In a Chinese phase II/III trial (ORIENT-32) reported in The Lancet Oncology, Ren et al found that the combination of the PD-1 inhibitor sintilimab and the bevacizumab biosimilar IBI305 prolonged progression-free and overall survival vs sorafenib in previously untreated unresectable or metastatic hepatitis B virus (HBV)-associated hepatocellular carcinoma.

Study Details

In the phase III portion of the multicenter open-label trial, 571 patients were randomly assigned 2:1 between February 2019 and January 2020 to receive sintilimab at 200 mg every 3 weeks plus IBI305 at 15 mg/kg every 3 weeks (n = 380) or sorafenib at 400 mg twice daily (n = 191), with treatment continued until disease progression or unacceptable toxicity. The co-primary endpoints were overall survival and progression-free survival on independent radiologic review committee assessment using Response Evaluation Criteria in Solid Tumors v1.1 in the intention-to-treat population.

Progression-Free and Overall Survival

At data cutoff (August 2020), median follow-up was 10.0 months (interquartile range [IQR] = 8.5–11.7 months) in the sintilimab/IBI305 group and 10.0 months (IQR = 8.4–11.7 months) in the sorafenib group. Median progression-free survival was 4.6 months (95% CI = 4.1–5.7 months) in the combination group vs 2.8 months (95% CI = 2.7–3.2 months) in the control group (stratified hazard ratio [HR] = 0.56, 95% CI = 0.46–0.70, P < .0001). Objective responses (all partial) were observed in 21% vs 4% of patients (P < .0001), with median response durations of not reached vs 9.8 months.

Subsequent therapy was received by 29% of the combination group and 47% of the control group, with 2% vs 21% receiving anti–PD-1 or anti–PD-L1 agents. At first interim analysis of overall survival, median overall survival was not reached (95% CI = not reached to not reached) in the combination group vs 10.4 months (95% CI = 8.5 months to not reached) in the control group (HR = 0.57, 95% CI = 0.43–0.75, P < .0001).

Adverse Events

Grade ≥ 3 adverse events occurred in 56% of the sintilimab/IBI3035 group vs 48% of the sorafenib group. The most common grade 3 or 4 events in the combination group were hypertension (14% vs 6% in control group) and decreased platelets (8% vs 3%); the most common in the control group were palmar-plantar erythrodysesthesia syndrome (12% vs 0%) and hypertension. Serious adverse events occurred in 32% vs 19% of patients. Grade 5 events occurred in 3% of each group. Of these events, death was considered related to treatment in six patients in the combination group, with causes consisting of abnormal liver function, hepatic failure and gastrointestinal hemorrhage, interstitial lung disease, hepatic failure and hyperkalemia, upper gastrointestinal hemorrhage, and intestinal volvulus; death was considered related to treatment in two patients in the control group, with causes consisting of gastrointestinal hemorrhage and unknown cause.

The investigators concluded: “Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients.”

Jia Fan, MD, of the Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Innovent Biologics. For full disclosures of the study authors, visit www.thelancet.com.