 60 70 80 90 100 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 29 67 59 194 1 5 1 15

• 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

Conclusions

CheckMate-066

Robert et al., NEJM 2015

Updated OS results from CheckMate 066 trial in BRAF wt advanced melanoma

Atkinson et al. abstract 3774 SMR 2015

Decrease of the risk of death 58% vs chemotherapy

n = 277

KEYNOTE-006 Study Design (NCT01866319)

Patients

• Unresectable, stage III or IV melanoma
• ≤1 previous therapy, excluding

anti–CTLA-4, PD-1, or PD-L1 agents

• Known BRAF statusa
• ECOG PS 0/1
• No active CNS metastases
• No serious autoimmune disease

Pembrolizumab 10 mg/kg IV Q2W for 2 years Ipilimumab 3 mg/kg IV Q3W × 4 doses

n = 279 n = 278

Pembrolizumab 10 mg/kg IV Q3W for 2 years

Stratification factors

• ECOG PS (0 vs 1)
• Line of therapy (first vs second)
• PD-L1 status (positiveb vs negative)
• Primary end points: PFS and OS
• Secondary end points: ORR and

safety

R (1:1:1) N = 834

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

Poststudy Drug Therapya

patient in pembrolizumab combined arm and 0 patients in the ipilimumab arm. dIncludes Ckit inhibitor, EGFR inhibitor, VEGF/VEGFR inhibitor, and unspecified investigational drug. Data cutoff: Dec 4, 2017.

Therapy, n (%) Pembrolizumab n = 555 Ipilimumab n = 256 ≥1 new systemic therapy 259 (47) 144 (56) Immunotherapyb 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) Chemotherapyc 67 (12) 34 (13) Otherd 10 (2) 12 (5)

Overall Survival

• comparison. bDerived by the product-limit (Kaplan-Meier) method for censored data. Data cutoff: Dec 4, 2017.

Events, n HRa (95% CI) Median,b mo (95% CI) Pembro 309 0.73 (0.61-0.89) 32.7 (24.5-41.6) Ipi 164

• 15.9 (13.3-22.0)

Events, n HRa (95% CI) Median,b mo (95% CI) Pembro 193 0.73 (0.57-0.93) 38.7 (27.3-NR) Ipi 104

• 17.1 (13.8-26.2)

All Patients

278 202 158 127 111 102 94 90 85 76 556 481 416 357 317 289 266 250 239 181

• No. at risk

Overall Survival, % Time, months 100 90 80 70 60 50 40 30 20 10 5 10 15 20 25 30 35 40 45 50 55 60

34.1% 41.7% 39.0% 49.9%

181 140 105 86 76 70 64 63 60 51 368 324 284 248 221 201 186 174 167 124

• No. at risk

Time, months 100 90 80 70 60 50 40 30 20 10 5 10 15 20 25 30 35 40 45 50 55 60

36.4% 44.3%

Treatment-Naive Patients

52.9% 41.5%

Overall Survival, %

Presented at ASCO 2018 by G Long

Progression-Free Survivala

treatment groups involved in a comparison for a particular stratum, then that stratum was excluded from treatment comparison. cDerived by the product-limit (Kaplan-Meier) method for censored data. Data cutoff: Dec 4, 2017.

Events, n HRb (95% CI) Median,c mo (95% CI) Pembro 378 0.56 (0.47-0.67) 8.3 (6.5-11.2) Ipi 204

• 3.3 (2.9-4.1)

Events, n HRb (95% CI) Median,c mo (95% CI) Pembro 230 0.54 (0.43-0.67) 11.2 (7.1-13.9) Ipi 130

• 3.7 (2.8-4.3)

278 93 47 32 27 22 20 15 7 3 556 324 251 213 183 148 132 115 95 35

• No. at risk

All Patients

Progression-Free Survival, % 5 10 15 20 25 30 35 40 45 50 55 60 Time, months 100 90 80 70 60 50 40 30 20 10

31.1% 13.3% 33.6% 14.8%

181 64 32 23 20 17 15 10 5 2 368 222 178 150 133 112 98 88 76 28

• No. at risk

Treatment-Naive Patients

Progression-Free Survival, % Time, months 5 10 15 20 25 30 35 40 45 50 55 60 100 90 80 70 60 50 40 30 20 10

15.9% 36.2% 38.7% 18.4%

Presented at ASCO 2018 by G Long

Are we curing advanced stage melanoma patients?

Evidence coming from the KN-001 and KN-006 studies

Keynote 006 PFS Total Population (Median Follow-Up, 4 years)

C Robert et al ASCO 2017

100 90 80 70 60 50 40 20 30 10 4 8 12 16 20 24 28 32 36 40 Time, months 556 278 347 110 269 64 231 40 211 32 182 27 155 23 138 20 88 14 12 2 Progression-Free Survival, %

• No. at risk

Pembrolizumab

31% 14% 34% 15%

Ipilimumab

Stop pembro

Ipilimumab Pembrolizumab

Disposition of Patients Completing ≥94 Weeks of Pembrolizumab Treatment

and then progressed. Data cutoff: Dec 4, 2017.

Median follow-up after ≥94 weeks pembro: 20.3 (0.03-24.8) mo

103 (18.5%) completed 2 year pembrolizumab treatment 556 patients received pembrolizumab 28 (27.2%) CR 65 (63.1%) PR 10 (9.7%) SD

• 55 patients had an
• ngoing response
• 9 (13.8%) confirmed PDa
• 1 (1.5%) unconfirmed PD
• 4 received 2nd course of

pembrolizumab

• 4 patient had an
• ngoing SD
• 3 (30%) confirmed PDa
• 1 (10%) unconfirmed PD
• 1 received 2nd course of

pembrolizumab

• 25 patients had an
• ngoing response
• 2 (7.1%) confirmed PDa
• 3 (10.7%) unconfirmed PD
• 3 received 2nd course of

pembrolizumabb Long et al ASCO 2018

PFSa in Patients Who Completed Protocol-Specified Time

• n Pembrolizumab (n = 103)

Time, months 100 90 80 70 60 50 40 30 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

• No. at risk

28 27 27 27 26 26 26 26 23 19 15 6 1 65 58 58 57 57 54 51 54 51 44 32 15 3 10 10 9 7 7 6 6 6 5 4 4 3 CR PR SD CR PR SD

Progression-Free Survival, %

66.7% 91.3% 95.8%

Long et al ASCO 2018

Analysis cutoff date: September 1, 2016.

Pts, N Events, n Median (95% CI) 152 76 (50%) 41.2 mo (27.2 mo-NR) Pts, N Events, n Median (95% CI) 655 388 (59%) 23.8 mo (20.2-30.4 mo) All Patients

10 20 30 40 50 60 70 80 90 100

Overall Survival, %

6 12 18 24 30 36 42 48 54 60

Time, months

• No. at risk

655 516 424 370 290 238 134 54 5 318

42% 37%

Treatment Naivea

Overall Survival, %

6 12 18 24 30 36 42 48 54 60

Time, months

10 20 30 40 50 60 70 80 90 100

• No. at risk

152 127 109 98 85 68 39 15 90

51% 48%

Keynote 001: phase I study of pembrolizumab in 655 metastatic melanoma patients. Median follow-up of 43 months

Robert et al EADO 2017

Pembrolizumab phase 1: Keynote 001 : Median Follow-Up 43 Months for 655 patients

Robert et al EADO 2017

Consent withdrawal 5% Discontinued for AEs: 25% Discontinued for PD: 42% On treatment: 16% Discontinue for physician Decision 11%

Range of follow-up: 36-57 months. Analysis cutoff date: September 1, 2016.

Complete Responders: Disposition

Median follow-up: 43 months

Robert et al EADO 2017

Analysis cutoff date: September 1, 2016.

14 (13%) remained on pembrolizumab 67 (64%) stopped pembrolizumab for

• bservation

24 (23%) discontinued for AEs (n = 12), PD (n = 2),

• r other reason (n = 10)

92 (88%) remained in CRa 105 (16%) patients had CR per irRC by investigator review

Complete Responders Who Stopped Pembrolizumab for Observation (N = 67)

Total bar length represents the time to the last scan. Analysis cutoff date: September 1, 2016.

6 12 18 24 30 36 42 48 54 60 Time, months

• Median time to CR: 13 mo ( 3-36 mo)
• 61 (91%) responses were maintained
• Median response duration: NR (6+ to 56+

mo)

PD PR CR Time to PD or last assessment Last dose Time to death

Robert et al J Clin Oncol 2017

Baseline parameters associated with CR

Robert et al , J Clin Oncol, 2017

Conclusions

• Anti-PD1 (nivolumab and pembrolizumab) is approved for advanced stage

melanoma

• Mostly given as frontline treatment with ORR of around 40%, with good safety

profile

• Patients with CR may stop earlier and have a durable response
• PDL1+ and low tumor burden is associated with higher CR rate
• Patient with CR and PR that stop at 2 year of treatment have durable benefit

Immunotherapy melanoma – CTLA4 + PD-1 blockade (ipilimumab + nivolumab)

Wolchok et al. ASCO 2013 # 9012

Callahan et al., J Clin Oncol 2017

Overall Survival Results From a Phase III Trial

• f Nivolumab Combined With Ipilimumab in Treatment-naïve

Patients With Advanced Melanoma (CheckMate 067)

James Larkin,1 Vanna Chiarion-Sileni,2 Rene Gonzalez,3 Piotr Rutkowski,4 Jean-Jacques Grob,5

• C. Lance Cowey,6 Christopher D. Lao,7 Dirk Schadendorf,8 Pier Francesco Ferrucci,9 Michael Smylie,10

Reinhard Dummer,11 Andrew Hill,12 John Haanen,13 Michele Maio,14 Grant McArthur,15 Dana Walker,16 Linda Rollin,16 Christine Horak,16 F. Stephen Hodi,17,* Jedd D. Wolchok18,*

1Royal Marsden Hospital, London, UK; 2Oncology Institute of Veneto IRCCS, Padua, Italy; 3University of Colorado Cancer Center, Denver, CO,

USA; 4Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland; 5Hospital de la Timone, Marseille, France;

6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA; 7University of Michigan, Ann Arbor, MI, USA; 8Department of

Dermatology, University of Essen, Essen, Germany; 9European Institute of Oncology, Milan, Italy; 10Cross Cancer Institute, Alberta, Canada;

11Universitäts Spital, Zurich, Switzerland; 12Tasman Oncology Research, QLD, Australia; 13Netherlands Cancer Institute, Amsterdam, The

Netherlands; 14University Hospital of Siena, Siena, Italy; 15Peter MacCallum Cancer Centre, Victoria, Australia; 16Bristol-Myers Squibb, Princeton, NJ, USA; 17Dana-Farber Cancer Institute, Boston, MA, USA; 18Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; *Contributed equally to this study.

Presented at AACR 2017 by Larkin

Unresectable or Metatastic Melanoma

• Previously untreated
• 945 patients

CA CA209-067: 067: Stu tudy Desi esign

CheckMate 067: Study Design

Treat until progression or unacceptable toxicity NIVO 3 mg/kg Q2W + IPI-matched placebo NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo

Randomize 1:1:1 Stratify by:

• BRAF status
• AJCC M stage
• Tumor PD-L1

expression <5% vs ≥5%*

N=314 N=316 N=315

Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone*

*The study was not powered for a comparison between NIVO and NIVO+IPI

Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms)

Presented at AACR 2017 by Larkin

NI NIVO+I +IPI (N (N=314) NI NIVO (N (N=316) IPI IPI (N (N=315) ORR, % % (95% CI CI)* 58. 58.9 (53.3–64.4) 44. 44.6 (39.1–50.3) 19. 19.0 (14.9–23.8) Be Best ov

• verall response — %

Complete response 17.2 14.9 4.4 Partial response 41.7 29.7 14.6 Stable disease 11.5 9.8 21.3 Progressive disease 23.6 38.6 51.1 Unknown 6.1 7.0 8.6 Me Median duration of response, mo months (95% CI) NR NR (NR–NR) 31. 31.1 1 (31.1–NR) 18. 18.2 2 (8.3–NR)

Response To Treatment

*By RECIST v1.1; NR = not reached.

• At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively

Database lock: Sept 13, 2016, minimum f/u of 28 months

Progression-Free Survival

Wolchok et al., NEJM 2017

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) Median PFS, mo (95% CI) 11.7 (8.9–21.9) 6.9 (4.3–9.5) 2.9 (2.8–3.2) HR (95% CI) vs. IPI 0.42 (0.34–0.51) 0.54 (0.45–0.66)

• HR (95% CI) vs. NIVO

0.76 (0.62–0.94)

Overall Survival

*P<0.0001

Wolchok et al., NEJM 2017

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) Median OS, mo (95% CI) NR NR (29.1–NR) 20.0 (17.1–24.6) HR (98% CI) vs. IPI 0.55 (0.42–0.72)* 0.63 (0.48–0.81)*

• HR (95% CI) vs. NIVO

0.88 (0.69–1.12)

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) Any subsequent therapy, n (%)* 129 (41) 169 (54) 225 (71) Systemic therapy 100 (32) 140 (44) 196 (62) Anti-PD-1 agents 30 (10) 32 (10) 132 (42) Anti-CTLA-4 19 (6) 83 (26) 12 (4) BRAF inhibitors 40 (13) 57 (18) 68 (22) MEK inhibitors 30 (10) 38 (12) 39 (12) Investigational agents** 8 (3) 6 (2) 15 (5) Median time to subsequent systemic therapy, mo (95% CI) NR (NR‒NR) 26.8 (18.0‒NR) 8.5 (7.3‒9.7) 2 year % of pts free of subsequent therapies 65.8 53.8 24.7

Subsequent Therapies: All Randomized Patients

*Patients may have received more than 1 subsequent therapy (e.g. radiation, surgery and systemic therapies) **Other than investigational immunotherapy, BRAF inhibitors, and MEK inhibitors

Presented at AACR 2017 by Larkin

<1% PD-L1 NIVO+IPI NIVO IPI Median OS, mo (95% CI) NR (26.5–NR) 23.5 (13.0–NR) 18.6 (13.7–23.2) HR (95% CI) vs NIVO 0.74 (0.52–1.06) ─ ─ ≥1% PD-L1 NIVO+IPI NIVO IPI Median OS, mo (95% CI) NR NR 22.1 (17.1–29.7) HR (95% CI) vs NIVO 1.03 (0.72–1.48) ─ ─

OS (%) Months

10 20 30 40 50 60 70 80 90 100 39 36 33 30 27 24 21 18 15 12 9 6 3 60% 49% 41%

OS (%) Months

10 20 30 40 50 60 70 80 90 100 39 36 33 30 27 24 21 18 15 12 9 6 3

113 IPI 1 10 32 43 44 50 57 61 71 79 87 96 117 NIVO 2 16 50 55 57 59 62 65 73 76 86 103 123 NIVO+IPI 4 18 66 72 74 74 79 82 82 91 102 113 164 IPI 2 21 64 74 77 83 89 102 115 126 138 155 171 NIVO 1 36 98 109 112 117 122 131 139 148 158 165 155 NIVO+IPI 3 27 85 99 101 102 105 112 116 127 132 144

67% 67% 48%

Outcomes Observed at PDL1 1% Cutoff

PD-L1 Expression Level <1% PD-L1 Expression Level ≥1%

Patients at risk: Patients at risk:

• ORR of 65.2% for NIVO+IPI and 55.0% for NIVO
• ORR of 54.5% for NIVO+IPI and 35.0% for NIVO

Presented at AACR 2017 by Larkin

Safety Summary

• With an additional 19 months of follow-up, safety was consistent with the initial report1
• Most select AEs were managed and resolved within 3-4 weeks (85–100% across organ

categories)

• ORR was 70.7% for pts who discontinued NIVO+IPI due to AEs, with median OS not reached

NI NIVO+IPI (N (N=3 =313) NI NIVO (N (N=3 =313) IP IPI (N (N=311) 311) Pa Patients reporting event, % Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 Tr Treatment-re related adverse event (AE)

95.8 58. 58.5 86.3 20. 20.8 86.2 27. 27.7

Tr Treatment-re related AE leading to di discontinua nuation

39.6 31.0 11.5 7.7 16.1 14.1

Tr Treatment-re related death, n (%)

2 (0.6)a 1 (0.3)b 1 (0.3)b

aCardiomyopathy (NIVO+IPI, n=1); Liver necrosis (NIVO+IPI, n=1). Both deaths occurred >100 days after the last treatment. bNeutropenia (NIVO, n=1); colon perforation (IPI, n=1).1

• 1. Larkin J, et al. NEJM 2015;373:23‒34.

Comparison nivolumab monotherapy versus combination with ipilimumab

• Median time to CR was 6.9 (2.3-44.0) months for NIVO+IPI and 10.6

(1.4-45.4) months for NIVO; median time to PR was 2.8 (1.9-35.8) for NIVO+IPI and 2.7 (1.2-20.8) for NIVO

Robert et al ESMO 2017 10 20 30 40 50 60 70 80 90 100 NIVO+IPI NIVO

20% CR 22% PD 8% UTD 9% UTD 18% CR 38% PR 26% PR 12% SD 11% SD 36% PD 58% ORR 44% ORR 71% DCR 55% DCR

NIVO+IPI n = 409 NIVO n = 526

Response (%)

Duration of response

Robert et al ESMO 2017

On treatment Off treatment (TFI) Censored CR TFI (SUBSEQ) SUBSEQ Last dose Last dose off treatment Death Start SUBSEQ

NIVO+IPI

On treatment Off treatment with TFI Subsequent systemic therapy

16 32 48 64 80 96 112 128 144 160 176 192 208 224

Weeks

NIVO

On treatment Off treatment with TFI Subsequent systemic therapy

16 32 48 64 80 96 112 128 144 160 176 192 208 224

Weeks

SUBSEQ, subsequent systemic therapy; TFI, treatment-free interval

Conclusions

• The combination of ipi + nivo induces high ORR of around 60%
• PDL1 expression may be used to select patients for

combination IT

• PFS and OS are numerical better compared to nivolumab single

agent

• This comes at the cost of high toxicity rates with grade 3-4 AEs
• f 60% (vs 20% for nivo)
• More patients stop treatment due to AEs compared to single

agent nivolumab, but tend to have high ORR and durable remissions

Where are we now?

Ugurel S et al., Eur J Cancer 2017

Primary and secondary resistances

Ugurel et al., Eur J Cancer 2017

More than 35% of patients are dead at 2 years

Perspectives

• How can we increase ORR and survival in stage IV

disease further?

• Patients with intrinsic resistance
• Immune desert tumors?
• Immune excluded tumors?
• Patients with acquired resistance
• Who would benefit from which combination?
• Patients with brain metastases
• Patients with BRAF wt tumors not responding to IT

Should we treat earlier? (adjuvant setting)

Gersenwald et al Cancer J Clinic 2017

EORTC 18071/CA184-029: Study Design

Stratification factors

• Stage (IIIA vs IIIB vs IIIC 1-3 positive lymph nodes vs IIIC ≥4 positive lymph nodes)
• Regions (North America, European countries, and Australia)

Enrollment Period: June 2008 to July 2011

Randomized, double-blind, phase 3 study evaluating the efficacy and safety of ipilimumab in the adjuvant setting for high-risk melanoma

INDUCTION Ipilimumab 10 mg/kg Q3W × 4 High-risk, stage III, completely resected melanoma INDUCTION Placebo Q3W × 4

R

MAINTENANCE Ipilimumab 10 mg/kg Q12W up to 3 years MAINTENANCE Placebo Q12W up to 3 years Treatment up to a maximum of 3 years, or until disease progression, intolerable toxicity, or withdrawal

N = 475 N = 476

Week 1 Week 12 Week 24

N = 951

Q3W = every 3 weeks; Q12W = every 12 weeks; R = randomization.

aStratified by stage provided at randomization.

CI = confidence interval. Patients Alive and Without Recurrence (%)

Ipilimumab Placebo Events/patients 264/475 323/476 HR (95% CI)a 0.76 (0.64, 0.89) Log-rank P valuea 0.0008 Median RFS, months (95% CI) 27.6 (19.3, 37.2) 17.1 (13.6, 21.6)

RFS (per IRC)

41% 30% Years

1 2 3 4 5 6 7 8 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk 264 475 283 217 184 161 77 13 1 323 476 261 199 154 133 65 17 Ipilimumab Placebo

Patients Alive (%)

aStratified by stage provided at randomization.

Ipilimumab Placebo Deaths/patients 162/475 214/476 HR (95.1% CI)a 0.72 (0.58, 0.88) Log-rank P valuea 0.001

OS

65% 54% Years

1 2 3 4 5 6 7 8 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk 162 475 431 369 325 290 199 62 4 214 476 413 348 297 273 178 58 8 Ipilimumab Placebo

Patient Disposition and Treatment

Ipilimumab (n = 471) Placebo (n = 474) Discontinuation, % 100 100 Reasons for discontinuation, % Normal completion (received study drug for entire 3 years) 13.4 30.2 Disease recurrence 28.7 59.5 AE related to study drug 49.7 1.9 Other reasonsa 8.2 8.4 Median doses, per patient, n 4.0 8.0 Receiving ≥1 maintenance dose, % 42.0 70.0 Receiving ≥7 doses (1 year of therapy), % 28.9 56.8

aIncludes AE unrelated to study drug, both related and unrelated to study drug, patient request, poor/noncompliance, death, pregnancy, patient

no longer eligible, other.

Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV Melanoma: A Randomized, Double-blind, Phase 3 Trial (CheckMate 238)

Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5

• C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10

Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15 Paola Queirolo,16 Veerle de Pril,17 Anila Qureshi,17 James Larkin,18* Paolo A. Ascierto19*

1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute, Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Cancer Center, Dallas, Texas, USA; 7Hospices

Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France; 12Princess Margaret Cancer Centre, Toronto, Ontario, Canada;

13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15Gallipoli

Medical Research Foundation and Princess Alexandra Hospital, Woolloongabba, and University of Queensland, Greenslopes, Queensland, Australia; 16IRCCS San Martino-IST, Genova, Italy; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust, London, UK; 19Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study.

CA CA209-067: 067: Stu tudy Desi esign

CA209-238: Study Design

Enrollment period: March 30, 2015 to November 30, 2015

Patients with high- risk, completely resected stage IIIB/IIIC or stage IV melanoma Follow-up Maximum treatment duration of 1 year NIVO 3 mg/kg IV Q2W and IPI placebo IV Q3W for 4 doses then Q12W from week 24 IPI 10 mg/kg IV Q3W for 4 doses then Q12W from week 24 and NIVO placebo IV Q2W 1:1 n = 453 n = 453

Stratified by: 1) Disease stage: IIIB/C vs IV M1a-M1b vs IV M1c 2) PD-L1 status at a 5% cutoff in tumor cells

Primary endpoint RFS: time from randomization until first recurrence (local, regional, or distant metastasis), new primary melanoma, or death Secondary endpoints OS, Safety and tolerability, RFS by PD-L1 tumor expression, HRQoL Duration of follow-up: minimum 18 months; 360 events

Primary Endpoint: RFS

RFS (%) Months

10 20 30 40 50 60 70 80 90 100 6 12 18 24 27 3 9 15 21

453 353 311 249 5 399 332 291 71 NIVO 453 314 252 184 2 364 269 225 56 IPI Number of patients at risk NIVO IPI

NI NIVO IPI PI Ev Events/patients 154/453 206/453 Me Median (9 (95% CI CI) NR NR (16.6, NR) HR (97.56% % CI) 0.65 (0.51, 0.83) Log-rank P value <0.0001

66% 53% 71% 61%

EORTC 1325/KN-54 study

Eggermont AACR 2018

Recurrence free survival in ITT population

Eggermont AACR 2018

Improvement in relapse-free survival (RFS) in high risk melanoma

Months 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 12 24 36 Proportion Alive and Relapse Free

88% 67% 58% 56% 44% 39%

COMBI-AD

N = 870 sIIIA-B-C HR 0.47

Long et al. NEJM 2017

placebo dabrafenib+trametinib

CheckMate-238

100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 Months RFS, %

71% 61% 66% 53% Weber et al. NEJM 2017

N = 906 sIIIB-C, sIV HR 0.65

ipilimumab nivolumab 75.4% 61.0% 53.2% 71.4%

EORTC 1325-MG/Keynote 054

N = 1019 sIIIA-B-C HR 0.57

3 6 9 12 15 18 21 24

Eggermont et al. AACR 2018

Months placebo pembrolizumab

Patients Alive and Without Recurrence (%)

41% 30% Years 1 2 3 4 5 6 7 8 10 20 30 40 50 60 70 80 90 100 ipilimumab placebo

N = 951 sIIIA-B-C HR 0.76

Eggermont et al. NEJM 2016

EORTC 18071

Years

Important questions to address

• Does adjuvant therapy improve overall survival

(OS) in addition to delaying relapses (RFS)?

• In patients with BRAF mutated melanoma,

should we use an anti-PD-1 or a BRAF+MEK inhibitor combo?

• How does adj anti-PD1 impact on treatment
• ptions in stage IV disease?

Neoadjuvant approach

• Phase I
• Opacin trial (neoadj ipi /nivo)
• Neoadj nivo or nivo/ipi (J Wargo MDACC)
• Neoadj pembro (AACR 2018)
• Phase II
• Opacin-neo trial (Blank et al. ESMO 2018)

Blank et al., Nat Med 2018; Wargo et al., submitted

Summary

• Metastatic melanoma survival has improved from 10-15% at to >50%

at 3 years

• This is almost solely the result from introduction of immunotherapy
• Further improvement of survival will be obtained by using IT in earlier

stage disease (adjuvant and neoadjuvant in stage III)

• Understanding the biology of resistance to therapy will likely give

direction on how the further improve survival.

• Precision immunotherapy will be the future

Questions?