FDA Grants Pembrolizumab Priority Review for HCC

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) for previously treated patients with advanced hepatocellular carcinoma (HCC), according to Merck (MSD), the manufacturer of the PD-1 inhibitor.

UPDATE 11/9/2018: FDA Approves Pembrolizumab for HCC

The sBLA is based on findings from the phase II KEYNOTE-224 trial, in which single-agent pembrolizumab induced an overall response rate (ORR) of 17% (95% CI, 11-26) among 104 patients with advanced HCC 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.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sBLA by November 9, 2018.

“There continues to be a significant need for new options in the treatment of advanced hepatocellular carcinoma, which is the most common type of liver cancer,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, said in a statement.

“The data supporting our application provide a clear rationale for the advancement of the Keytruda clinical program for hepatocellular carcinoma, and we are grateful for the opportunity to work with the FDA to potentially bring Keytruda to patients living with this difficult-to-treat cancer.”

The nonrandomized, open-label phase II KEYNOTE-224 trial enrolled and treated 104 patients with HCC and prior sorafenib between June 7, 2016, and February 9, 2017, at 47 medical centers and hospitals in 10 countries. 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, 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 duration of response was not reached (range, 3.1-14.6+ 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.

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.