Randomized phase II evaluation of nivolumab (nivo), or relatlimab (rela), or combined nivo-rela lead-in followed by nivo-rela as first line therapy for patients (pts) with advanced melanoma (mel).

9525 Background: A phase II study of nivo and rela was designed to evaluate the separate antitumor activity of nivo and rela vs. the combination for first-line treatment of pts with advanced mel. We report objective response rate (ORR) at week (wk) 4 and 16, progression-free survival (PFS) for pts receiving lead-in with nivo or rela vs. combination, and correlations with immune-related pathological response (irPR) at wk 4 tumor biopsy. Methods: Pts were randomized (1:1:1) to lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy in all pts. The primary endpoint was ORR to nivo-rela by RECISTv.1.1 at wk 16. Secondary endpoints included progression-free survival (PFS), ORR according to lead-in therapy at wk4, safety, and major pathological response on biopsy at 4wk (MPRbx) per Stein et al, Ann Oncol (2019). Results: The trial enrolled 43 advanced mel pts, median age=67 years, female=15 (35%), ECOG PS 0=34 (79%), BRAFmutant=18 (42%), Stage IV=35 (81%), and LDH >ULN=37 (86%). Pts were randomized to nivo=15, rela=14, and nivo-rela=14 lead-in arms. ORR at wk 4 were 3 (20%), 1 (7.1%), and 0 (0%) in nivo, rela, and nivo-rela lead-in arms, respectively. Among 41 evaluable pts who received at least one cycle of nivo-rela radiological assessment at wk16 was partial response (PR)=14 (34.2%), stable disease (SD)=15 (36.6%), and progressive disease (PD)=12 (29.3%). ORR at wk 16 were 6 (42.9%), 2 (15.4%), and 6 (42.9%) for nivo, rela, and nivo-rela lead-in arms, respectively. Median PFS for the whole cohort was 6.5 mos (95%CI 2.2-not reached NR), 4.7 mos, 1.8 mos, and NR in nivo, rela, and nivo-rela lead-in arms, respectively. After adjusting for BRAF status, rela lead-in was significantly associated with worse PFS (HR=3.41, 95% CI 1.11-10.4, p=0.03). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 14 (32.6%) pts. & TRAEs (any grade) leading to treatment discontinuation were observed in 9 (20.9%). After 1 cycle of nivo one pt developed myocarditis leading to death without proceeding to nivo-rela. MPRbx at wk 4 was observed in 11 (31.4%) of 35 evaluable pts and were 50%, 0%, and 43% in nivo, rela, and nivo-rela lead-in arms, respectively. MPRbx was associated with wk16 radiological response (p=0.04) and improved PFS (HR=0.29, 95% CI 0.10-0.87, p=0.03). Nivo-rela resulted in increased CD8 and CD4+FOXP3- cell densities at wk4 (p<0.01 and p=0.03, respectively) and CD8 density at wk 4 was associated with improved PFS (p=0.02). Conclusions: Nivo-rela results in 34.2% ORR and median PFS of 6.5m in pts with advanced mel after lead-in nivo, rela or combination therapy. This first single agent lead-in rela evaluation demonstrated wk 4 ORR of 7%, wk 16 ORR of 15.4% and median PFS 1.8 mos. MPRBx and CD8 density at wk4 are associated with improved PFS. Clinical trial information: NCT03743766 .