Sintilimab in combination with the bevacizumab biosimilar, IBI305, is associated with a significant overall survival and progression-free survival benefit over sorafenib in the first-line setting for the treatment of Chinese patients with unresectable, hepatitis B virus-associated hepatocellular carcinoma.
Sintilimab (Tyvyt) in combination with the bevacizumab (Avastin) biosimilar, IBI305, is associated with a significant overall survival (OS) and progression-free survival (PFS) benefit over sorafenib (Nexavar) in the first-line setting for the treatment of Chinese patients with unresectable, hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), according to published results from the ORIENT-32 study.
HBV infection is the main causative factor for HCC in China. These patients, who have substantial unmet clinical needs, often have a poor prognosis. The combination of a PD-1 inhibitor and the bevacizumab (Avastin) biosimilar, IBI305, may help to improve survival in this vulnerable patient population.
The phase 2/3 ORIENT-32 study (NCT03794440) enrolled 24 patients in the phase 2 portion of the study and 571 patients in the phase 2 portion. The study follows an open-label, randomized, parallel assignment design and has coprimary end points of OS and PFS. Secondary end points include objective response rate (ORR), disease control rate (DCR), duration of response, time to progression, and anti-drug antibodies.
In order to participate in the study, individuals must have a documented HCC diagnosis, an ECOG performance status between 0 and 1, no systematic anti-tumor treatment, at least 1 lesion with measurable disease at baseline per RECIST v1.1, and adequate organ and bone marrow function. Patients with fibrous lamellar HCC, a history of hepatic encephalopathy, clinical symptoms requiring drainage of pleural effusion, central nervous system metastasis, uncontrolled high blood pressure, or local treatment for liver lesions within 4 weeks were not eligible to participate.
Patients were enrolled between February 11, 2019, and January 15, 2020, during phase 3, and 380 patients were entered into the combination arm versus the sorafenib monotherapy arm, which included 191 patients. All patients were evaluable for efficacy and safety.
During phase 3, the median follow-up was 10.0 months in the combination cohort and 10.0 months in the monotherapy cohort. At that time, 64% of the experimental group had progressive disease or had died while 74% in the sorafenib group had progressive disease or had died. By independent review committee assessment (IRRC), the median PFS was 4.6 months for the combination group (95% CI, 4.1-5.7) and 2.8 months (95% CI, 2.7-3.2) for the monotherapy arm (stratified HR, 0.56; 95% CI, 0.46-0.70; P <.0001). Median OS was not reached in the combination arm while it was reached at 10.4 months in the monotherapy arm. Additionally, patients who received the combination had a longer time to the deterioration of global health status 6.7 months (95% CI 5.5-7.3) compared with at 4.1 months (95% 2.9-5.2) in the sorafenib arm (stratified HR, 0.73; 95% CI, 0.56-0.94).
The median duration of treatment for sintilimab was 7 months, 6.6 months for the bevacizumab biosimilar, and 3.5 months for sorafenib. AEs interrupted the treatment of 49% of patients in the combination group and 41% of patients in the monotherapy group.
Of the 571 patients, 565 were included in the safety analysis. The safety profile of the combination was tolerable, with the most common grade 3/4 adverse event (AE) being hypertension and palmar planter erythrodysaesthesia syndrome. In the combination group the rate of hypertension was 14% versus 6% in the monotherapy group. For palmer-plantar erythrodysaesthesia syndrome, the rate of occurrence was 0% in the combination group and 12% in the monotherapy group. Overall, 32% of patients in the experimental arm had a serious AEs compared to the 19% in the control group. TRAEs lead to death in 6 patients in the experimental group due to 1 patient with abnormal liver function, 1 patient with both hepatic failure and gastrointestinal hemorrhage, 1 patient with interstitial lung disease, 1 patient with both hepatic failure and hyperkalemia, 1 patient with upper gastrointestinal hemorrhage, and 1 patient with intestinal volvulus). TRAEs lead to 2 deaths in the sorafenib group due to 1 patient with gastrointestinal hemorrhage and 1 patient with death of unknown cause.
According to IRRC-assessed modified RECIST, the confirmed objective response rate (ORR) was 21% (95% CI, 17%-25%) in the combination cohort and 4% in the monotherapy cohort (P <.0001). All responses in both treatment arms were partial response (PRs). In terms of stable disease (SD), 52% in the combination cohort saw stable disease compared to 60% in the monotherapy cohort. Twenty seven percent of patients in the experimental arm had progressive disease (PD) compared to 33% in the control cohort.
In the combination arm, there was a confirmed DCR of 72% (95% CI, 67%-77%) versus 64% in the monotherapy cohort (95% CI, 56%-71%). DOR was not evaluable (NE) in the combination cohort compared with 9.8 months in the monotherapy cohort (2.6-NE.). In the combination cohort. Finally, the duration of disease control was 7.0 months (95% CI, 5.1-8.2) in the experimental arm versus 2.9 months (95% CI, 2.6-3.7) in the control arm.
The prior part of the study (phase 2) followed patients for a median of 15.8 months (interquartile range [IQR], 15.2-16.1 months), investigators assessed an ORR 25.0% (95% CI, 10%-47%) per RECIST 1.1. All responses were PRs. SD was observed in 58% of patients and 17% had PD. The DCR was 83% (95% CI, 63%-95%). The median duration of response was 12.6 months the median TTP was 8/2 months and the median TTR was 2.9 months. Death occurred in 5% of patients. The PFS at 6 months was 61% (38%-78%) and at 9 months it was 42% (22%-61%). The 9-month survival rate was 8% and the 12-month survival was 83%.
The median age of phase 2 participants was 53 years old (43-71), 83% were male, and 54% had an ECOG score of 1. Ninety-six percent of patients had a Child-Pugh classification of A and 79% had a Barcelona Clinic Liver Cancer Stage of C, 58% ad alpha-fetoprotein levels of less than 400ng/mL. The rate of extrahepatic metastasis was 75% and the rate of hepatitis C virus infection was 4%. All patients in this cohort received prior local therapy for HCC at least once. Half had undergone surgery, 8% have received radiation therapy, and 46% had received ablation.
Overall, the safety profile of sintilimab plus IBI305 was acceptable. All patients experienced treatment-emergent adverse events (TEAEs), and 92% experienced treatment-related AEs (TRAEs). Grade 3-4 AEs occurred in 29% of patients. No AEs leading to death were reported. TEAEs lead to interruption of therapy in 46% of patients, and discontinuation in 8% of patients.
The most common any-grade TRAEs observed with the patients treated in phase were proteinuria (42%), platelet count decreased 8 (33%), alanine aminotransferase increased (29%), Aspartate aminotransferase increased (29%), and hypertension (25%). The grade 3/4 TRAE most commonly observed during the phase 2 analysis was proteinuria (13%).
During phase 2, serious adverse events related to either study drug occurred in 25% of patients, with the most common being hepatobiliary disorders (17%). Broken down, abnormal hepatic function occurred in 13% of patients and immune-mediated hepatitis occurred in 4% of patients. Hyperthyroidism occurred in 4% of patients and immune-mediated pneumonitis occurred in 4% of patients. Additionally, 4% of patients experienced a duodenal ulcer.
Concluding the research, the study authors wrote “…sintilimab–bevacizumab biosimilar showed a significant overall survival and PFS benefit compared with sorafenib in Chinese patients with previously untreated, HBV-associated hepatocellular carcinoma with a tolerable and manageable safety profile. This combination regimen could provide a novel treatment option for this patient population.”