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Background Simultaneous blockade of LAG-3 and PD-1 enhances anti-tumor activity in patients with melanoma. 1–3 The individual immune modulatory effects of these agents and their relation to clinical outcomes of the combination compared to the single modalities remains unknown.Methods Here we report final results of a randomized phase 2 trial ( NCT03743766) comparing lead-in treatment with one cycle of relatlimab-(n=14), nivolumab-(n=15), and nivolumab+relatlimab (n=14) followed by nivolumab+relatlimab in first-line advanced melanoma. Overall primary objective was objective response rate (ORR) to nivolumab+relatlimab therapy. Primary objective of the lead-in design was to distinguish the clinical and immunological impacts of each component therapy upon immune populations within the tumor and in blood. Lead-in analysis of immunomodulatory changes in relation to ORR, progression-free survival (PFS), and major pathologic response on biopsy (MPRbx W4)4 were assessed as secondary and exploratory objectives, respectively.Results At data cutoff (5/2025) median follow-up was 49 months, all patients had discontinued study therapy. Intention-to-treat analysis including all enrolled 43 patients showed ORR=49%, while with differential ORR by lead-in arm (21% relatlimab, 60% nivolumab, 64% nivolumab+relatlimab). Median PFS was 6.5 months (95% CI, 2.2 to 21.7) with significant lower PFS in relatlimab- (1.9 months) compared to nivolumab+relatlimab- (14.7 months) (HR 2.64, p=0.04), and numerically inferior PFS in nivolumab- (4.7 months) vs. nivolumab+relatlimab- lead-in arms (HR=2.29, p=0.08). The 24-month PFS rates were 14%, 20%, and 50% for relatlimab, nivolumab and combination lead-in arms respectively. MPRbx at week 4 was significantly higher with nivolumab- and combination vs. relatlimab- lead-in (50% vs 0%, p=0.01 and 43% vs 0%, p=0.02) respectively. MPRbx was mechanistically correlated with higher IFN-g and TCR signaling in CD8+ T cells following nivolumab and nivolumab+relatlimab lead-in therapy, respectively and was associated with superior ORR and PFS, serving as an early surrogate marker for assessment of clinical activity. Relatlimab lead-in was characterized by clustering of CD8+ T and FOXP3+ T regulatory cells in the tumor microenvironment, characterized enrichment in immune checkpoint pathways and associated with worse PFS. The combination therapy increased the fraction of CD8+ TEM cells in association with response to therapy, while patients with progressive disease demonstrated decrease in CD14+ CD16- HLA-DRlow CD33dim monocytic populations.Conclusions This first analysis of LAG3 and PD1 components in a novel lead-in trial design has identified differential clinical and immunological effects of anti-PD1 and anti-LAG3 compared to the combination that warrant consideration in clinical practice.Acknowledgements The authors would like to thank the Vignali lab (Vignali-lab.com; @Vignali_Lab) for discussions and critically reading the manuscript. This study was supported by the NIH-NCI (P50 SPORE CA254865 to J.M.K., D.A.A.V., T.C.B.) and Bristol-Myers Squibb (CA224-070 to J.M.K., T.C.B., and D.A.A.V.) for funding. We also thank Bristol-Myers Squibb for providing drug for this study. This research was supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. Bioinformatics analysis in the project described was performed by Cancer Bioinformatics Services (CBS), supported in part by NCI through the UPMC Hillman Cancer Center CCSG award (P30CA047904).Trial Registration NCT03743766References Andrews LP, Cillo AR, Karapetyan L, Kirkwood JM, Workman CJ, Vignali DAA. Molecular pathways and mechanisms of LAG3 in cancer therapy. Clin Cancer Res 2022;28:5030–5039.Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med 2022;386:24–34.Cillo AR, Cardello C, Shan F, Karapetyan L, Kunning S, Sander C, Rush E, Karunamurthy A, Massa RC, Rohatgi A, Workman CJ, Kirkwood JM, Bruno TC, Vignali DAA. Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8(+) T cells to promote antitumor immunity. Cell 2024;187:4373-4388.e4315.Stein JE, Soni A, Danilova L, Cottrell TR, Gajewski TF, Hodi FS, Bhatia S, Urba WJ, Sharfman WH, Wind-Rotolo M, Edwards R, Lipson EJ, Taube JM. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol 2019;30:589–596.Ethics Approval This study was approved by University of Pittsburgh IRB MOD19090233-024Consent The written informed consent was obtained from the patients prior to enrollment in this clinical trial.