Novel Combination of Sintilimab and Bevacizumab Biosimilar IBI305 Shows Significant Survival Benefit in HCC

Sintilimab (Tyvt) in combination with the bevacizumab (Avastin) biosimilar IBI305 showed a significant increase in survival benefit compared to frontline sorafenib (Nexavar) for patients with unresectable, hepatitis B virus (HBV)-associated, hepatocellular carcinoma (HCC), according to data published in The Lancet.1

The randomized, open-label, phase 2/3 ORIENT-32 (NCT03794440) study looked at 595 patients 18 years or older on the combination of the PD-1 inhibitor sintilimab and IBI305 biosimilar who had confirmed unresectable or metastatic HCC. At a median follow up of 10 months (8.5–11.7) in both the sintilimab/bevacizumab biosimilar and sorafenib groups, researchers found that patients on the combination therapy had a significantly longer median progression-free survival at 4.6 months (95% CI, 4.1-5.7) compared to 2.8 months (95% CI, 2.7-3.2) in the sorafenib group (HR 0.56; 95% CI, 0.46-5.7; P <.0001).

An interim analysis of overall survival (OS) also showed that patients treated with sintilimab plus IBI305 had a significantly longer OS compared to just sorafenib (HR 0.57; 95% CI, 0.43-0.75; P <.0001). While the median OS was not reached at the time of data collection for the combination group there 122 OS events compared to 87 in the single-agent arm, which had a median OS of 10.4 months (95% CI, 8.5-not examined).

"ORIENT-32 is the first large-scale study to show the benefit of first-line treatment in HBV-associated HCC with combination immunotherapy,” said professor Fan Jian, MD, president of Zhongshan Hospital of Fudan University and leader of the trial, in a press release.2 “Despite the COVID-19 pandemic, the collaborative joint effort of the ORIENT-32 trial investigators and patients enabled us to successfully reach this milestone. We hope these results can help to provide a new treatment option for patients with hepatocellular carcinoma."

The 595 patients on the trial were enrolled across 50 medical sites in China, with 24 enrolled directly into the phase 2 safety run in and 571 randomly assigned to sintilimab plus IBI305 (n = 380) or sorafenib (n = 191). During the phase 2 part of the trial 24 patient with HCC received at least 1 dose of sintilimab plus IBI305 and had an objective response rate of 25% (95% CI, 9.8-46.7). Preliminary safety data in the phase 2 portion of the study showed that grade 3 or worse treatment-related adverse events (TRAEs) occurred in 7 of 24 patients, which led to the start of the phase 3 portion of the trial. Eligible patients enrolled on the trial had an ECOG performance status of 0 or 1 and had no previous systemic treatment for their HCC.

During the phase 2 portion of the study, patients received 200 mg of sintilimab intravenously every 3 weeks along with 15 mg/kg of IBI305 intravenously every 3 weeks. At the phase 3 portion of the study patients were then randomly assigned 2:1 to receive either sintilimab plus IBI305 or 400 mg of sorafenib orally twice a day. Treatment was continued until disease progression or unacceptable toxicity was reached.

Findings from the phase 3 portion of the trial showed that the most common grade 3-4 treatment emergent adverse events were hypertension and palmar-plantar erythrodysaesthesia syndrome. In the combination group 55 of 380 patients experienced hypertension compared to 11 of 185 patients in the sorafenib group, whereas no patients on sintilimab plus IBI305 experienced palmar-plantar erythrodysaesthesia syndrome but 22 patients on sorafenib did. Serious AEs were experienced by 32% of patients in the combination arm compared to 19% in the single agent group, moreover, TRAEs that led to death occurred in 2 patients in the sorafenib group and 6 patients in the sintilimab plus IBI305 group. Causes of death included abnormal liver function, hepatic failure and gastrointestinal hemorrhage, interstitial lung disease, hepatic failure and hyperkalemia, upper gastrointestinal hemorrhage, intestinal volvulus, and 1 cause of death was unknown.

"ORIENT-32 is the first hepatocellular carcinoma study in the world of a PD-1 inhibitor-based combination therapy to achieve its primary end point of overall survival,” concluded Zhou Hui, MD, senior vice president of clinical development at Innovent Biologics, Inc., the manufacturer of sintilimab, in the release. “We are pleased that these study results have been published in The Lancet Oncology and hope to bring this regimen as a new treatment option for Chinese patients with hepatocellular carcinoma in the near future."

Patients with HCC typically have a poor prognosis and China has a high burden of HCC with HBV as the main cause of the disease. According to the researchers, they believe the combination of sintilimab and IBI305 could be a novel treatment to help this patient population with unmet clinical needs. In China sintilimab has been approved in 3 different indications with the combination of sintilimab and bevacizumab injection under regulatory review for the treatment of HCC.

_References

1. _{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 Jun 15:S1470-2045(21)00252-7. doi: 10.1016/S1470-2045(21)00252-7}
2. _{Study results of sintilimab in combination with bevacizumab biosimilar IBI305 for the first-line treatment of hepatocellular carcinoma published in The Lancet Oncology. News release. June 20, 2021. Accessed June 23, 2021. https://prn.to/3gSetgi}