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).

person Lilit Karapetyan H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL info_outline Lilit Karapetyan, Arivarasan Karunamurthy, Anthony Cillo, Shuachao Wang, Ryan Campbell Massa, Anjali Rohatgi, Christopher Deitrick, Yana G. Najjar, Diwakar Davar, Jason J. Luke, Cindy Sander, Amy Rose, Elizabeth Rush, Marion Joy, Sheryl Kunning, Riyue Bao, Hong Wang, Tullia C. Bruno, Dario Vignali, John M. Kirkwood

Authors person Lilit Karapetyan H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL info_outline Lilit Karapetyan, Arivarasan Karunamurthy, Anthony Cillo, Shuachao Wang, Ryan Campbell Massa, Anjali Rohatgi, Christopher Deitrick, Yana G. Najjar, Diwakar Davar, Jason J. Luke, Cindy Sander, Amy Rose, Elizabeth Rush, Marion Joy, Sheryl Kunning, Riyue Bao, Hong Wang, Tullia C. Bruno, Dario Vignali, John M. Kirkwood Organizations H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, University of Pittsburgh, Pittsburgh, PA, UPMC Hillman Cancer Center, Pittsburgh, PA, Penn Medicine Abramson Cancer Center, Philadelphia, PA, Washington University School of Medicine in St. Louis, St. Louis, MO, Department of Immunology, University of Pittsburgh, Pittsburgh, PA Abstract Disclosures Research Funding BMS 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%), BRAF mutant=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.

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