Nivolumab plus relatlimab vs nivolumab in previously untreated metastatic or unresectable melanoma: 3-year subgroup analyses from RELATIVITY-047

BackgroundRELATIVITY-047 demonstrated a statistically significant improvement with nivolumab (NIVO) + relatlimab (RELA) vs NIVO for the primary endpoint of PFS per BICR. At the 3-y follow-up, NIVO + RELA continued to show clinically meaningful benefit vs NIVO for PFS, OS, and ORR per BICR in patients (pts) with previously untreated metastatic or unresectable melanoma. Here we report post hoc subgroup analyses with ∼3 y follow-up.MethodsPts were randomized 1:1 to receive NIVO 480 mg + RELA 160 mg as a fixed-dose combination or NIVO 480 mg intravenously Q4W. Descriptive post hoc analyses were performed according to baseline (BL) location of metastases (mets; pts could be counted in ≥ 1 category) and no. of mets sites, and by the presence of liver/lung mets (n = 581; mucosal and acral pts were excluded). Efficacy based on BL LDH level and BRAF mutation status was examined in all pts (n = 714).ResultsMedian follow-up was 33.8 mo. Efficacy according to BL location/no. of mets sites favored NIVO + RELA vs NIVO in most subgroups (Table). In pts with BL liver mets, PFS and OS were longer with NIVO + RELA vs NIVO (HR [95% CI]: PFS 0.80 [0.53–1.22]; OS 0.59 [0.36–0.97]); ORR was higher (9.4% ORR difference; 95% CI, −7.7 to 25.6). The benefit of NIVO + RELA was similar for pts with BL lung mets. In pts with BL LDH > ULN, PFS and OS were longer with NIVO + RELA vs NIVO (HR [95% CI]: PFS 0.79 [0.59–1.05]; OS 0.78 [0.58–1.05]). PFS and OS also favored NIVO + RELA vs NIVO in BRAF mutant pts (HR [95% CI]: PFS 0.72 [0.54–0.96]; OS 0.75 [0.53–1.07]) and BRAF wild-type pts (HR [95% CI]: PFS 0.84 [0.67–1.06]; OS 0.84 [0.65–1.08]). No new or unexpected safety signals were identified.ConclusionsWith ∼3 y follow-up, efficacy outcomes continued to favor NIVO + RELA vs NIVO in pts with cutaneous nonacral melanoma regardless of BL location/no. of mets sites and in pts with BL liver/lung mets. NIVO + RELA was also favored in pts with LDH > ULN and regardless of BRAF mutation status. Additional analyses will be presented. Table: 1092P n PFS per BICR OS ORR per BICR HR (95% CI) HR (95% CI) ORR difference, % (95% CI) Location of mets Skin 22 0.53 (0.19–1.47) 0.55 (0.17–1.84) 18.3 (−20.7 to 50.5) Soft tissue 65 0.82 (0.44–1.50) 0.71 (0.39–1.31) 7.4 (−14.9 to 29.4) Liver 122 0.80 (0.53–1.22) 0.59 (0.36–0.97) 9.4 (−7.7 to 25.6) Adrenal gland 36 0.89 (0.42–1.88) 1.47 (0.61–3.59) 7.4 (−23.6 to 32.6) Lung 252 0.75 (0.55–1.01) 0.74 (0.52–1.06) 13.1 (0.9–24.7) No. of met sites 1 223 0.73 (0.51–1.04) 0.89 (0.59–1.35) 8.1 (−5.1 to 20.9) 2–3 284 0.82 (0.62–1.10) 0.69 (0.49–0.96) 10.4 (−1.1 to 21.4) ≥ 4 61 0.45 (0.24–0.84) 0.55 (0.29–1.02) 23.6 (−0.2 to 43.1) Unstratified HR; NIVO + RELA vs NIVO. N = 581/714 (mucosal and acral patients excluded). Clinical trial identificationNCT03470922.Editorial acknowledgementProfessional medical writing and editorial assistance were provided by Jessica R. Augello, PhD and Michele Salernitano of Ashfield MedComms, an Inizio company, and funded by Bristol Myers Squibb.Legal entity responsible for the studyBristol Myers Squibb.FundingBristol Myers Squibb.DisclosureD. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, MSD, Merck Serono, Sanofi, Neracare, SunPharma; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi/Regeneron, Pfizer, Philogen, Neracare, InFlarX, BioAlta, Daiichi Sanyko, NoviGenix, Anaveon, AstraZeneca, PamGene, BioNTech, Immatics, CureVac, Erasca, Formycon, Replimune, Seagen, SunPharma, Ultimovacs; Financial Interests, Personal, Steering Committee Member: Novartis, BMS, MSD; Financial Interests, Institutional, Coordinating PI: Novartis, BMS, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Institutional, Local PI: Sanofi, Philogen; Non-Financial Interests, Member of Board of Directors: EORTC-MG; Non-Financial Interests, Leadership Role, Founding member and SC chair: European Melanoma Registry (EuMelaReg). H.A. Tawbi: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Novartis, Genentech, Eisai, Karyopharm, Iovance, Pfizer, Jazz Pharmaceuticals; Financial Interests, Institutional, Trial Chair: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Merck, RAPT Pharmaceuticals; Financial Interests, Institutional, Steering Committee Member: Novartis, Genentech; Financial Interests, Institutional, Funding: GSK, Eisai. F.S. Hodi: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Merck, Novartis, Compass Therapeutics, Apricity, Bicara, Checkpoint Therapeutics, Bioentre, Gossamer, Iovance, Catalym, Immunocore, Kairos, Rheos, Bayer, Zumutor, Corner Therapeutics, Puretech, Curis, AstraZeneca, Solu Therapeutics; Financial Interests, Personal, Advisory Board: Apricity; Financial Interests, Personal, Stocks/Shares: Apricity, Bicara, Checkpoint Therapeutics, Solu Therapeutics; Financial Interests, Personal, Licencing Fees or royalty for IP, Publication number: 20170343552. Patent number: 10106611, Antibodies against EDIL3 and methods of use thereof: Methods for Treating MICA-Related Disorders (#20100111973), Tumor antigens and uses thereof (#7250291), Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603), Compositions and Methods for Identification, Assessment, Preve; Financial Interests, Personal, Research Funding: Bristol Myers Squibb, Merck, Genentech, Seattle Genetics; Financial Interests, Personal, Principal Investigator: PI of ECOG Trial EA6141. E.J. Lipson: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Sanofi, Regeneron, Genentech, Eisai, Instil Bio, Natera, Nektar Therapeutics, Pfizer, Rain Therapeutics, CareDx, Immunocore, Novartis, Replimune, HUYA Bioscience International, Sun Pharma, Merck KGaA, Syneos; Financial Interests, Personal, Other, Consultant: OncoSec; Financial Interests, Personal, Stocks/Shares: Iovance; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb, Haystack Oncology; Financial Interests, Institutional, Local PI: Regeneron, Merck, Sanofi. P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, Novartis, Merck Serono, Sun Pharma, Sanofi, Sandoz, Immunocore, Boehringer Ingelheim Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant, Advisory Role and Travel support: MSD, Pierre Fabre; Financial Interests, Personal, Other, Consultant and Advisory Role.Travel support: Pfizer/Array; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Consultant Role: Pfizer, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Other, Consultant role and travel support: Bio-AI Health; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role.Travel support: Replimmune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Personal, Other, Consultant and Advisory: Erasca; Financial Interests, Personal, Other, Consultant: Philogen; Financial Interests, Personal, Advisory Board: BionTech, Anaveon; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche Genentech, Pfizer/Array, Sanofi; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, AIOM, SMR. M. Maio: Financial Interests, Personal, Advisory Board: BMS, roche, GSK, Sanofi, Alfasigma, Amgen, Sciclone, Eli Lilly, MSD, Incyte, Pierre Fabre, AstraZeneca, Pfizer, Merck Serono; Financial Interests, Personal, Stocks/Shares: EPIGEN, Theravance. M. Hernberg: Financial Interests, Personal, Advisory Board: BMS, Pierre Fabre, Novartis, Med Engine; Financial Interests, Personal, Invited Speaker: Novartis, BMS. J. Mackiewicz: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Novartis; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre; Other, Other, Travel grant: Bristol Myers Squibb, MSD, Novartis, Roche, Pierre Fabre. S. Prey: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Merck Sharps Dohme, Sanofi. V.G. Atkinson: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Pierre Fabre, QBiotics; Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre Fabre, Limbic; Financial Interests, Personal, Other, Travel Support: BMS; Financial Interests, Personal, Other, Travel support: Pierre Fabre; Financial Interests, Personal, Other, Advisory Board: Immunocore. J.C. Hassel: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Sanofi, MSD, SunPharma, Amgen, GSK, Pierre Fabre, Immunocore, Delcath; Financial Interests, Institutional, Advisory Board: MSD, Novartis, BMS, Immunocore, Philogen, Sanofi; Financial Interests, Personal, Advisory Board: Pierre Fabre, SunPharma, GSK, Onkowissen, Pierre Fabre; Financial Interests, Institutional, Writing Engagement: BMS; Financial Interests, Institutional, Research Grant: BMS, SunPharma, Sanofi; Financial Interests, Institutional, Local PI: Philogen, Genentech, 4SC, BioNTech, Iovance, Pierre Fabre, Regeneron, Sanofi, Replimune, Immatics, MSD, Pfizer, Agenus; Financial Interests, Institutional, Coordinating PI: BMS, Immunocore, Novartis, Genmab, Seagan; Financial Interests, Personal, Steering Committee Member: Immunocore, IO Biotech; Non-Financial Interests, Leadership Role: DeCOG; Non-Financial Interests, Member: ASCO. G. Cinat: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Merck Sharp & Dohme (MSD); Financial Interests, Personal, Other, expert testimony: Bristol Myers Squibb, Novartis, Merck Sharp & Dohme (MSD); Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Novartis, Merck Sharp & Dohme (MSD), Roche; Financial Interests, Personal, Invited Speaker, Consensus Conference: Americas Health Foundation; Financial Interests, Personal, Full or part-time Employment: Angel H. Roffo Oncology Institute, University of Buenos Aires; Financial Interests, Personal and Institutional, Local PI, For studies CA209-238 and CA224-047 at Alexander Fleming Institute and studies CA224-047, CA022-001, CA030-001 and CA224-098 at CIDEA Foundation: Bristol Myers Squibb ; Financial Interests, Personal and Institutional, Local PI, For study COMBI-I at Alexander Fleming Institute and studies COMBI-APlus and COMBI-AD at CIDEA Foundation: Novartis; Financial Interests, Personal and Institutional, Local PI, For MK7339-007 and MK3475-630 at CIDEA Foundation: Merck Sharp & Dohme (MSD); Financial Interests, Personal and Institutional, Local PI, For study ARRAY-818-201/C4221006 at CIDEA Foundation: Pfizer; Financial Interests, Personal, Member, Member since 1996: ASCO; Financial Interests, Personal, Member, Member since 1990: Argentina Association of Clinical Oncology (Asociación Argentina de Oncología Clínica - AAOC); Financial Interests, Personal, Other, Received travel expenses for assistance to medical educational meetings: Bristol Myers Squibb, Merck Sharp & Dohme (MSD), Novartis, Roche. S. Keidel: Financial Interests, Personal, Full or part-time Employment, Full time employee of BMS including receiving shares: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares, Share ownership: Bristol Myers Squibb. S. Rodriguez: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. P.T. Wang: Financial Interests, Personal, Full or part-time Employment, Biostatistician employed full-time: BMS (Bristol Myers Squibb); Financial Interests, Personal, Stocks/Shares: BMS (Bristol Myers Squibb). S. Dolfi: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L, IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials: GL is PI on over 30 clinical trials. All other authors have declared no conflicts of interest.