Feasibility of achieving a tumor- and drug-free state through conversion therapy followed by curative hepatectomy for patients with initially unresectable hepatocellular carcinoma (GUIDANCE009)

Abstract

Background: Whether initially unresectable hepatocellular carcinoma (HCC) patients who receive curative resection after conversion therapy can maintain long-term tumor-free survival in a drug-free state after postoperative drug withdrawal is unclear. This study aimed to compare the effectiveness of adjuvant PD-1 inhibitors versus a drug-free state in these patients. Methods: Data were retrospectively analyzed for patients with initially unresectable HCC who underwent curative hepatectomy after conversion therapy at 13 medical centers in China between January 2019 and June 2023. Tumor-free survival (TFS) and overall survival (OS) were compared between patients who received PD-1 inhibitors and patients in a drug-free state after hepatectomy. Results: Relative to the 311 patients in a drug-free state, the 114 who received PD-1 inhibitors showed comparable TFS (HR 0.85, 95%CI 0.63-1.15) and OS (HR 0.66, 95%CI 0.44-1.00). Similar results were obtained for subsets of patients matched to each other through propensity scoring, for the subset of 123 patients who achieved pathological complete response after resection, and for the entire cohort in 12-month landmark survival analysis. An adjuvant PD-1 inhibitor regimen lasting at least 6 months led to similar survival as shorter regimens, whether in terms of TFS (HR 0.61, 95% CI 0.35-1.04) or OS (HR 0.51, 95% CI 0.22-1.19). Multivariable analyses identified multiple tumors, tumor satellites, and absence of pathological complete response as independent adverse predictors of impaired TFS and OS; albumin-bilirubin grade 2 independently predicted inferior TFS only. No treatment-related deaths occurred in the entire cohort. Conclusions: We failed to demonstrate a survival benefit of adjuvant PD-1 inhibitors compared with drug-free state in patients with initially unresectable HCC who underwent curative hepatectomy after conversion therapy. Given the relatively short follow-up, small sample size, and retrospective design, these findings should be need further validation in prospective randomized controlled trials.