Donafenib extends OS in advanced liver cancer
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Donafenib conferred a modest but statistically significant OS improvement as first-line therapy for advanced hepatocellular carcinoma, according to study results presented during the ASCO20 Virtual Scientific Program.
The novel multikinase inhibitor also exhibited a favorable safety and tolerability profile, results of the randomized phase 2/phase 3 trial showed.
“Hepatocellular carcinoma is characterized by an insidious onset with rapid progression,” Feng Bi, MD, oncologist at West China Hospital at Sichuan University in China, said during a presentation. “Many patients already have advanced disease at the time of diagnosis. Additionally, this disease is the fourth-leading cause of cancer-related mortality.”
Sorafenib (Nexavar, Bayer) remains the standard first-line therapy for advanced HCC. A previous phase 1B study suggested donafenib (CM-4307, Suzhou Zelgen Biopharmaceuticals) also may be an effective treatment for this disease.
Bi and colleagues randomly assigned 688 patients with unresectable or metastatic HCC to oral donafenib dosed at 0.2 g (n = 334) or sorafenib dosed at 0.4 g (n = 334) twice daily until disease progression or unacceptable toxicity.
All patients had a Child-Pugh liver function score of 7 or less and no prior systemic therapy.
Researchers included 659 patients (donafenib group, n = 328; sorafenib group, n = 331) in a full analysis set, upon which they primarily based efficacy analysis.
OS served as the primary endpoint.
Results showed donafenib conferred significantly longer median OS in both the full analysis set (12.1 months vs. 10.3 months; HR = 0.83; 95% CI, 0.69-0.98) and the intention-to-treat population (12 months vs. 10.1 months; HR = 0.84; 95% CI, 0.7-0.99).
Researchers observed no significant differences between the donafenib and sorafenib groups with regard to median PFS (3.7 months vs. 3.6 months), objective response rate (4.6% vs. 2.7%) and disease control rate (30.8% vs. 28.7%).
Grade 3 or higher adverse events occurred among 191 patients in the donafenib group and 224 patients in the sorafenib group. Fewer patients in the donafenib group reported serious adverse events compared with the sorafenib group (n = 55 vs. 67). Common adverse events with donafenib included hand-foot skin reaction (50.5%), increased aspartate aminotransferase (40.5%), increased blood bilirubin (39%), decreased platelet count (37.8%) and diarrhea (36.6%).
“This trial data confirmed that donafenib is a promising new first-line therapy for advanced HCC,” Bi said. “We can conclude that this drug should be an optimal treatment for these patients.”
Perspective
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Thomas Karasic, MD
Researchers showed that donafenib is superior to sorafenib among patients in China. In that population, donafenib probably is practice changing and will replace sorafenib as an option for front-line therapy.
It can be very difficult to apply results from an East Asian population to patients in the United States or Europe, where the risk factors for underlying liver disease are very different. Some drugs perform differently in the US and Europe than they do in Asia.
Here, we have had results from the IMbrave 150 study and the FDA approval of atezolizumab (Tecentriq, Genentech) and bevacizumab (Avastin, Genentech). That combination looks much more potent than what is presented in this trial.
In the US population, results from the IMbrave 150 study are becoming the standard of care. That regimen was adopted as a first-line regimen and received FDA approval in May.
This study is significant for OS but not PFS. Those curves look like they completely overlap, and the toxicity is not better than what was presented in the IMbrave 150 study. You would have to replicate this in a US or Europe population for it to be valid here, but I can’t picture any enthusiasm for testing anymore TKIs because the field has moved on to immunotherapy combinations. We are likely to see more trials with immunotherapy combinations come through rather than any more TKI trials.
Reference:
Galle PR, et al. Abstract 476. Presented at: Gastrointestinal Cancers Symposium; Jan. 23-25, 2020; San Francisco.
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Bi F, et al. Abstract 4506. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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