Adjuvant sintilimab plus bevacizumab following curative resection of spontaneously ruptured hepatocellular carcinoma: A prospective exploratory phase II study (CLEAR-2).

Abstract

TPS4254 Background: Spontaneous rupture of hepatocellular carcinoma (srHCC) is a life-threatening complication associated with acute hemorrhage, aggressive tumor biology, and an exceptionally high risk of postoperative recurrence. Even after successful hemostasis and curative (R0) resection, outcomes remain poor, with early relapse—particularly peritoneal dissemination—being a dominant failure pattern. Patients with srHCC have been systematically excluded from most pivotal phase III adjuvant trials in hepatocellular carcinoma, resulting in a critical evidence gap for postoperative systemic management. Current adjuvant strategies are largely extrapolated from non-ruptured HCC or based on retrospective analyses, and no prospective studies have specifically evaluated immunotherapy-based adjuvant therapy in this population. Immune checkpoint inhibitor–based combinations with anti-angiogenic agents have demonstrated survival benefits in advanced HCC and have recently been explored in the adjuvant setting for high-risk resected disease. Given the unique biological behavior of srHCC, characterized by tumor cell spillage at rupture and a strong propensity for early systemic and peritoneal relapse, adjuvant systemic therapy targeting micrometastatic disease is biologically rational and urgently needed. The CLEAR-2 study is designed to prospectively explore the efficacy and safety of adjuvant sintilimab combined with bevacizumab following curative resection of srHCC. Methods: CLEAR-2 is a prospective, multicenter, single-arm, exploratory phase II study. Eligible patients are adults (18–75 years) with radiologically or intraoperatively confirmed spontaneous rupture of HCC who have undergone curative (R0) hepatic resection, with Child-Pugh A liver function and ECOG performance status 0–1. Preoperative transarterial embolization (TAE) for hemostasis is permitted if performed once and within 2 weeks prior to surgery, without chemotherapeutic agents. A total of 35 patients will be enrolled. Adjuvant treatment is initiated 4–8 weeks postoperatively and consists of sintilimab 200 mg plus bevacizumab 15 mg/kg intravenously every 3 weeks for up to 1 year or until recurrence, unacceptable toxicity, or withdrawal. Radiologic assessment is performed every 12 weeks. The primary endpoint is disease-free survival (DFS). Secondary endpoints include overall survival (OS), safety graded per CTCAE v5.0, and recurrence patterns (intrahepatic, extrahepatic, and peritoneal). Clinical trial information: NCT07331883 .