Randomized phase II study of neoadjuvant (neoadj) anti-PD-1 dostarlimab (D) vs. D + anti-TIM-3 cobolimab (C) in high-risk resectable melanoma (mel) (NEO-MEL-T): Primary analysis.
Meghan J. Mooradian, Arivarasan Karunamurthy, Hong Wang, Elizabeth I. Buchbinder, Suthee Rapisuwon, Justine V. Cohen, Geoffrey T. Gibney, Ryan J. Sullivan, Jason J. Luke, Yana G. Najjar, John M. Kirkwood, Hassane M. Zarour, Diwakar Davar
Abstract
LBA9504 Background: Neoadj immunotherapy improves outcomes in high-risk resectable mel, although novel combinations that enhance efficacy while minimizing toxicity are needed. TIM-3 is highly expressed on dysfunctional CD8T cells and APCs within TME. Dual PD-1 and TIM-3 blockade promotes expansion and function of antigen-specific T cells, resulting in potent antitumor immunity. D and C are monoclonal antibodies targeting PD-1 and TIM-3. D+C has efficacy in PD-1 relapsed/refractory mel (Ribas, ASCO 2022) and NSCLC (Davar, SITC 2023). NEO-MEL-T is a randomized phase II study of neoadj D vs. D+C in patients (pts) with clinical stage III (AJCC IIIB-D) cutaneous mel. Methods: Pts aged >18 yo with clinical stage III mel were randomized (1:1) to neoadj D (500mg Q3W; Arm A) or D+C (500mg Q3W D + 300mg Q3W C; Arm B) for 2 cycles prior to surgery. Post-surgery, pts received further D (500mg Q3W x4; then 1000mg Q6W x6). Primary endpoint was major pathologic response (MPR) rate assessed by blinded pathologist. Secondary endpoints included safety, radiographic response rate (ORR), event-free survival (EFS), distant metastasis free survival (DMFS), and overall survival (OS). Target enrollment of 28 evaluable pts per arm (56 total) provided 80% power (1-sided α 0.05) to distinguish between null hypothesis of 28% MPR rate (historical neoadj PD-1) and alternative hypothesis of >50% in either arm. Primary analysis was a 1-sided z test. Results: Between 6/2020-11/2024, 57 pts were enrolled and randomized to either Arm A with neoadj D (n=30, 52.6%) or Arm B with neoadj D+C (n=27, 47.4%). Majority of pts were either stage IIIB (n=25, 43.9%) or IIIC (n=25, 43.9%), balanced across both arms. Median time to surgery was 51 days (range: 38-82), and all pts underwent curative surgery. Median follow-up time was 22 mos (range: 2-55). MPR rate was 33.3% (Arm A) and 51.9% (Arm B). MPR rate in Arm B was significantly greater than historical control (p=0.0029,1-sided z-test). Across both arms, median EFS was superior in MPR (unreached) vs. non-MPR (48 mos) (p=0.0380, log-rank test) pts, while median DMFS and OS have not been reached. 1-year EFS estimates were greater in Arm B (92%) compared to Arm A (82%), although this was not significant. The 1-year EFS in Arm B was significantly greater than historical adjuvant anti-PD-1 (p=0.0365, 1-sided z test). The proportion of pts with grade 3+ irAEs was similar in Arms A (16.7%) and B (14.9%) (p=0.4273). Conclusion: Neoadj D+C was safe and efficacious. The 1-year EFS of 92% in Arm B was significantly improved relative to adjuvant anti-PD-1, and this combination warrants further investigation. Clinical trial information: NCT04139902 . Arm A (D) (N=30) Arm B (D+C) (N=27) MPR (%; 95% CI) 10 (33;17-53) 14 (52;33-71) 1-year EFS (95% CI) 82 (61-92) 92 (71-98) 1-year EFS in MPR (95% CI) 100 (54-100) 100 (74-100) 1-year EFS in non-MPR (95% CI) 73 (47-88) 82% (45-95)