Pembrolizumab Granted Accelerated FDA Approval for HCC


Pembrolizumab (Keytruda) has received an accelerated approval from the FDA for the treatment of patients with hepatocellular carcinoma who have previously received sorafenib (Nexavar).

Pembrolizumab (Keytruda) has received an accelerated approval from the FDA for the treatment of patients with hepatocellular carcinoma (HCC) who have previously received sorafenib (Nexavar). The approval was announced today by Merck (MSD), the manufacturer of the agent.

The approval of the PD-1 inhibitor is based on findings from the phase II KEYNOTE-224 trial. Results from the trial showed an overall response rate (ORR) of 17% (95% CI, 11-26) with single-agent pembrolizumab among 104 patients with advanced HCC who were previously treated with sorafenib (Nexavar). Among the 18 patients who responded, there was 1 complete response and 17 partial responses. Forty-six patients had stable disease, 34 patients had progressive disease, and 6 patients were not evaluable.

“Hepatocellular carcinoma is the most common type of liver cancer in adults, and while we have seen recent therapeutic advancements, there are still limited treatment options for advanced recurrent disease,” Andrew X. Zhu, MD, PhD, lead investigator and director of liver cancer research at Massachusetts General Hospital and professor of medicine at Harvard Medical School, said in a statement.

“Today’s approval of Keytruda is important, as it provides a new treatment option for patients with hepatocellular carcinoma who have been previously treated with sorafenib," added Zhu.

A total of 104 patients with HCC at 47 medical centers and hospitals in 10 countries were enrolled and treated in the nonrandomized, open-label phase II KEYNOTE-224 trial between June 7, 2016, and February 9, 2017. There were 86 males and 18 females in the trial, and the median age was 68 (range, 62-73). Eighty-one percent of patients were white, 13% were Asian, and 3% were black.

All patients had an ECOG performance score of 0 (61%) or 1 (39%). Ninety-four percent of patients were Child Pugh Class A and 76% had Barcelona Clinic Liver Cancer stage C disease. Eighty percent of patients had discontinued sorafenib due to progressive disease and 20% had become intolerant to sorafenib.

All patients were treated with 200 mg of IV pembrolizumab administered every 3 weeks on day 1 of each 3-week cycle. Treatment continued until progression, unacceptable toxicity, withdrawal of patient consent, investigator decision, or a maximum of 35 cycles (approximately 2 years).

The primary endpoint was ORR, with secondary endpoints including duration of response (DOR), disease control, time to progression, progression-free survival (PFS), overall survival (OS), and safety. There were 17 (16%) patients still receiving pembrolizumab at the February 13, 2018, data cutoff.

The median time to response was 2.1 months (IQR, 2.1-4.1). At the data cutoff, 12 of the 18 responses were ongoing and the median DOR was not reached (range, 3.1-14.6+ months). Eighty-nine percent of the responders had a DOR ≥6 months, and 56% had a DOR ≥12 months. 

The median PFS was 4.9 months (95% CI, 3.4-7.2), and the 12-month PFS rate was 28% (95% CI, 19-37). The median OS was 12.9 months (95% CI, 9.7-15.5) and the 12-month OS rate was 54% (95% CI, 44-63).

Patients received pembrolizumab for a median of 4.2 months (range, 2.1-7.7). Progressive disease (57%) and adverse events (AEs; 23%) were the most frequent cause of treatment discontinuation. Post-progression treatment included cabozantinib (Cabometyx) in 1 patient and regorafenib (Stivarga) in 20 patients.

Twenty-four percent (n = 25) of patients experienced grade 3 treatment-related AEs, with the most common being increased AST (7%), increased ALT (4%), and fatigue (4%). There was 1 case of grade 4 treatment-related hyperbilirubinemia, and 1 patient death associated with ulcerative esophagitis was linked to treatment. Additionally, 3 patients had immune-mediated hepatitis, but no incidents of viral flares were reported.

The accelerated approval of pembrolizumab in HCC is contingent on the results of a confirmatory trial.

Pembrolizumab has approved indications in melanoma, lung cancer, head and neck cancer, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high cancer, gastric cancer, and cervical cancer.


Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial [published online June 1, 2018].Lancet Oncol. doi: 10.1016/S1470-2045(18)30351-6.

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