Donafenib May Improve Survival vs Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma

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In a Chinese phase II/III trial reported in the Journal of Clinical Oncology, Qin et al found that donafenib, a multikinase inhibitor and deuterated sorafenib derivative, improved overall survival vs sorafenib in the first-line treatment of unresectable or metastatic hepatocellular carcinoma.

As related by the investigators, donafenib is a modified derivative of sorafenib with a trideuterated N-methyl group that may enhance molecular stability and improve pharmacokinetic characteristics. The agent has been found to exhibit increased stability and reduced susceptibility to hepatic drug-metabolizing enzymes, potentially resulting in increased plasma exposure and reduced toxic metabolites.

Study Details

In the multicenter open-label trial, 668 patients (intent-to-treat population) were randomly assigned between March 2016 and April 2018 to receive oral donafenib at 0.2 g (n = 334) or sorafenib at 0.4 g (n = 334) twice daily until disease progression or intolerable toxicity. Efficacy was primarily assessed in the full analysis set, consisting of 328 patients in the donafenib group and 331 in the sorafenib group without major eligibility violation who received at least one dose of the study drug. The primary endpoint was overall survival, tested for noninferiority and superiority.

Overall Survival

Median overall survival in the full analysis set was 12.1 months in the donafenib group vs 10.3 months in the sorafenib group (hazard ratio [HR] = 0.831, 95% confidence interval [CI] = 0.699–0.988, P = .0245; both noninferiority and superiority criteria were met). Rates at 12 and 18 months were 50.6% vs 45.0% and 35.4% vs 28.1%. In the intent-to-treat population, median overall survival was 12.0 months vs 10.1 months (HR = 0.839, 95% CI = 0.706–0.996, P = .0309).

Median progression-free survival in the full analysis set was 3.7 vs 3.6 months (HR = 0.909, 95% CI = 0.763–1.082, P = .0570). Objective response was observed in 4.6% vs 2.7% of patients (P = .2448); the disease control rate was 30.8% vs 28.7% (P = .5532).

Adverse Events

Grade ≥ 3 adverse events occurred in 57% of patients in the donafenib group vs 67% of the sorafenib group (P = .0082) and were considered drug-related in 38% vs 50% (P = .0018), with the most common drug-related events in the donafenib group being hypertension (9% vs 9%) and hand-foot skin reactions (6% vs 12%). The most common drug-related adverse events of any grade were hand-foot skin reactions (50% vs 67%) and diarrhea (30% vs 47%).

Serious adverse events occurred in 17% vs 20% of patients and were considered treatment-related in 7% vs 7%. Dose interruption or reduction due to adverse events occurred in 30% vs 42% and were considered treatment-related in 25% vs 36%. Treatment discontinuation due to adverse events occurred in 10% vs 13% and were considered treatment-related in 6% vs 8%. Adverse events led to death for 6 patients in the donafenib group and 12 patients in the sorafenib group; only two deaths were considered treatment-related, due to hepatic dysfunction and pulmonary infection in 1 patient each in the sorafenib group.

The investigators concluded, “Donafenib showed superiority over sorafenib in improving overall survival and has favorable safety and tolerability in Chinese patients with advanced hepatocellular carcinoma, showing promise as a potential first-line monotherapy for these patients.”

Feng Bi, MD, of West China Hospital, Sichuan University, Chengdu, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Suzhou Zelgen Biopharmaceuticals Co, Ltd. For full disclosures of the study authors, visit

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