Safety and efficacy of durvalumab plus bevacizumab in unresectable hepatocellular carcinoma: Results from the phase 2 study 22 (NCT02519348).

436 Background: The phase 2 Study 22 trial (NCT02519348) investigated durvalumab (anti-programmed cell death ligand-1 [PD-L1] antibody) and tremelimumab (anti-cytotoxic T-lymphocyte associated antigen 4 antibody) as monotherapy, or durvalumab in combination with tremelimumab or bevacizumab (anti-vascular endothelial growth factor [VEGF] antibody), for the treatment of patients with unresectable hepatocellular carcinoma (uHCC). Results of Study 22 that evaluated durvalumab and tremelimumab as monotherapy or in combination were reported previously. PD-L1 inhibition plus VEGF inhibition with bevacizumab may exhibit an additive effect to improve clinical activity. Herein, we report results from a single-arm cohort of Study 22, evaluating durvalumab plus bevacizumab as first-line treatment in patients with uHCC. Methods: Patients with uHCC who had not received any prior systemic therapy were administered durvalumab 1120 mg plus bevacizumab 15 mg/kg once every 3 weeks. Adequate endoscopic therapy according to institutional standards was required for patients with a history of gastrointestinal bleeding for >12 months or those at high risk for esophageal varices. The primary endpoint was safety. Secondary endpoints included confirmed objective response rate (ORR; assessed by blinded independent central review [BICR] according to RECIST v1.1), duration of response (DoR; RECIST v1.1 by BICR) and overall survival (OS). Results: At the data cut-off (November 6, 2020), 47 patients were allocated to receive treatment. Median total treatment duration was 6.2 months (durvalumab) and 4.1 months (bevacizumab). Thirty-three (70.2%) patients experienced an adverse event possibly related to treatment (TRAE). Grade 3 or 4 TRAEs occurred in 4 (8.5%) patients; serious TRAEs occurred in 5 (10.6%) patients, including gastric ulcer perforation, ascites, and liver tumor rupture, possibly related to bevacizumab, and raised creatinine and pneumonitis, possibly related to durvalumab. There were 3 (6.4%) discontinuations and no deaths associated with TRAEs. Objective responses (RECIST 1.1 by BICR) were confirmed in 10 patients (ORR, 21.3%; 95% CI, 10.7–35.7); median DoR (RECIST 1.1 by BICR) was not reached. Median OS was not reached (95% CI, 12.52 months–non-estimable). Conclusions: Durvalumab plus bevacizumab was well tolerated and showed promising clinical activity in patients with uHCC. Durvalumab with or without bevacizumab in combination with transarterial chemoembolization is being investigated as locoregional therapy in patients with HCC not amenable to curative treatment in the phase 3 EMERALD-1 study (NCT03778957), and durvalumab with or without bevacizumab is being investigated in patients with HCC at high risk of recurrence after curative treatment in the phase 3 EMERALD-2 study (NCT03847428). Clinical trial information: NCT02519348.