1 University of California, Los Angeles, Los Angeles, CA.
2 Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
3 Lyon North Hospital, Lyon, France.
4 Kindai University Faculty of Medicine, Osaka, Japan.
5 Beaujon University Hospital, Assistance Publique-Hôpitaux de Paris, Clichy, France.
6 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
7 NN Blokhin National Medical Research Center of Oncology, Ministry of Health, Moscow, Russian Federation.
8 Centre Eugène Marquis, Rennes, France.
9 Taipei Veterans General Hospital, Taipei, Taiwan.
10 Chiba University Graduate School of Medicine, Chiba, Japan.
11 The University at Hong Kong, Hong Kong, People's Republic of China.
12 Pontificia Universidad Catolica de Chile, Santiago, Chile.
13 State Key Laboratory of Translation Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
14 Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
15 Ospedale del Mare, Napoli, Italy.
16 Merck, Kenilworth, NJ.
17 Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
18 National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
PURPOSE: Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population.
PATIENTS AND METHODS: This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug.
RESULTS: Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified.
CONCLUSION: In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.