SHR-8068 plus adebrelimab and bevacizumab for advanced hepatocellular carcinoma (aHCC): A phase 1b/2 study.

4093 Background: Combination of an anti-PD-1/L1 antibody with an anti-angiogenic agent is currently the preferred 1L treatment for aHCC. Addition of a CTLA-4 inhibitor may further improve anti-tumor activity, with complementary immunostimulatory effects from CTLA-4 and PD-1/L1 blockade. We conducted a multicenter, open-label, phase 1b/2 trial (NCT05444088) to assess SHR-8068, a novel anti-CTLA-4 monoclonal antibody (mAb), combined with adebrelimab (A, anti-PD-L1 mAb) and bevacizumab (B) in patients (pts) with aHCC. Methods: Pts with or without prior treatment were enrolled (phase 1b: failed or refused standard therapy; phase 2: ≤1L systemic therapy, no immunotherapy [IO]). SHR-8068 was evaluated in 2 dosing regimens with AB: 1 mg/kg Q6W (Combo 1) or 4 mg/kg priming dose (Combo 2). An additional cohort evaluated AB alone (Combo 3). A was dosed at 20 mg/kg Q3W and B at 15 mg/kg Q3W for all regimens. Results: As of Oct 31, 2024, a total of 27, 53 and 21 pts received Combo 1, 2, and 3, respectively, across 2 study phases (overall: IO naïve, 97.0%; prior anti-angiogenic therapy, 32.7%); median follow-up was 16.7, 11.1 and 11.3 mo, respectively. In pts treated with Combo 2, the objective response rate (ORR) was 47.2% (25/53; 95% CI 33.3%–61.4%), with a median duration of response (DoR) of 12.7 mo (95% CI 5.8–NR). The median progression-free survival (PFS) was 8.7 mo (95% CI 5.5–11.6); median overall survival (OS) was not reached, with a 12-mo OS rate of 76.0% (95% CI 59.3%–86.6%). Numerically improved ORR and survival outcomes were seen with Combo 2 vs Combo 1 and 3 (Table 1). Overall, grade ≥3 treatment-related adverse events (TRAEs) occurred in 55.6%, 41.5% and 42.9% of pts with Combo 1, 2 and 3. The most common grade ≥3 TRAEs (incidence ≥10% for any Combo) were decreased platelet count (22.2%, 5.7%, and 4.8% for Combo 1, 2, and 3) and hypertension (18.5%, 7.5%, and 9.5%, respectively). TRAE led to discontinuation of any study agent in 11.1%, 1.9% and 9.5% of pts, respectively. There was 1 treatment-related death (Combo 3). Conclusions: SHR-8068 combined with adebrelimab and bevacizumab showed promising efficacy and manageable safety in aHCC. A more favorable benefit-risk profile was observed for SHR-8068 given as a priming dose. A phase 3 trial (NCT06618664) is currently underway to further assess the combination as 1L treatment for aHCC. Clinical trial information: NCT05444088 . Efficacy outcomes. Combo 1 (n=27) Combo 2 (n=53) Combo 3 (n=21) ORR, % (95% CI) 29.6 (13.8–50.2) 47.2 (33.3–61.4) 19.0 (5.5–41.9) Median DoR * , mo (95% CI) NR (9.4–NR) 12.7 (5.8–NR) NR (7.0–NR) 9-mo DoR rate * , % (95% CI) 100.0 (NR–NR) 69.8 (41.7–86.3) 66.7 (5.4–94.5) DCR, % (95% CI) 77.8 (57.7–91.4) 77.4 (63.8–87.7) 81.0 (58.1–94.6) Median PFS * , mo (95% CI) 6.9 (2.7–NR) 8.7 (5.5–11.6) 6.7 (2.8–9.5) 12-mo OS rate * , % (95% CI) 70.4 (49.4–83.9) 76.0 (59.3–86.6) 70.8 (46.2–85.7) Tumor response was assessed by investigator per RECIST v1.1. * Kaplan-Meier method. NR, not reached.