ASCO 2020-DOBRAFENIB FOR HCC

Donafenib significantly improved overall survival (OS) rates compared with sorafenib in patients with hepatocellular carcinoma (HCC) and did so with favorable safety and tolerability, according to a new study (Abstract 4506).

In part because of the considerable adverse effects (AEs) associated with sorafenib, “there’s a growing need of new medications with potential better efficacy and safety,” Dr. Bi said.

In part because of the considerable adverse effects associated with sorafenib, “there’s a growing need of new medications with potential better efficacy and safety,” Dr. Bi said.

Study Results

This open-label study enrolled 668 patients across 37 sites in China; patients were randomly assigned 1:1 to oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression occurred. Primary endpoint was OS. The treatment arms were well balanced: 87% of the patients had Barcelona C staging, approximately 73% of patients had portal vein invasion and/or extrahepatocellular metastasis, and approximately 90% of the patients had hepatitis B etiologies.

Prof. Tim Meyer

In the full analysis set , donafenib was associated with a significantly longer median OS than sorafenib (12.1 vs. 10.3 months; HR 0.831, 95% CI [0.699, 0.988]; p = 0.0363). These results were consistent with those of the intent-to-treat group (12.0 vs. 10.1 months; HR 0.839, 95% CI [0.706, 0.996]; p = 0.0446).

There were no significant differences in median progression-free survival (3.7 vs. 3.6 months; p = 0.2824), objective response rate (4.6% vs. 2.7%; p = 0.2448), or disease control rate (30.8% vs. 28.7%; p = 0.5532). Grade 3 or worse AEs occurred in 191 patients (57.4%) in the donafenib group and in 224 patients (67.5%) in the sorafenib group (p = 0.0082). AEs of special interest occurred in 287 patients (86.2%) versus 309 patients (93.1%; p = 0.0049), and those leading to treatment interruption occurred in 101 patients (30.3%) versus 141 patients (42.5%; p = 0.0013). Fewer patients reported serious AEs with donafenib than with sorafenib (55 [16.5%] vs. 67 [20.2%]; p = 0.2307). Common AEs in the donafenib arm were hand-foot-skin reaction (50.5%), aspartate aminotransferase increase (40.5%), blood bilirubin increase (39.0%), platelet count decrease (37.8%), and diarrhea (36.6%).

“This trial data confirmed [that] donafenib is a promising new first-line therapy for advanced HCC, based on superior OS, fewer severe adverse events, and lower incident of almost all common AEs, and exhibited favorable tolerability compared with sorafenib. We can conclude that donafenib should be considered as an optimal first-line therapy for patients with advanced HCC,” Dr. Bi said.

Caution Advised

Discussant Tim Meyer, MD, PhD, of the University College London Cancer Institute and Royal Free Hospital, London, put these results in context with other phase III studies of first-line tyrosine kinase inhibitors that “all failed to meet their primary endpoints versus sorafenib,” he said.

This study showed “an HR of 0.83, which is of borderline clinical relevance,” Prof. Meyer said.

However, the study population had an extremely high rate of hepatitis B (90%), “which begs the question that, if the donafenib trial had been run in a global study, perhaps it would not have been superior to sorafenib,” he said.

He added that the limitations of the study include questionable applicability outside the hepatitis B population and that “donafenib seems to be inferior to atezolizumab plus bevacizumab in a similar population.”¹

– Michelle Dalton, ELS