Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study
Mené en Chine sur 595 patients atteints d'un carcinome hépatocellulaire non résécable, cet essai de phase II/III compare l'efficacité, du point de vue de la survie globale et de la survie sans progression, et la toxicité du sorafénib et d'un traitement de première ligne combinant sintilimab (un inhibiteur de PD-1) et IBI305 (un biosimilaire du bévacizumab)
Background : China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infectionis the main causative factor. Patients with hepatocellular carcinoma have a poor prognosisand a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenibas a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. Methods : This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China.Patients aged 18 years or older with histologically or cytologically diagnosed orclinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performancestatus of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) toreceive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) orsorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation,with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline
α-fetoprotein, and ECOGperformance status. The primary endpoint of the phase 2 part of the study was safety,assessed in all patients who received at least one dose of study drug. The co-primary
endpoints of the phase 3 part of the study were overall survival and independent radiological
review committee (IRRC)-assessed progression-free survival according to Response EvaluationCriteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population.The study is registered with ClinicalTrials.gov, NCT03794440. The study is closed to new participants and follow-up is ongoing for long-term outcomes. Findings
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Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolleddirectly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab
–bevacizumabbiosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patientsreceived at least one dose of the study drug, with an objective response rate of 25·0%(95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase2 part, in which grade 3 or worse treatment-related adverse events occurred in seven(29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumabbiosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in thesintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed medianprogression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenibgroup (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70;p<0·0001). In the first interim analysis of overall survival, sintilimab–bevacizumabbiosimilar showed a significantly longer overall survival than did sorafenib (mediannot reached [95% CI not reached–not reached] vs 10·4 months [8·5–not reached]; HR 0·57, 95% CI 0·43–0·75; p<0·0001). The most commongrade 3–4 treatment-emergent adverse events were hypertension (55 [14%] of 380 patientsin the sintilimab–bevacizumab biosimilar group vs 11 [6%] of 185 patients in the sorafenib group) and palmar-plantar erythrodysaesthesiasyndrome (none vs 22 [12%]). 123 (32%) patients in the sintilimab–bevacizumab biosimilar group and36 (19%) patients in the sorafenib group had serious adverse events. Treatment-relatedadverse events that led to death occurred in six (2%) patients in the sintilimab–bevacizumabbiosimilar group (one patient with abnormal liver function, one patient with bothhepatic failure and gastrointestinal haemorrhage, one patient with interstitial lungdisease, one patient with both hepatic faliure and hyperkalemia, one patient withupper gastrointestinal haemorrhage, and one patient with intestinal volvulus) andtwo (1%) patients in the sorafenib group (one patient with gastrointestinal haemorrhageand one patient with death of unknown cause). Interpretation : Sintilimab plus IBI305 showed a significant overall survival and progression-freesurvival benefit versus sorafenib in the first-line setting for Chinese patients withunresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile.This combination regimen could provide a novel treatment option for such patients.
The Lancet Oncology 2021