FDA Approves Pembrolizumab for Hepatocellular Carcinoma Previously Treated With a Kinase Inhibitor

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ON NOVEMBER 9, 2018, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda) for patients with hepatocellular carcinoma who have been previously treated with the kinase inhibitor sorafenib (Nexavar).


APPROVAL WAS based on KEYNOTE-224, 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.

Of the patients enrolled, 21% were hepatitis B virus (HBV)-seropositive, 25% were hepatitis C virus (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 at 200 mg as an intravenous infusion every 3 weeks 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 according to Response Evaluation Criteria in Solid Tumors, version 1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ).

Key Findings

THE CONFIRMED independent central review–assessed overall response rate was 17% (95% confidence interval [CI] = 11%–26%), with 1 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 the pembrolizumab product labeling; 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 trials of pembrolizumab were elevated aspartate aminotransferase (20%), alanine aminotransferase (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. This indication was granted accelerated approval, based on tumor response rate and durability of response.