On November 9, 2018, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co., Inc.) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
Approval was based on KEYNOTE 224 (NCT02702414), a single-arm, multicenter trial enrolling 104 patients with hepatocellular carcinoma. Patients were required to have disease progression on or after sorafenib or were intolerant to sorafenib, have measurable disease, and Child-Pugh Class A liver impairment. Twenty-one percent of the patients enrolled were HBV seropositive, 25% were HCV seropositive, and 9 patients (9%) were seropositive for both HBV and HCV. Patients with active autoimmune disease, more than one etiology of hepatitis, medical conditions requiring immunosuppression, or clinical evidence of ascites by physical exam were ineligible. Patients received pembrolizumab 200 mg as an intravenous infusion every three week until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
The major efficacy outcome measure was confirmed overall response rate, as assessed by independent central review (ICR) according to RECIST 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ). The confirmed ICR-assessed overall response rate was 17% (95% CI: 11, 26), with one complete response and 17 partial responses. Response durations ranged from 3.1 to 16.7 months; 89% of responders had response durations of 6 months or longer and 56% had response durations of 12 months or longer.
Adverse reactions occurring in patients with hepatocellular carcinoma were similar to those described in KEYTRUDA product labelling; however, there were increased incidences of grade 3 or 4 ascites (8%) and immune-mediated hepatitis (2.9%). Grade 3 and 4 laboratory abnormalities that occurred at a higher incidence than in other KEYTRUDA trials were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).
The recommended pembrolizumab dose for hepatocellular carcinoma is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks.
FDA granted priority review for this application, which is approved under the provisions of accelerated approval. As a condition of accelerated approval, further studies are required. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
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