Combination Improves Survival in Hepatitis-Related Liver Cancer

Combining a PD-1 inhibitor and a bevacizumab biosimilar led to significant improvement in progression-free survival (PFS) and overall survival (OS) in untreated, unresectable hepatitis-associated hepatocellular carcinoma (HCC) versus targeted therapy, a China-led randomized trial showed.

Median PFS improved from 2.8 months with sorafenib (Nexavar) to 4.6 months with sintilimab and IBI305. The first interim analysis of OS showed a median value of 10.4 months with sorafenib whereas the median had yet to be reached with sintilimab/IBI305. Nonetheless, the difference was associated with a statistically significant 43% reduction in the survival hazard in favor of the combination, reported Jia Fan, MD, of Zhongshan Hospital and Fudan University in Shanghai, and colleagues, in Lancet Oncology.

“Compared with similar studies of first-line therapies for patients with advanced hepatocellular carcinoma, sintilimab-bevacizumab biosimilar reduced the risk of death and disease progression,” they stated. “To our knowledge, this was the first large-scale study to show the benefit of first-line treatment in HBV [hepatitis B]-associated hepatocellular carcinoma, providing support for a clinical benefit with combined immunotherapy versus targeted therapy in this population.”

The sintilimab-IBI305 combination is the second of its type to show a survival benefit in unresectable/metastatic HCC. The IMbrave150 randomized trial of atezolizumab (Tecentriq) and bevacizumab (Avastin) showed a 42% reduction in the survival hazard and a 41% reduction in the risk of progression as compared with sorafenib. The results supported FDA approval of the combination as initial treatment for unresectable or metastatic HCC.

Fan and colleagues noted several differences between the IMbrave150 and ORIENT-32 patient populations. Patients in ORIENT-32 were about 10 years younger, a majority with ECOG performance status 1 (rather than 0), a greater prevalence of extrahepatic metastasis, more heavily pretreated with local therapy, inclusion of patients with Child-Pugh B liver impairment, and a majority with HBV-associated cancer.

IMbrave150 excluded patients with esophageal varices because of an increased risk of gastroesophageal hemorrhage. In ORIENT-32, patients without prior endoscopy underwent the procedure at investigator discretion to identify those with a high risk of bleeding.

“Therefore, the population in our study might have been more representative of the population observed in routine clinical practice for management of hepatocellular carcinoma,” the authors stated.

Investigators in ORIENT-32 enrolled a total of 595 patients, which included 24 enrolled into a phase II safety evaluation. After safety confirmation (grade ≥3 adverse events in 29%), 571 patients were randomized 2:1 to sintilimab-IBI305 or sorafenib. The co-primary endpoints of the phase III portion of the trial were OS and independent radiologic assessment of PFS.

After a median follow-up of 10 months in both treatment arms, the 1.8-month absolute difference in median PFS translated into a 44% reduction in the hazard for progression or death (95% CI 0.46-0.70, P<0.0001). The interim analysis of OS yielded a hazard ratio of 0.57 (95% CI 0.43-0.75, P<0.0001).

The most common grade 3/4 treatment-emergent adverse event with sintilimab and IBI305 was hypertension (14% vs 6%), whereas palmar-plantar erythrodysesthesia occurred most often with sorafenib (12% vs 0%). Serious adverse events occurred in 32% of patients who received combination therapy and 19% of those randomized to the targeted agent. Six treatment-related deaths occurred in the sintilimab-IBI305 arm versus two in the sorafenib group.

Last Updated August 03, 2021