Sintilimab Plus Bevacizumab Biosimilar IBI305 Demonstrates OS and PFS Benefit Over Sorafenib in HCC

Patients with unresectable hepatitis B virus–positive hepatocellular carcinoma have achieved significantly better overall survival and progression-free survival following treatment with sintilimab plus IBI305 vs sorafenib.

Sintilimab (Tyvyt) plus IBI305, a bevacizumab (Avastin) biosimilar, yielded positive outcomes in overall survival (OS) and progression-free survival (PFS) for patients with unresectable hepatitis B virus (HBV)–positive hepatocellular carcinoma (HCC), according to the results of the phase 2/3 ORIENT-32 study (NCT03794440).

Findings from the phase 3 portion of the study indicated that the sintilimab plus IBI305 cohort had a median progression-free survival (PFS) of 4.6 months (95% CI, 4.1-5.7), compared with the sorafenib group, which had median PFS of 2.8 months (95% CI, 2.7-3.2; HR, 0.56; 95% CI 0.46-0.70; P< .0001).

During the first interim overall survival (OS) analysis of both groups, 32% (n = 122) of patients in the sintilimab plus IBI305 group and 46% (n = 87) in the sorafenib group had died. Investigators found that prolonged OS was significantly better in the sintilimab cohort vs the sorafenib cohot (HR 0.57, 95% CI, 0.43-0.75; P<. 0001). The median OS was not reached in the sintilimab group (95% CI, not reached [NR]–NR) and was 10.4 months in the sorafenib group (95% CI, 8.5-NR).

“To our knowledge, ORIENT-32 is the first large-scale, phase 2/3 study of a PD-1 inhibitor in combination with an anti-angiogenesis inhibitor, and the findings contribute to understanding immunotherapies in combination with anti-VEGF therapies in patients with [HCC]. Compared with similar studies of first-line therapies for patients with advanced hepatocellular carcinoma, sintilimab/bevacizumab biosimilar reduced the risk of death and disease progression,” the study’s investigators wrote.

In the randomized, open-label study, investigators examined the efficacy of sintilimab, a PD-1 inhibitor, plus IBI305 vs sorafenib (Nexavar) as a first-line treatment for HCC. The study took place in 50 different institutions across China. Overall, 595 patients were enrolled, 380 of whom were randomized to the sintilimab plus IBI305 group and 191 to the sorafenib group.

In the phase 2 portion of the study, patients in the sintilimab group were given 200 mg plus IBI305 at 15mg/kg intravenously every 3 weeks. In the third phase, patients were randomized 2:1 to either the sintilimab plus IBI305 cohort or the sorafenib cohort, in which the agent was administered at 400mgorally twice daily.

The primary end point for phase 2 of the study was assessing the safety in patients who had one dose of the treatment, while the secondary end point was objective response rate (ORR). In phase 3, the co-primary end points were OS and PFS.

The trial reached phase 2 in August 2020, wherein 24 patients achieved a median OS of 15.8 months (Interquartile range, 15.2-16.1). Additionally, patients experienced an ORR of 25.0%. Treatment-emergent adverse effects (TEAEs) occurred in 22 patients (92.0%), with 29.0% of patients (n = 7) experiencing grade 3/4 AEs. No deaths occurred from TEAEs.

During phase 3, 571 patients were randomly assigned to either the sintilimab (n = 380) or sorafenib group (n = 191). The median follow-up was 10 months in the sintilimab plus IBI305 group and 10 months in the sorafenib group. In the sintilimab and sorafenib groups, 245 and 142, respectively, had progressive disease or had died.

Of the total patient population, 565 received at least one dose of the study treatment. Sintilimab had a median duration of treatment (DOR) of 7 months (95% CI, 0.7-15.2) and IBI305 had a median DOR of 6.6 months (95% CI, 0.7-15.2) . Moreover, sorafenib had a median DOR of 3.5 months (95% CI, 0.02-14.2).

During the study, 188 patients in sintilimab cohort and 75 in the sorafenib cohort had their treatment interrupted due to TEAEs. In both cohorts, treatment was discontinued for 52 (14%) and 11 (6%) patients, respectively, due to TEAEs. Additionally, TEAEs of any grade occurred in 376 patients (99%) in the experimental arm and 181 (98%) in the control arm. The most common TEAEs that were grade 3 or higher included hypertension, decreased platelet count, and proteinuria.

TEAEs that led to death occurred in 10 (3%) patients in the sintilimab plus IBI305 group and 6 (3%) in the sorafenib group. Additionally, TEAEs occurred in 6 (2%) of patients in the sintilimab plus IBI305 group and included abnormal liver function, hepatic failure, and gastrointestinal hemorrhage. Two patients (1%) in the sorafenib group had TEAE in 2 (1%), including gastrointestinal hemorrhage and death of an unknown case.

This study was impacted by COVID-19, with 139 patients in the sintilimab plus IBI305 group and 36 in the sorafenib group were affected by the virus. This led to drug administration being delayed and radiographic assessment of tumors being missed. No patients were infected with COVID-19 to the investigators’ knowledge.


Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021;22(7):977-990. doi:10.1016/S1470-2045(21)00252-7

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