Among patients with unresectable hepatitis B virus (HBV)-positive hepatocellular carcinoma, sintilimab (a programmed death-1 [PD-1] inhibitor) in combination with IBI305 significantly prolonged survival compared with sorafenib in the first-line setting, according to the results of the ORIENT-32 study published in The Lancet Oncology.
IBI305, a vascular endothelial growth factor (VEGF) inhibitor, is a bevacizumab biosimilar approved by the National Medical Products Administration of China (NMPA) based on its similarity to a reference drug (Avastin® (bevacizumab); Roche Genentech; San Francisco, CA) in terms of pharmacokinetics and efficacy, the study authors explained.
As stated by the authors, “Considering differences in the treatment efficacy of PD-1 and [programmed death ligand-1] inhibitors across various [tumor] types, combination treatment with an anti-PD-1 antibody and an anti-angiogenesis agent might be a potential first-line treatment for patients with hepatocellular carcinoma.”
The randomized, open-label, phase 2 to 3 ORIENT-32 trial (ClinicalTrials.gov Identifier: NCT03794440) enrolled a total of 595 patients at 50 sites in China. Of the total enrolled, 24 patients were enrolled in the preliminary phase 2 portion of the safety analysis. Grade 3 or worse treatment-related adverse events (AEs) were reported among 7 (29%) of 24 patients. Phase 2 analysis yielded an objective response rate of 25% (95% CI, 9.8-46.7) with the study drug, which formed the basis for the initiation of the phase 3 trial.
In the phase 3 portion of the ORIENT-32 trial, the remaining 571 patients were randomly assigned to receive sintilimab plus IBI305 (380 patients) or sorafenib (191 patients). The average follow-up was 10.0 months in both the treatment arms.
The median progression-free survival (PFS) rate was significantly longer for patients in the sintilimab plus IBI305 arm (4.6 months; 95% CI, 4.1-5.7) compared with the sorafenib arm (2.8 months; 95% CI, 2.7-3.2; stratified hazard ratio [HR], 0.56; 95% CI, 0.46-0.70; P <.0001).
The confirmed objective response was significantly higher in the sintilimab plus IBI305 arm compared with the sorafenib arm (P <.0001). A larger proportion of patients in the sintilimab-IBI305 arm (72%) had confirmed disease control compared with the sorafenib arm (64%). The duration of disease control was 7 months for the sintilimab-IBI305 arm compared with 2.9 months for the sorafenib arm.
The combination treatment resulted in a significantly longer overall survival (OS). Per the first interim analysis, the median OS was not reached for the sintilimab plus IBI305 arm (95% CI, not reached-not reached) compared with the sorafenib arm (10.4 months; 95% CI, 8.5-not reached; HR, 0.57; 95% CI, 0.43-0.75; P <.0001).
Grade 3 to 4 treatment-emergent AEs included hypertension that was observed more frequently in the sintilimab plus IBI305 arm (14%) compared with the sorafenib arm (6%). Patients in the sorafenib arm developed grade 3 to 4 palmar-plantar erythrodysesthesia syndrome (12%), which was not seen in patients who received the combination treatment.
Serious AEs were reported among 32% of the patients in the sintilimab plus IBI305 arm and 19% of the patients in the sorafenib arm. In the sintilimab-IBI305 arm, treatment-related AEs resulted in 6 deaths, each attributed to abnormal liver function, hepatic failure and gastrointestinal hemorrhage, interstitial lung disease, hepatic failure and hyperkalemia, upper gastrointestinal hemorrhage, and intestinal volvulus. In the sorafenib arm, 1 patient died from a gastrointestinal hemorrhage, and another patient died from an unknown cause.
“This combination regimen could provide a novel treatment option for this patient population,” the study authors concluded.
Disclosure: This research was supported by Innovent Biologics. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
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