Poorer Overall Survival With Sunitinib vs Sorafenib in Advanced Hepatocellular Cancer
In an open-label phase III superiority/noninferiority trial reported in Journal of Clinical Oncology by Ann-Lii Cheng, MD, of National Taiwan University Hospital in Taipei, sunitinib (Sutent) was associated with significantly poorer overall survival compared with sorafenib (Nexavar) in a population of mostly Asian patients with advanced hepatocellular carcinoma. Results differed in Asian-region vs non-Asian patients and according to presence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
Study Details
In this international trial, 1,074 patients with locally advanced or metastatic hepatocellular carcinoma were randomly assigned to receive sunitinib 37.5 mg once daily or sorafenib 400 mg twice daily. The primary endpoint was overall survival. The study was designed to detect a hazard ratio (HR) of 0.8045 for overall survival in favor of sunitinib and assumed 30 months of enrollment plus median survival of 10.7 months with sorafenib and 13.3 months with sunitinib; this required 929 patient deaths for a one-sided stratified log-rank superiority test with a significance level of 0.025 and 90% power and a noninferiority test with a one-sided significance level of 0.025 and approximately 80% power. The futility stopping boundaries (sunitinib vs sorafenib) were hazard ratios of 1.207 or worse and 0.940 or worse for the first and second interim analyses.
Patient groups were generally well balanced for baseline characteristics. Asian patients accounted for 77.5% of the sunitinib group and 77% of the sorafenib group, 79% and 76% had vascular invasion or extrahepatic spread, and 87% and 83.5% had retrospectively staged Barcelona Clinic Liver Cancer (BCLC) stage C disease. In both groups, Asian-region patients had more advanced disease than non-Asian patients based on Cancer of the Liver Italian Program (CLIP) score and BCLC stage: 32% and 32% of Asian-region patients had CLIP scores ≥ 3 compared with 22% and 16% of non-Asian patients, and BCLC stage C disease was present in 90% and 88% of Asian-region patients compared with 78% and 69% of non-Asian patients. BCLC stage C disease was more common in non-Asian patients in the sunitinib vs sorafenib group (78% vs 69%).
Overall, 55% of sunitinib patients and 53% of sorafenib patients had HBV infection, 21% and 22% had HCV infection, and 50% and 45% had underlying cirrhosis. HBV infection was more common in Asian-region patients (67% and 64%) than in non-Asian patients (16% and 19%), and HCV infection was more common in non-Asian patients (37.5% and 29%) than in Asian-region patients (16% and 19.5%). Among all patients with HBV infection and HCV infection, 49% and 66.5% had cirrhosis.
Overall Survival Worse With Sunitinib
After disease progression, 1% of sunitinib patients and 6% of sorafenib patients remained on assigned therapy, 14.5% crossed over from sunitinib to sorafenib, and 2% crossed over from sorafenib to sunitinib.
The trial was terminated early due to futility and safety reasons after the hazard ratio for overall survival crossed the futility boundary. For sunitinib vs sorafenib, median overall survival was 7.9 vs 10.2 months (HR = 1.30, 95% confidence interval [CI] = 1.13–1.50; one-sided P = .9990, two-sided P = .0014). Median progression-free survival (3.6 vs3.0 months, HR = 1.13, 95% CI = 0.99–1.30; one-sided P = .8785, two-sided P = .2286) and median time to progression (4.1 vs3.8 months, HR = 1.13, 95% CI = 0.98–1.31; one-sided P = .8312, two-sided P = .3082) were similar in the two groups.
Results Similar in Asian-Region and HBV-Infected Patients
Median overall survival was similar with sunitinib vs sorafenib among Asian-region patients (7.7 vs 8.8 months, HR = 1.21, 95% CI = 1.03–1.32; one-sided P =.9829) and HBV-infected patients (7.6 vs 8.0 months, HR = 1.10, 95% CI = 0.92–1.33; one-sided P = .8286), but was markedly shorter with sunitinib in non-Asian patients (9.3 vs 15.1 months, HR = 1.64, 95% CI = 1.20–2.26; one-sided P = .9964) and HCV-infected patients (9.2 vs 17.6 months, HR = 1.52, 95% CI = 1.09–2.13; one-sided P = .9835).
Adverse Events
The most common adverse events of any grade were thrombocytopenia (51%) and diarrhea (47%) in sunitinib patients and hand-foot syndrome (61%) and diarrhea (47%) in sorafenib patients. Grade 3 or 4 adverse events occurred in 82% of sunitinib patients and 74% of sorafenib patients, with the most common being thrombocytopenia (30% vs 5%), neutropenia (26% vs 2%), hand-foot syndrome (13% vs 21%), and leukopenia (13% vs < 1%) in sunitinib patients and hand-foot syndrome, diarrhea (9% vs 7%), and increased AST (9% vs 9%) in sorafenib patients. Bleeding events occurred in 37% of sunitinib patients and 20% of sorafenib patients, with grade 3 to 5 events occurring in 11% and 5%. Adverse events led to dose reductions in 30% of sunitinib patients and 35% of sorafenib patients, treatment interruption in 77% and 59%, and discontinuation in 13% and 13%.
The investigators concluded, “[Overall survival] with sunitinib was neither superior nor equivalent but significantly inferior to that with sorafenib. [Overall survival] was comparable in Asian and HBV-infected patients. In HCV-infected patients, superior [overall survival] was seen with sorafenib. Sunitinib was associated with more frequent and severe toxicities than sorafenib.”
The study was supported by Pfizer.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
