New hepatocellular carcinoma approval for Pembrolizumab – KN-224

By Ajay V. Patil

The US FDA granted pembrolizumab (Keytruda) an accelerated approval for the treatment of patients with hepatocellular carcinoma (HCC) who have previously received sorafenib (November 9, 2018 press release Merck & Co.). The accelerated approval of pembrolizumab in HCC is contingent on the results of a confirmatory trial.

The base study which supported this decision, phase II KEYNOTE-224 trial, showed that pembrolizumab singularly induced an overall response rate (ORR) of 17% (95% CI, 11-26) among 104 patients with advanced HCC previously treated with sorafenib. Among the 18 responding patients, there was 1 complete response and 17 partial responses. Among the responding patients (n=18), 89 percent experienced a duration of response (DOR) for six months or longer and 56 percent experienced a DOR for 12 months or longer. 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 most frequent causes of the treatment discontinuation.

KEYNOTE-224 Study Design

Nonrandomized, open-label phase II 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. Eighty percent of patients had discontinued sorafenib due to progressive disease and 20% had become intolerant to sorafenib. There were 86 males and 18 females in the trial, and the median age was 68 (range, 62-73). Ninety-four percent of patients were Child Pugh Class A and 76% had Barcelona Clinic Liver Cancer stage C disease. 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%).

Patients were treated with 200 mg of intravenous 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, and secondary endpoints included duration of response (DOR), disease control, time to progression, progression-free survival (PFS), overall survival (OS), and safety. Seventeen (16%) patients still receiving pembrolizumab (at the February 13, 2018, data cutoff).

This is another major milestone for pembrolizumab in HCC space, post its announcement of data at 2018 ASCO annual meeting from investigational studies of lenvatinib and pembrolizumab combination therapy in four different tumor types including HCC.

References

1. https://investors.merck.com/news/press-release-details/2018/FDA-Approves-Mercks-KEYTRUDA-pembrolizumab-for-the-Treatment-of-Patients-with-Hepatocellular-Carcinoma-HCC-Who-Have-Been-Previously-Treated-with-Sorafenib/default.aspx
2. https://www.onclive.com/web-exclusives/fda-approves-pembrolizumab-for-hcc
3. https://www.eisai.com/news/2018/news201843.html

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