Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti–PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations
Authors: P.A. Ascierto, P. Bono, S. Bhatia, I. Melero, M.S. Nyakas, I-M. Svane, J. Larkin, C. Gomez-Roca, D. Schadendorf, R. Dummer, A. Marabelle, C. Hoeller, M. Maurer, C.T. Harbison, P. Mitra, S. Suryawanshi, K. Thudium, E. Muñoz Couselo
Journal: Annals of Oncology (2017)

Background: Simultaneous blockade of LAG-3 and PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study (NCT01968109), BMS-986016 (anti–LAG-3) + nivolumab (anti–PD-1) showed promising antitumor activity in the mel prior IO cohort (Ascierto et al. J Clin Oncol. 2017;35(suppl) [abstr 9520]). Here, we describe updated efficacy and safety in a larger mel prior IO cohort in all-comer and biomarker-enriched populations. Methods: Pts in the mel prior IO cohort received BMS-986016 80 mg + nivolumab 240 mg Q2W. Primary objectives were safety and objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) per RECIST v1.1. Biomarker and efficacy correlations were also evaluated. Results: As of June 15, 2017, 68 pts were treated; 57% had prior anti–CTLA-4 and 46% had ≥ 3 lines of prior therapy. In 61 efficacy-evaluable pts, ORR was 11.5% (1 complete, 6 partial [1 unconfirmed] responses); DCR was 49%. Median DOR was not reached (min [0.1+], max [39.3+]). ORR was ≥ 3.5-fold higher in pts with LAG-3 expression ≥ 1% vs < 1%, regardless of PD-L1 expression (Table 1). Response relationships with biomarker status and disease characteristics will be presented. Treatment-related AEs occurred in 51% (gr 3/4, 10%; discontinuation [DC], 3.8%) of pts across all expansion cohorts (N = 262) and in 41% (gr 3/4, 4.4%; DC, 1.5%) of pts in the mel prior IO cohort (n = 68).TableLBA18 Response by LAG-3aImmunohistochemistry (IHC) with percentage of positive cells among all nucleated cells within the tumor and invasive margin using mouse antibody clone 17B4. Expression ≥ 1% was identified in 33/53 (62%) of evaluable samples. and PD-L1bTumor cell expression determined using Dako PD-L1 IHC 28-8 kit. Expression ≥ 1% was identified in 20/44 (45%) of evaluable samples. expressionAll PatientsLAG-3 ≥ 1%LAG-3 < 1%nORR (%)nORR (%)nORR (%)All617 (11)336 (18)201 (5.0)PD-L1 expression≥ 1%201 (5.0)161 (6.3)40< 1%244 (17)113 (27)131 (7.7)a Immunohistochemistry (IHC) with percentage of positive cells among all nucleated cells within the tumor and invasive margin using mouse antibody clone 17B4. Expression ≥ 1% was identified in 33/53 (62%) of evaluable samples.b Tumor cell expression determined using Dako PD-L1 IHC 28-8 kit. Expression ≥ 1% was identified in 20/44 (45%) of evaluable samples. Open table in a new tab Conclusions: This is the largest report of outcomes in pts treated with anti–LAG3 + anti–PD-1. BMS-986016 + nivolumab is well tolerated with a safety profile similar to nivolumab monotherapy and provides encouraging efficacy in a heavily pretreated, anti–PD-1/PD-L1 progressed melanoma population. Enhanced responses correlated with LAG-3 expression, irrespective of PD-L1 expression. Clinical trial identification: NCT01968109 Legal entity responsible for the study: Bristol-Myers Squibb Funding: Bristol-Myers Squibb Disclosure: P.A. Ascierto: Grants/personal fees from BMS, Roche-Genentech, and Array (all consultant/advisory role and research funds), personal fees from Novartis, Amgen, Merck Serono, Pierre Fabre, and MSD (all consultant/advisory role) outside the submitted work. P. Bono: Honoraria from Pfizer, BMS, Orion Pharma, Novartis and MSD; research grant from Novartis, outside the submitted work; Stock Ownership: Tilt Biotherapeutics. S. Bhatia: Grants from Bristol-Myers-Squibb during the conduct of the study (research funding to institution (UW)) I. Melero: Grants/personal fees from BMS, Roche, Alligator, and Tusk; personal fees Bayer, AstraZeneca, Merck, Novartis, outside the submitted work. I-M. Svane: Grants from BMS (fee paid to my institution for covering of expenses for patients included in the study) J. Larkin: Grants from BMS, MSD, Pfizer, Novartis; Personal fees from Esai, BMS, MSD, GSK, Kymab, Pfizer, Novartis, Roche, Genentech, Secarna, Pierre Fabre, and EUSA Pharma not related to the submitted work. D. Schadendorf: Personal fees and other from Novartis and GSK during conduct of study; personal fees from Amgen, Boehringer Ingelheim and Leo Pharma, personal fees and other from Roche, Merck/MSD and BMS outside the submitted work R. Dummer: Consultancy - BMS A. Marabelle: Personal fees from roche/genentech, personal fees from BMS, personal fees from Merck, personal fees from Pfizer, personal fees from Astra Zeneca, outside the submitted work C. Hoeller: Study fees from BMS, during the conduct of the study; personal fees from BMS, Astra-Zeneca, Amgen, MSD, Novartis, Pierre Fabre, Roche, outside the submitted work M. Maurer, C.T. Harbison, P. Mitra, S. Suryawanshi, K. Thudium: BMS employee, owner of BMS stock. All other authors have declared no conflicts of interest.