Feasibility and Efficacy of Perioperative Nivolumab with or Without Relatlimab for Patients with Potentially Resectable Hepatocellular Carcinoma

Abstract Background: Most patients with hepatocellular carcinoma (HCC) experience recurrence after curative-intent resection, highlighting the need for effective perioperative therapies. Neoadjuvant immunotherapy has shown feasibility and pathological changes in clinical trials of early-stage HCC. Here, we evaluate the feasibility of perioperative nivolumab monotherapy and nivolumab plus relatlimab, as dual PD-1 and LAG-3 blockade may synergistically restore T-cell function. Methods: From 2021 to 2025, we conducted an open label, noncomparative, randomized phase II clinical trial (NCT04658147) in patients with potentially resectable HCC with high-risk features (large tumor size, multinodular disease, macrovascular involvement). Patients were randomized to receive 2 doses over 8 weeks of nivolumab (Arm A) or nivolumab with relatlimab (Arm B) prior to surgical resection. Eligible patients continued systemic therapy following resection for up to 10 months. The primary endpoint was feasibility, defined as the proportion of patients who experienced an unacceptable treatment-related adverse which prevented surgery. Secondary endpoints included proportion of complete/major pathologic response, objective response rate (ORR), disease-free survival (DFS), and overall survival (OS). Results: Thirty patients were randomized and received at least one dose of systemic therapy (n=15 per study arm). In both study arms, the trial met its primary endpoint as no patients experienced treatment-related adverse events that precluded surgery. In both study arms, 4/15 (26.7%) patients had grade 3+ treatment-related adverse events. There were no grade 5 toxicities. In Arm A, 13 patients (86.7%) completed neoadjuvant therapy and underwent successful surgery (R0 resection: 86.7% [95% CI: 59.5-98.3%]). Two patients had disease progression prior to surgery. Of the 15 patients in Arm A, 3 (20.0% [4.3-48.1%]) had a complete or major pathologic response. ORR in Arm A at time of neoadjuvant RECIST was 13.3% [1.7-40.4%]. In Arm B, 13 patients (86.7%) completed neoadjuvant therapy and underwent successful surgery (R0 resection: 73.3% [44.9-92.2%]); one patient had a complete radiographic response prior to surgery, and one patient had an aborted surgery due to advanced cirrhosis. Of 15 patients in Arm B, 4 (26.7% [7.8-55.1%]) had a complete or major pathologic/radiologic response. ORR in Arm B at time of neoadjuvant RECIST was 20.0% [4.3-48.1%]. DFS at 2-years was 73.3% in Arm A and 88.9% in Arm B. OS at 2 years was 68.5% in Arm A and 84.8% in Arm B. At C2D1, there was nearly 100% peripheral LAG-3 receptor occupancy (RO) on CD8+ T-cells. At C2D15, LAG-3 RO was approximately 25% in the tumor microenvironment (TME). Conclusions: Nivolumab, and nivolumab with relatlimab, is feasible in the perioperative HCC setting and can result in significant pathologic responses. Ongoing work is evaluating the effects of therapy on the TME. Citation Format: Howard L. Li, Sarah M. Shin, Anne M. Noonan, Chester Kao, Christopher Shubert, Ewa Kulikowicz, Dimitrios N. Sidiropoulos, Jennifer N. Durham, Mari Nakazawa, Waqar Arif, Benjamin Philosophe, William R. Burns, Jin He, Kelly Lafaro, Richard A. Burkhart, Marco Dal Molin, Brad Wilt, Robert A. Anders, Tania Nevers, Elizabeth M. Jaffee, Daniel A. Laheru, Hao Wang, Marina Baretti, Won Jin Ho, Mark Yarchoan. Feasibility and efficacy of perioperative nivolumab with or without relatlimab for patients with potentially resectable hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT016.