Sintilimab/Bevacizumab Biosimilar Combo Shows Superior OS, PFS Over Sorafenib in Advanced Unresectable HCC

November 21, 2020 -Frontline sintilimab injection (Tyvyt) in combination with bevacizumab (Avastin) biosimilar injection (Byvasda; IBI305) resulted in a significant improvement in overall survival (OS) and progression-free survival (PFS) per Independent Radiographic Review Committee (IRRC) versus sorafenib (Nexavar) in patients with advanced unresectable hepatocellular carcinoma (HCC), according to results from the phase 3 ORIENT-32 trial (NCT03794440) presented during the ESMO Asia Virtual Congress 2020.¹

Results showed that the median OS was not evaluable (NE) in the combination arm (95% CI, NE-NE) versus 10.4 months (95% CI, 8.5-NE) in the sorafenib arm (HR, 0.569; 95% CI, 0.431-0.751; P <.0001). The OS rates at 12 months were 62.4% and 48.5% in the investigational and control arms, respectively.

Additionally, the median IRRC-PFS with the sintilimab injection/bevacizumab biosimilar combination was 4.6 months (95% CI, 4.1-5.7) versus 2.8 months (95% CI, 2.7-3.2) with sorafenib (HR, 0.565; 95% CI, 0.455-0.701; P <.0001). At 6 months, the PFS rates in the combination and monotherapy arms were 43.6% and 19.5%, respectively; these rates were 32.7% and 11.6%, respectively, at 9 months.

“ORIENT-32 is the first randomized phase 3 study reporting the efficacy and safety of anti–PD-1 antibody plus bevacizumab biosimilar versus sorafenib as a first-line treatment in patients with advanced unresectable HCC with a large proportion of hepatitis B virus [HBV] infection,” Zhenggang Ren, MD, PhD, of Zhongshan Hospital of Fudan University said during a presentation on the data. “[The trial] demonstrated a significantly improved OS and IRRC-PFS clinical benefit. The superior OS and PFS benefits with sintilimab plus bevacizumab biosimilar over sorafenib was generally consistent across all subgroups.”

The standard frontline options available for patients with unresectable HCC include sorafenib and lenvatinib (Lenvima), although these agents induce only modest survival benefits. The combination of atezolizumab (Tecentriq) and bevacizumab, however, has been shown to induce a substantial improvement in survival compared with sorafenib in patients with unresectable disease in the phase 3 IMbrave150 trial (NCT03434379).

In the open-label, multicenter phase 3 ORIENT-32 trial, investigators set out to evaluate the safety and efficacy of the anti–PD-1 antibody sintilimab combined with the bevacizumab biosimilar compared with sorafenib in patients with unresectable or metastatic, systemic treatment-naïve HCC.

To be eligible for enrollment, patients had to be 18 years of age or older, have an ECOG performance status of 0 or 1, BCLC stage C or stage B disease, Child-Pugh of 7 or less, and at least 1 measurable lesion per RECIST v1.1 criteria.

Patients were randomized 2:1 to receive either intravenous (IV) sintilimab at 200 mg on day 1 every 3 weeks plus IV bevacizumab biosimilar at a dose of 15 mg/kg on day 1 every 3 weeks (n = 380) or oral sorafenib at a dose of 400 mg twice daily (n = 191). Stratification factors were comprised of macrovascular invasion and/or extrahepatic metastasis, baseline alpha fetoprotein, and ECOG performance status. Treatment was administered until progressive disease or intolerable toxicity.

The co-primary end points of the trial were OS and PFS by IRRC per RECIST v1.1 criteria. Secondary end points comprised PFS by investigator per RECIST v1.1 criteria, objective response rate by IRRC and investigator per RECIST v1.1 criteria, and ORR by IRRC per HCC modified RECIST criteria.

With regard to the statistical testing hierarchy-actual, the overall alpha for the study was 2-sided 0.05. The main analysis of PFS was tested at a 2-sided alpha of 0.002. An interim analysis of OS was conducted with a 2-sided alpha of 0.0035 with 209 events. Each secondary end point, such as ORR, was tested at a 2-sided alpha of 0.05.

The baseline characteristics between the 2 treatment arms were well balanced. The median age in the combination arm was 53.0 years versus 54.0 years in the monotherapy arm. ECOG performance status of 1 in the combination and monotherapy arms was reportedly 51.8% and 52.4%, respectively. Additionally, 94.5% and 93.7% of patients on the investigational and control arms, respectively, had HBV; 1.6% and 4.2% of patients, respectively, had hepatitis C virus.

Results from the run-in part phase 2 study demonstrated preliminary efficacy with the combination. Here, the median OS had not yet been reached at a median follow-up of 9.0 months. The median PFS reported was 8.4 months. At the ESMO Asia Congress 2020, Ren reported the data from the phase 3 part of the research.

Additional results showed that the IRRC-ORR per RECIST v1.1 criteria was 20.5% (95% CI, 16.5-25.1) in the combination arm versus 4.1% (95% CI, 1.7-8.2) in the monotherapy arm (P <.0001). Moreover, the investigator ORRs per RECIST v1.1 criteria were 19.6% (95% CI, 15.7-24.1) and 2.9% (95% CI, 0.9-6.6) in the investigational and control arms, respectively (P <.0001). Lastly, the IRRC-ORRs per modified RECIST v1.1 criteria were 24.3% (95% CI, 20.0-29.0) versus 7.6% (95% CI, 4.1-12.6) in the combination and monotherapy arms, respectively (P <.0001).

The median duration of response (DOR) was NE (95% CI, NE-NE) with the combination versus 9.8 months (95% CI, 2.8-NE) with the monotherapy per IRRC and RECIST v1.1 criteria. The median DOR had not been evaluable in either arm per investigator and RECIST v1.1 criteria. The median DOR was NE (95% CI, 8.2-NE) in the combination arm versus 6.6 months (95% CI, 2.6-NE) with the monotherapy per IRRC and modified RECIST v1.1 criteria.

With regard to safety, all-grade adverse effects (AEs) were reported in 98.9% versus 97.8% in the combination and monotherapy arms, respectively; 88.7% versus 93.5%, respectively, were treatment related. Grade 3 or 4 toxicities were reported in 54.5% and 47.0% of patients in the investigational and control arms, respectively; 33.7% and 35.7%, respectively, were treatment related. Serious toxicities were experienced by 32.4% of those in the combination arm versus 19.5% in the monotherapy arm; 17.1% and 10.3%, respectively, were treatment related. In the combination and monotherapy arms, 1.6% and 1.1% of patients, respectively, experienced a treatment-related toxicity that resulted in death.

Moreover, 13.7% of patients in the combination arm had an AE that resulted in treatment discontinuation of any study drug versus 5.9% of those in the monotherapy arm. Almost half, or 49.5%, of patients on the combination arm experienced a toxicity that led to dose interruption versus 40.5% of those on the monotherapy arm.

The most common AEs observed in the combination arm were proteinuria, platelet decrease, and aspartate aminotransferase (AST) increase. In the sorafenib arm, patients experienced Palmar-plantar erythrodysesthesia and AST increase.

Of antidrug-antibody–evaluable patients (n = 363) in the trial, only 3.3% (n = 12) tested positive for treatment-emergent ADA of sintilimab. The incidence of patients testing positive for ADA was very low, which indicates a potentially higher clinical benefit with this combination.

“Sintilimab plus bevacizumab biosimilar could be a candidate of first-line treatment option for patients with unresectable or metastatic HCC,” concluded Ren.

Reference

1. Ren Z, Fan J, Xu J, et al. Sintilimab plus bevacizumab biosimilar vs sorafenib as first-line treatment for advanced hepatocellular carcinoma (ORIENT-32). Presented at: 2020 ESMO Asia Virtual Meeting; November 20-22, 2020; Virtual. Abstract LBA2.