Prognostic Usefulness of Clinical Complete Response after PD-1 Inhibitor-Based Combination Therapy for Unresectable Hepatocellular Carcinoma (GUIDANCE006).

Background: Outcomes of patients with unresectable hepatocellular carcinoma (HCC) who achieve clinical complete response (cCR) to PD-1 inhibitor-based combination therapy are unclear. This study aimed to explore whether cCR after combination therapy is an accurate and reliable prognostic indicator and to identify predictors of cCR and pathological complete response that could aid in managing patients with HCC. Methods: Data were analyzed retrospectively for 1,266 patients with initially unresectable HCC who received combination therapy involving PD-1 inhibitors and interventional therapy at 23 medical centers across China between 2019 and 2023. Survival was compared between patients who showed cCR or not after combination therapy, and subgroup analyses differentiated further between patients who experienced pathological complete response or not after combination therapy and patients who subsequently underwent curative hepatectomy or not. Results: Among all patients, 200 (15.8%) achieved cCR after combination therapy, and 360 (28.4%) underwent curative hepatectomy following combination therapy. Survival rates at 3 years were significantly higher among those who achieved cCR after combination therapy than those who did not, whether overall survival (82.4 vs. 35.9%; HR 0.15, 95% CI: 0.12-0.19) or progression-free survival (63.4 vs. 26.4%; HR 0.19, 95% CI: 0.16-0.23). Similar results were obtained with subsets of patients matched through propensity scoring based on baseline characteristics. Patients who underwent hepatectomy showed significantly longer overall and progression-free survival than those who did not; and among those who underwent surgery, cCR after combination therapy was associated with significantly better survival. Multivariable analysis identified the following independent predictors of cCR: α-fetoprotein <400 ng/mL, single tumor, absence of macrovascular invasion, absence of extrahepatic metastasis, and combined with anti-angiogenic agents. cCR correlated strongly with pathological complete response (Φ = 0.633) and independently predicted it (OR 17.43, 95% CI: 5.69-53.35). Conclusions: cCR following PD-1 inhibitor-based combination therapy is associated with excellent survival in patients with unresectable HCC. Such response and the clinical characteristics that predict it may be useful for assessing prognosis after combination therapy.