Overall Survival Improves With Donafenib Versus Sorafenib for Hepatocellular Carcinoma

Patients with hepatocellular carcinoma treated in the frontline setting showed significant improvements in overall survival when treated with donafenib compared with sorafenib.

Investigational donafenib (CM-4307) improved overall survival (OS) versus sorafenib (Nexavar) for Chinese patients with hepatocellular carcinoma (HCC) who were receiving treatment in the frontline setting, according to a study published in the Journal of Clinical Oncology.

The median overall survival (OS) in the full-set analysis (FAS) was significantly longer in the dorafenib group (n = 328) at 12.1 months compared with sorafenib (n = 331) at 10.3months (HR, 0.831; 95% CI, 0.699-0.988; P = .0245). Additionally, the median progression-free survival (PFS) was also improved at 3.7 months versus 3.6 months (HR, 0.909; 95% CI, 0.763-1.082; P = .0570) in the dorafenib and sorafenib groups, respectively.

“To our knowledge, this pivotal head-to-head comparison study is the first to demonstrate noninferiority and superiority of a monotherapy, donafenib, with statistically significant extension in OS over sorafenib for first-line treatment of advanced HCC. The favorable OS benefit of donafenib was consistent across almost all prespecified subgroups.,” said investigators of the study.

This study randomly enrolled 668 patients to the intent-to-treat population in a 1:1 fashion (ITT; 334 in each arm). There were 6 patients excluded from the FAS donafenib group because of not receiving the study drug, not meeting the inclusion criteria, having received prior systemic treatment, or having prior liver transplantation. In the sorafenib FAS group, 3 patients were excluded because they did not receive the study drug, or they had a prior history of liver transplant.

The baseline characteristics of the 659 patients in FAS showed that 594 (90%) had hepatitis B viral infection, 576 (87%) had Barcelona Clinic Liver Cancer (BCLC) stage C disease, 642 (97%) had Child-Pugh Class A disease, 522 (64%) had an ECOG performance score of 1, 350 (53%) had baseline a-fetoprotein (AFP) less than or greater to 400 ng/mL, and 484 (73%) had portal vein invasion and/or extrahepatic metastases.

In the ITT population, OS results were similar to FSA with medians of 12.0 months in the donafenib group and 10.1 months in the sorafenib group (HR, 0.839; 95% CI, 0.706-0.996; P = .0309).

Median time to progression for FAS was similar both groups, at 3.7 months each (HR, 0.931; 95% CI, 0.777-1.117; P = 1.029). The 18-month survival rate was 35.4% in the donafenib group and 28.1% in the sorafenib group (P = .0460).

In the FAS group, 1 (0.3%) patient achieved a complete response (CR) and 19 (58%) achieved a partial response (PR) in the donafenib group. In the sorafenib group, no patients achieved CR and 12 (3.6%) achieved PR. The overall response rates (ORRs) were 4.6% in the donafenib group and 2.7% in the sorafenib group, while the disease control rates (DCRs) were 30.8% and 28.7%, respectively. However, at week 24, patients in the donafenib group achieved disease control at a rate of 20.7% versus sorafenib group at 15.7%, a measure which has a confirmed impact of long-term survival (P<.0001).

Drug-related dverse effects (AEs) were reported by 314 patients (94%) in the donafenib group and 321 (97%) in the sorafenib group. In the donafenib arm, 6 patients (2%) compared with 12 (4%) in the sorafenib group died from reported AEs. Investigators considered only 2 events in the sorafenib arm as possibly relating to the investigational drug.

In the donafenib group, 55 (17%) patients reported a serious AEs (SAEs) versus 67 (20%) in the sorafenib group. Of the patients in the donafenib group, 23 reported drug-related SAEs compared with the sorafenib group with 22 events. The most common drug-related SAEs reported were hepatic dysfunction (1% vs 2%), upper gastrointestinal hemorrhage (1% each), and diarrhea (1% vs <1%).

Patients in the donafenib and sorafenib groups reported the most frequent drug-related AEs as being hand-foot skin reaction (HFSR) (50% vs 67%, respectively) and diarrhea (30% vs 47%). There were 191 patients receiving donafenib (57%) and 224 receiving sorafenib (67%) who reported at least 1 grade 3 or greater AE (P = .0082). Drug-related AEs of grade 3 or greater were lower with donafenib (38%) compared with sorafenib (50%).

Dose interruptions or reductions because of AEs occurred in 101 patients (30%) in the donafenib group and 141 (42%) of patients in the sorafenib group (P = .0013). Investigators found that 84 (25%) patients in the donafenib group and 120 (36%) in the sorafenib group had drug-related AEs leading to dose interruptions or reductions (P = .0025) whereas those who needed to discontinue therapy due to drug-related events comprised 10% and 13%, respectively.

“Patients enrolled in this study were representative of the HCC population in China [with 90% or more being] HBV-positive, relatively poor performance status and liver function, high AFP levels, and a higher proportion of patients with BCLC stage C. Compared with international trials, patients in this study presented with more severe baseline disease states, further emphasizing the positive response observed with donafenib,” concluded the investigators.


Qin S, Bi F, Gu S, et al. Donafenib Versus Sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: A randomized, open-label, parallel-controlled phase II-III trial. J Clin Oncol. Published online June 29, 2021. doi:10.1200/JCO.21.00163

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