COMBINATION IMMUNOTHERAPY How to achieve maximal patient benefit
John Haanen MD PhD Disclosures
• I have provided consultation, attended advisory boards, and/or
provided lectures for: Pfizer, MSD, BMS, IPSEN,
Roche/Genentech, NEON Therapeutics, Novartis for which NKI
received honoraria
• Through my work NKI received grant support from BMS, MSD,
Novartis
• I declare no conflict of interest Why combining immunotherapies? Cancer Immunogram
Tumor foreignness Mutational load
Tumor sensitivity to immune effectors General immune status MHC expression Lymphocyte count IFN-γ sensitivity
Absence of inhibitory Immune cell tumor metabolism infiltration LDH, glucose utilization Intratumoral T cells
Absence of soluble inhibitors Absence of Checkpoints IL6->CRP/ESR PD-L1
Blank, Haanen et al. Science 2016 Cancer Immunophenotypes
Chen & Mellman Nature 2017 Combinations with immunotherapy
Melero, .., Haanen Nat Rev Canc 2015 Most combinations have anti-PD1/PDL1 as backbone
Melero, .., Haanen Nat Rev Canc 2015 Combinations
• Anti-CTLA4 + anti-PD1/PDL1 • IDO1/2 inhibitor + anti-PD1 • Oncolytic virus + anti-PD1 • Anti-LAG3 + anti-PD1 PD1 blockade synergizes with aCTLA-4
Curran et al., PNAS 2010 Immunotherapy melanoma – CTLA4 + PD-1 blockade (ipilimumab + nivolumab)
Wolchok et al. ASCO 2013 # 9012 Overall Survival Results From a Phase III Trial of 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. Wolchok 18,*
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; 10 Cross Cancer Institute, Alberta, Canada; 11 Universitäts Spital, Zurich, Switzerland; 12 Tasman Oncology Research, QLD, Australia; 13 Netherlands Cancer Institute, Amsterdam, The Netherlands; 14 University Hospital of Siena, Siena, Italy; 15 Peter MacCallum Cancer Centre, Victoria, Australia; 16 Bristol-Myers Squibb, Princeton, NJ, USA; 17 Dana-Farber Cancer Institute, Boston, MA, USA; 18 Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; *Contributed equally to this study.
Presented at AACR 2017 by Larkin CheckMateCA209-067: 067: Study Study Design Design
Randomized, double-blind, phase III study to compare NIVO+IPI NIVO 1 mg/kg + or NIVO alone to IPI alone* IPI 3 mg/kg Q3W for N=314 4 doses then NIVO 3 mg/kg Q2W
Stratify by: Unresectable or • BRAF status Metatastic Melanoma N=316 Treat until • Previously untreated Randomize • AJCC M stage 1:1:1 NIVO 3 mg/kg Q2W + progression or • 945 patients • Tumor PD-L1 IPI-matched placebo unacceptable expression <5% toxicity vs ≥5%*
N=315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo
Database lock: Sept 13, 2016 (median follow-up ~30 months in both NIVO-containing arms)
*The study was not powered for a comparison between NIVO and NIVO+IPI
Presented at AACR 2017 by Larkin Response To Treatment
NIVO+IPI NIVO IPI (N=314) (N=316) (N=315) ORR, % (95% CI)* 58.9 (53.3–64.4) 44.6 (39.1–50.3) 19.0 (14.9–23.8) Best overall 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
Median duration of response, months (95% CI) NR (NR–NR) 31.1 (31.1–NR) 18.2 (8.3–NR)
*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
NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) 100 Median PFS, mo (95% 11.7 6.9 2.9 CI) (8.9–21.9) (4.3–9.5) (2.8–3.2) 90 0.42 0.54 HR (95% CI) vs. IPI -- 80 (0.34–0.51) (0.45–0.66) 0.76 HR (95% CI) vs. NIVO -- -- 70 (0.62–0.94)
60 50% 50 43%
40 43% Percentage of PFS of Percentage 30 37% Progression-free Survival (%) Survival Progression-free 20 NIVO+IPI 18% 10 NIVO 12% IPI 0 0 3 6 9 12 15 18 21 2427 30 33 36 Months
Patients at risk: NIVO+ IPI 314 218 176 156 137 132 125 118 110 104 71 16 0
NIVO 316 178 151 132 120 112 107 103 97 88 62 16 0
IPI 315 136 77 58 46 43 35 33 30 27 16 5 0
Database lock: Sept 13, 2016, minimum f/u of 28 months Presented at AACR 2017 by Larkin Overall Survival
NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) Median OS, mo (95% NR 20.0 NR CI) (29.1–NR) (17.1–24.6)
0.55 0.63 100 HR (98% CI) vs. IPI -- (0.42–0.72)* (0.48–0.81)*
90 0.88 HR (95% CI) vs. NIVO -- -- (0.69–1.12) 80 73% *P< 0.0001 70 74% 64% 60 67% 59% 50
40 45% Percentage of PFS of Percentage Overall Survival (%) Survival Overall 30
20 NIVO+IPI NIVO 10 IPI 0 0 3 6 9 12 15 18 21 2427 30 33 36 39
Months Patients at risk: NIVO+IPI 314 292 265 247 226 221 209 200 198 192 170 49 7 0 NIVO 316 292 265 244 230 213 201 191 181 175 157 55 3 0 IPI 315 285 254 228 205 182 164 149 136 129 104 34 4 0
Database lock: Sept 13, 2016, minimum f/u of 28 months Presented at AACR 2017 by Larkin Subsequent Therapies: All Randomized Patients
NIVO+IPI NIVO IPI (N=314) (N=316) (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
*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 Outcomes Observed at PDL1 1% Cutoff
PD-L1 Expression Level <1% PD-L1 Expression Level ≥1%
NIVO+IPI NIVO IPI NIVO+IPI NIVO IPI <1% PD-L1 ≥1% PD-L1 18.6 22.1 Median OS, NR 23.5 Median OS, (13.7– NR NR (17.1– mo (95% CI) (26.5–NR) (13.0–NR) mo (95% CI) 23.2) 29.7) 0.74 1.03 100 HR (95% CI) 100 HR (95% CI) (0.52– ─ ─ (0.72– ─ ─ vs NIVO vs NIVO 1.06) 1.48) 90 90
80 80
70 70 67% 60% 60 60 67% 49% 50 50 41% OS (%) OS (%) OS 40 40 48%
30 30
20 20
10 • ORR of 54.5% for NIVO+IPI and 35.0% for NIVO 10 • ORR of 65.2% for NIVO+IPI and 55.0% for NIVO
0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Months
Patients at risk: Patients at risk:
NIVO+IPI 123 113 102 91 82 82 79 74 74 72 66 18 4 0 NIVO+IPI 155 144 132 127 116 112 105 102 101 99 85 27 3 0
NIVO 117 103 86 76 73 65 62 59 57 55 50 16 2 0 NIVO 171 165 158 148 139 131 122 117 112 109 98 36 1 0
IPI 113 96 87 79 71 61 57 50 44 43 32 10 1 0 IPI 164 155 138 126 115 102 89 83 77 74 64 21 2 0 Presented at AACR 2017 by Larkin Safety Summary • With an additional 19 months of follow-up, safety was consistent with the initial report 1
NIVO+IPI NIVO IPI (N=313) (N=313) (N=311)
Patients reporting event, % Any Grade Grade 3-4 AnyGrade Grade 3-4 AnyGrade Grade 3-4
Treatment-related adverse event (AE) 95.8 58.5 86.3 20.8 86.2 27.7
Treatment-related AE leading to discontinuation 39.6 31.0 11.5 7.7 16.1 14.1
Treatment-related death, n (%) 2 (0.6) a 1 (0.3) b 1 (0.3) b
• 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
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. Rapid complete remission after combination immunotherapy with anti-CTLA4 and anti-PD1
Chapman et al., NEJM 2015 Conclusions
• Combination of ipilimumab + nivolumab is highly effective in patients with metastatic melanoma with ORR of 58.9%, PFS of 11.6 months and 2 year OS rate of 64% Conclusions
• NIVO+IPI and NIVO significantly improved OS and PFS vs. IPI alone in patients with untreated advanced melanoma
• In descriptive analyses, NIVO+IPI resulted in numerically higher OS, PFS and ORR vs. NIVO alone
• Results consistently favored NIVO+IPI across clinically relevant subgroups, including PD-L1 expression <5% or <1%, mutant BRAF , and elevated LDH
– Although similar prolongation of OS was observed with NIVO and NIVO+IPI for PD-L1 expression ≥5% or ≥1%, NIVO+IPI resulted in higher ORR regardless of PD-L1 expression
• For NIVO+IPI, median DOR and time to subsequent therapy are still not reached
• The safety profile of the combination showed high rate of grade 3-4 IR toxicity, but early discontinuation due to AEs did not preclude benefit Epacadostat Plus Pembrolizumab in Patients With Advanced Melanoma: Phase 1 and 2 Efficacy and Safety Results From ECHO- 202/KEYNOTE-037
• O. Hamid ,1 T. F. Gajewski, 2 A. E. Frankel, 3 T. M. Bauer, 4 A. J. Olszanski, 5 J. J. Luke, 2 A. S. Balmanoukian, 1 E. V. Schmidt, 6 B. Sharkey, 7 J. Maleski, 7 M. M. Jones, 7 T. C. Gangadhar 8
• 1The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 2University of Chicago, Chicago, IL, USA; 3University of Texas Southwestern Medical Center, Dallas, TX, USA*; 4Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 5Fox Chase Cancer Center, Philadelphia, PA, USA; 6Merck & Co., Inc., Kenilworth, NJ, USA; 7Incyte Corporation, Wilmington, DE, USA; 8Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA
Presentation #1214O Session: Melanoma and Other Skin Tumours Presented at the ESMO Annual Meeting 2017 Madrid, Spain September 9, 2017 IDO1 Enzyme and Epacadostat
• Tumors may evade immunosurveillance through numerous mechanisms (eg, immune checkpoint inhibition of T-cell activation and upregulation of the IDO1 enzyme)
• IDO1 is an IFN γ-induced intracellular enzyme that catalyzes the first and rate- limiting step of tryptophan degradation in the kynurenine pathway 1
• In tumors, depletion of tryptophan and production of kynurenine and other metabolites shift the local TME to an immunosuppressive state that helps tumor cells evade immunosurveillance 1
• Epacadostat is a potent and specific oral inhibitor of the IDO1 enzyme 2
• Combining epacadostat with an immune checkpoint inhibitor may improve patient outcomes
IDO1, indoleamine 2,3 dioxygenase 1; IFN γ, interferon gamma; PD-1, programmed death 1; PD-L1, programmed death ligand 1. 1. Moon YW, et al. J Immunother Cancer . 2015;3:51. 2. Liu X, et al. Blood. 2010;115(17):3520-3530. Objective and Study Design
Objective: To report the efficacy, safety, and tolerability data for epacadostat plus pembrolizumab in patients with advanced melanoma in the phase 1/2 ECHO-202/KEYNOTE-037 study (NCT02178722)
Phase 1b Phase 2 Phase 1/2 Melanoma Patients (N=65)
Dose Safety Open-Label • ≥18 years of age Escalation Expansion Cohort • Histologically or cytologically Expansion confirmed melanoma Epacadostat 25 mg BID + • Life expectancy >12 weeks Pembrolizumab 2 mg/kg Epacadostat Q3W • ECOG PS 0 or 1 100 mg BID + • ALT, AST, ALP <2.5x ULN; Epacadostat 50 mg BID Epacadostat 50 mg BID conjugated bilirubin <2.0x ULN + + Pembrolizumab Pembrolizumab 2 mg/kg Pembrolizumab 200 mg 200 mg Q3W • No previous IDO inhibitor or Q3W Q3W immune checkpoint inhibitor Tumor cohorts treatment Epacadostat 100 mg Epacadostat 100 mg Melanoma , SCCHN, BID BID • Phase 2 requirements + + UC, NSCLC (TPS Pembrolizumab 2 mg/kg Pembrolizumab 200 mg ≥50%,* TPS <50%), – Documented BRAF V600E- Q3W Q3W RCC, TNBC, OC, mutation status or consent for Epacadostat 300 mg Epacadostat 300 mg MSI-High CRC,* † BRAF mutation testing during BID BID DLBCL,* GC,* HCC* † screening + + Pembrolizumab 200 mg Pembrolizumab 200 mg – Ocular melanoma excluded Q3W Q3W ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; CRC, colorectal cancer; DLBCL, diffuse large B-cell lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; GC, gastric cancer; HCC, hepatocellular carcinoma; IDO, indoleamine 2,3 dioxygenase; MSI, microsatellite instability; NSCLC, non -small cell lung cancer; OC, ovarian cancer; Q3W, every 3 weeks; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple-negative breast cancer; TPS, tumor proportion score; UC, urothelial cancer; ULN, upper limit of normal. * Ongoing patient enrollment at data cutoff (June 9, 2017). † Ongoing patient enrollment at time of European Society for Medical Oncology presentation (September 9, 2017). Patient Disposition Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma
Phase 1/2 Melanoma (N=65; Enrollment Complete)
Treatment Discontinued (n=27) Treatment Ongoing • Disease progression (n=32) (n=15) • Adverse event (n=6) ‒ Treatment related (n=4) • Death (n=3) • Patient decision (n=1) Treatment Completed* • Other (n=2) (n=6)
Median (range) follow-up: 45+ (2 to 144+) weeks Median (range) epacadostat exposure: 34+ (<1 to 145+) weeks
* Patients received 24 months of study treatment or achieved complete response and elected to discontinue treatment following the protocol- defined minimum amount of treatment ( ≥24 weeks before discontinuation and ≥2 cycles of combination treatment beyond the date of initial complete response). Best Objective Response by RECIST v1.1 Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma
Treatment-Naive for Treatment-Naive for All Advanced Disease, All E Advanced Disease, E 100 Patients Doses mg (N=65) (n=54) (n=39) Per-protocol evaluable,* n n=63 n=53 n=38 (%) ORR (CR+PR) 35 (56) 29 (55) 22 (58) CR 9 (14) 7 (13) 3 (8) PR 26 (41) 22 (42) 19 (50) SD 10 (16) 9 (17) 6 (16) DCR (CR+PR+SD) 45 (71) 38 (72) 28 (74) PDor death 18 (29) 15 (28) 10 (26) Not evaluable † n=2 n=1 n=1
Response Observed Across Patient Subgroups (N=63*) • For all patients, based on irRECIST (n=63*): ORR=59% (9 CR, 28 PR); DCR=75% (10 SD) • Liver metastases yes (n=24) vs no (n=39): 46% vs 62% ORR • M1c (n=35) vs non-M1c (n=28): 49% vs 64% ORR • BRAF -mutation–positive (n=18) vs –negative (n=43): 50% vs 56% ORR • LDH normal (n=39) vs elevated (n=23): 62% vs 48% ORR Best Percentage Change From Baseline in Target Lesions Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma
All Patients Treatment-Naive Patients
PD-L1 Positive E 100 mg BID PD-L1 Negative Other E Doses PD-L1 Unknown
CR, complete response; DCR, disease control rate; E, epacadostat, irRECIST, immune-related RECIST; MEL, melanoma; ORR, objective response rate; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Note: PD-L1 positive defined as MEL Score ≥2 (membranous PD-L1 expression in ≥1% of tumor cells or inflammatory cells in nests of tumor cells) as assessed by immunohistochemistry using the 22C3 antibody. * SD per target lesion but PD per RECIST v1.1. † PR per target lesion but PD per RECIST v1.1. ‡ PR per target lesion but SD per RECIST v1.1. § PD per target lesion per RECIST v1.1 (PR per irRECIST). ǁ CR per target lesion but PD per new lesion per RECIST v1.1 (PR per irRECIST); ¶ CR per target lesion but PR per RECIST v1.1 (nontarget lesions still present). Percentage Change From Baseline in Target Lesions Over Time All Patients Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma Progression-Free Survival Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma
All Patients All Treatment-naive, All E Doses Treatment-naive E 100 mg BID
BID, twice daily; E, epacadostat. Immune related adverse events Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma
All Grade Grade 3/4 Adverse Event,* n (%) (N=65) (N=65) Total 12 (19) 6 (9)
Hypothyroidism 4 (6) 0
Severe skin reactions † 4 (6) 3 (5)
Colitis 2 (3) 2 (3)
Uveitis ‡ 2 (3) 0
Autoimmune hepatitis § 1 (2) 1 (2)
* Adverse events of special interest include adverse events with an immune-related cause, regardless of attribution to study treatment by the investigator. † Includes grade ≥3 rash generalized, rash maculopapular, rash pruritic, and erythema multiforme minor. ‡ Includes iritis and uveitis. § Includes grade 3 elevations of alanine aminotransferase and aspartate aminotransferase, and biopsy confirmed. Conclusions Epacadostat Plus Pembrolizumab, P1/2 Advanced Melanoma
• Epacadostat plus pembrolizumab demonstrated promising antitumor activity in patients with advanced melanoma
Treatment-Naive for Advanced Treatment-Naive for Advanced All Patients (n=63) Disease, All E Doses (n=53) Disease, E 100 mg (n=38)
• 56% ORR (14% CR) • 55% ORR (13% CR) • 58% ORR (8% CR) • 71% DCR • 72% DCR • 74% DCR • 12.4 month median PFS* • 22.8 month median PFS* • Median PFS not reached* • 49% landmark 18-month • 52% landmark 18-month • 55% landmark 18-month PFS* PFS* PFS*
• Epacadostat plus pembrolizumab demonstrated a favorable safety profile in these phase 1/2 melanoma patients that is consistent with previous reports; 1,2 the incidence of related grade 3/4 toxicity was 20%
• These results support the ongoing phase 3 investigation of epacadostat plus pembrolizumab in patients with advanced melanoma (ECHO-301/KEYNOTE- 252; N=706, fully accrued) Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy
Ribas et al., Cell 2017 Study design: Phase 1b study
21 patients with stage IIIB/C or IV melanoma
Ribas et al., Cell 2017 Best overall response
Ribas et al., Cell 2017 Objective responses observed in all stages
Ribas et al., Cell 2017 Objective responses were durable
Ribas et al., Cell 2017 PFS and OS
Ribas et al., Cell 2017 Converting Cold into Hot Tumors by Combining Immunotherapies
Haanen Cell 2017 Efficacy of BMS-986016 (relatlimab), a Monoclonal Antibody That Targets Lymphocyte Activation Gene-3 (LAG-3), in Combination With Nivolumab in Patients With Melanoma Who Progressed During Prior Anti–PD-1/PD-L1 Therapy in All-Comer and Biomarker-Enriched Populations
• Paolo Antonio Ascierto, 1 Petri Bono, 2 Shailender Bhatia, 3 Ignacio Melero, 4 Marta Nyakas, 5 Inge Marie Svane, 6 James Larkin, 7 Carlos A. Gomez-Roca, 8 Dirk Schadendorf, 9 Reinhard Dummer, 10 Aurélien Marabelle, 11 Christoph Hoeller, 12 Matthew Maurer, 13 Christopher Harbison, 13 Priyam Mitra, 13 Satyendra Suryawanshi, 13 Kent Thudium, 13 Eva Muñoz-Couselo 14
1Istituto Nazionale Tumori Fondazione "G. Pascale," Napoli, Italy; 2Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 3University of Washington, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA; 4Clinica Universidad de Navarra, Pamplona, Spain; 5Oslo University Hospital, Oslo, Norway; 6Copenhagen University Hospital, Herlev, Denmark; 7Royal Marsden Hospital, NHS Foundation Trust, London, United Kingdom; 8Institut Universitaire du Cancer, Oncopole, Toulouse, France; 9Westdeutsches Tumorzentrum, University Hospital Essen & German Cancer Consortium, Essen, Germany; 10 UniversitätsSpital Zürich, Skin Cancer Center University Hospital, Zürich, Switzerland; 11 Gustave Roussy, Paris, France; 12 Medical University of Vienna, Vienna, Austria; 13 Bristol-Myers Squibb, Princeton, NJ; 14 Vall d´Hebron Institute of Oncology, Barcelona, Spain
Presented at ESMO 2017 by Ascierto Potential Role of LAG-3 in T-Cell Exhaustion and Anti–PD-1 Resistance
• LAG-3 regulates a checkpoint pathway that limits the activity of T cells 1 • LAG-3 and PD-1 receptors are overexpressed and/or co-expressed on tumor-infiltrating lymphocytes in melanoma 2,3
+ Nivolumab Tumor or other + Relatlimab infiltrating cell I-O therapy naive: PD-1 PD-L1 LAG-3 may limit I-O response
LAG-3 MHC II Effector + + CD4 /CD8 + Antigen PD-L1 MHC II T cell PD-1 LAG-3 PD-1
+ Nivolumab I-O therapy experienced: + Nivolumab LAG-3 may contribute to + Relatlimab resistance Acquired resistance
Nivolumab
Relatlimab (BMS-986016/anti–LAG-3) I-O, immuno-oncology; MHC II, major histocompatibility complex class II; PD-1, programmed death-1; PD-L1, programmed death ligand 1. 1. Grosso JF et al. J Clin Invest . 2007;117:3383 ‒3392. 2. Goding SR et al. J Immunol . 2013;190:4899–4909. 3. Taube JM et al. Clin Cancer Res . 2015;21:3969–3976. Study Rationale and Design
• Relatlimab + nivolumab demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity in advanced solid tumors (dose-escalation cohort; NCT01968109) 1 • Antitumor activity was previously reported in 55 patients with melanoma who progressed during prior anti–PD-1/PD-L1 therapy (ORR, 12.5%; DCR, 54%)—LAG-3 expression correlated with higher rates of response and disease control a,2 • Updated results in this ongoing study are presented (median follow-up, not reached [range, 0.1+ to 53+ weeks])
Study Endpoints (dose expansion) Dose Dose Escalation Relatlimab (80 mg) + Expansion • Co-Primary: Preliminary N = 8 Nivolumab (240 mg) IV Q2W N = 262 efficacy and safety/tolerability (advanced • Other: Immunogenicity, QTc, solid tumors) PK, PD, biomarkers
Efficacy: Melanoma (progressed during prior I-O) n = 68b
Safety: All patients
DCR, disease control rate; IV, intravenous; ORR, objective response rate; PD, pharmacodynamics; PK, pharmacokinetics; Q2W, every 2 weeks; QTc, corrected QT interval. aLAG-3 expression was evaluated by IHC. bSixty-one patients were response evaluable. 1. Lipson E et al. J Immunother Cancer . 2016;4(suppl 1):173. 2. Ascierto et al. J Clin Oncol . 2017;35(suppl) [abstract 9520]. Prior Therapies
Mel Prior PD-(L)1 n = 68 • Patients in the melanoma prior Prior radiotherapy, n (%) 19 (28) PD-(L)1 cohort were heavily pretreated, with approximately 77% Prior systemic therapy, n (%) 68 (100) having ≥ 2 prior therapies Immunotherapy 68 (100) Anti–CTLA-4a 39 (57) • Most patients (57%) also received Anti–PD-1/PD-L1 b 68 (100) prior anti–CTLA-4 therapy Best response to prior anti– • 46% of patients had a best response c PD-1/PD-L1 of PD to prior anti–PD-1/PD-L1 CR 1 (1.5) therapy PR 12 (18) SD 20 (29) aFour patients received anti–PD-1/PD-L1 + anti–CTLA-4, 8 patients received anti–CTLA-4 after anti–PD-1/PD-L1, and 33 patients received PD 31 (46) anti–CTLA-4 before anti–PD-1/PD-L1; prior anti–CTLA-4 therapy was not reported in 2 patients bThirty-three patients received nivolumab, 33 BRAF inhibitors 19 (28) patients received pembrolizumab, and 2 patients received other therapies. cResponse in 1 patient was reported as not applicable. MEK inhibitors 13 (19) Number of systemic regimens 1 16 (24) 2 21 (31) ≥ 3 31 (46) Median (range) 2 (1–5) Antitumor Activity of Relatlimab + Nivolumab
Mel Prior PD-(L)1 a
LAG-3 ≥ All 1% b • ORR was 11.5% and DCR was 49% n = 61 n = 33 • LAG-3 expression ( ≥ 1%) enriched ORR, n (%) c 7 (11.5) d 6 (18) d for response 4.7, 22 7, 35.5 95% CI • Median duration of response was BOR, n (%) c not reached (range, 0.1+ to 39+)
CR 1 (1.6) 1 (3.0)
PR 6 (9.8) d 5 (15) d
SD 23 (38) 15 (45)
PD 25 (41) 8 (24)
Clinical progression e 6 (9.8) 4 (12) DCR (CR + PR + SD), n (%) c 30 (49) 21 (64) 36, 62 45, 80 95% CI
BOR, best overall response. aResponse-evaluable patients; all progressed during prior anti–PD-1/PD-L1 therapy. bImmune-cell LAG-3 expression (percent of positive cells within invasive margin, tumor, and stroma) evaluated by IHC in tumor sections with antibody clone 17B4. cTumor response evaluated by investigator per Response Evaluation Criteria in Solid Tumors v1.1. dOne response was unconfirmed. eOccurred prior to first radiographic scan . Best Change in Target Lesion Size by LAG-3 and PD-L1 Expression
LAG-3 ≥ 1% LAG-3 < 1% LAG-3 Unknown n = 29 n = 17 n = 8 100 100 100
80 80 80
60 60 60 45% with tumor 24% with tumor 13% with tumor a,b 40 reduction 40 reduction 40 reduction
20 20 20
0 0 0
-20 -20 -20
-40 -40 -40 diameters from baseline -60 -60 -60
-80 -80 -80 Best percent changepercentBest in of sum target lesion
-100 -100 -100
Pink : PD-L1 ≥ 1% Blue : PD-L1 < 1% Gray : PD-L1 unknown
aSix patients with clinical progression prior to their first scan and 1 with PD due to a new symptomatic brain metastasis prior to getting full scans were not included. bOne patient with best change from baseline > 30% had a best response of SD. Depth and Duration of Response by LAG-3 and PD-L1 Expression
LAG-3 ≥ 1% LAG-3 < 1% LAG-3 Unknown n = 29 n = 17 n = 8 100
80 • Responses were more likely in patients with 60 LAG-3 expression ≥ 1% 40 • PD-L1 expression did a not appear to enrich 20 for response
0 : Appearance of new lesions Pink : PD-L1 ≥ 1% from from baseline -20 Blue : PD-L1 < 1%
-40 Gray : PD-L1 unknown
-60
-80 Best percent changepercentBest in of sum target lesion diameters -100
0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Weeks aSix patients with clinical progression prior to their first scan and 1 patient with PD due to a new symptomatic brain metastasis prior to getting full scans were not included. Safety of Relatlimab 80 mg + Nivolumab 240 mg Q2W
All Patients a N = 270 • The safety profile of the melanoma Any Grade Grade 3–4 prior PD-(L)1 cohort was similar to n (%) n (%) that of the overall population Any TRAE b 137 (51) 27 (10) • No treatment-related deaths TRAEs in ≥ 5% of patients were reported d Fatigue 30 (11) 0 Pruritus 19 (7.0) 0 Diarrhea 18(6.7) 3(1.1) Arthralgia 17 (6.3) 0 Infusion-related reaction 15 (5.6) 0 Any serious TRAE b 18 (6.7) 12 (4.4) Serious TRAEs in > 1 patient Colitis 4(1.5) 3 (1.1) Pneumonitis 2 (0.7) 2(0.7) Myocarditis c 2 (0.7) 0 Pyrexia 2 (0.7) 0 Any TRAE leading to discontinuation b 11 (4.1) 8 (3.0) Summary
• With additional follow-up, clinically meaningful antitumor activity with relatlimab + nivolumab was observed in a heavily pretreated population of patients with melanoma who had progressed during prior anti ─PD-1/PD-L1 therapy
• Responses were more likely in patients with LAG-3 expression ≥ 1%, while PD-L1 expression did not appear to enrich for response
• The combination is well tolerated, with a safety profile similar to that of nivolumab monotherapy
• Further investigations of the combination of relatlimab + nivolumab are ongoing, in melanoma and other tumor types, in both I-O–naive and I-O–experienced patients Conclusions
• Many new combinations of immunotherapy are being investigated in clinical trials in melanoma • These combination trials should be based on biological rationale and target active escape/resistance mechanisms • Several of these new combinations are highly promising and appear to be safe (compared to CTLA4 + PD1/PDL1 combo’s)