Pembrolizumab (pembro) in patients (pts) with sorafenib-treated (cohort 1) and treatment (tx)-naive (cohort 2) advanced hepatocellular carcinoma (aHCC) after additional follow-up in the phase 2 KEYNOTE-224 study.
Authors: Finn Richard S. , Kudo Masatoshi , Borbath Ivan , Edeline Julien , Cattan Stéphane , Van Vlierberghe Hans , Verslype Chris , Palmer Daniel H. , Stål Per , Ogasawara Sadahisa , Vogel Arndt , Karwal Mark , Chan Stephen Lam , Knox Jennifer J. , Daniele Bruno , Odeleye-Ajakaye Amos , Hatogai Ken , Siegel Abby B. , Cheng Ann-Lii , Van Laethem Jean-Luc 
Published: June 2024

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Background: Based on the results of the open-label, phase 2 KEYNOTE-224 study (NCT02702414), pembro received US FDA and the Center for Drug Evaluation of the China National Medical Products Administration approval for pts with sorafenib-treated aHCC (cohort 1). Durable activity and manageable safety were also observed for pts with tx-naive aHCC in cohort 2 of KEYNOTE-224. We report updated efficacy and safety from both cohorts of KEYNOTE-224 after approximately 7 and 5 years of median follow-up, respectively. Methods: Adults with pathology-confirmed aHCC whose disease progressed after or who were intolerant to sorafenib tx (cohort 1) and adults with histologically, cytologically, or radiologically confirmed aHCC with no prior systemic tx (cohort 2) were eligible. Pts in both cohorts had BCLC stage C or B not amenable or refractory to locoregional therapy and not amenable to curative tx, Child-Pugh A liver function, measurable disease per RECIST v1.1, and ECOG PS 0 or 1. Pts received pembro 200 mg IV Q3W for ≤35 cycles (~2 y). Primary end point was ORR per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS (all per RECIST v1.1 by BICR), OS, and safety/tolerability. Results: A total of 155 pts enrolled in cohorts 1 (n = 104) and 2 (n = 51) received ≥1 dose of pembro. Median follow-up, defined as time from first dose to data cutoff (Sept 29, 2023), was 83.0 mo (range, 79.3-87.3) for cohort 1 and 58.8 mo (range, 55.3-60.8) for cohort 2. In each cohort, 90% of pts discontinued, mostly due to progressive disease (59%); 10% of pts in each cohort completed 2 y of tx. ORR was 18.3% (95% CI, 11.4-27.1) for cohort 1 (5 CRs [4.8%] and 14 PRs [13.5%]) and 17.6% (95% CI, 8.4-30.9) for cohort 2 (2 CRs [3.9%] and 7 PRs [13.7%]). Median DOR was 21.0 mo (range, 3.1 to 75.8+) for cohort 1 and 24.7 mo (range, 3.1 to 53.4+) for cohort 2; 77%/43% and 76%/64% of responders, respectively, had a response duration of ≥12 mo/≥24 mo per the Kaplan-Meier method for censored data. Data for PFS, TTP, and OS are shown in the Table. Tx-related AEs were reported in 76 pts (73.1%; grade 3-5, 27 [26.0%]) in cohort 1 and 28 pts (54.9%; grade 3-5, 8 [15.7%]) in cohort 2. Conclusions: Pembro continued to provide durable responses in pts with aHCC with or without prior systemic therapy, with some lasting beyond 20 mo; long-term effects on OS beyond 24 mo and manageable safety were also observed. Together with data from KEYNOTE-394 and KEYNOTE-240, these data support the efficacy and safety of pembro as a tx option for aHCC. Clinical trial information: NCT02702414 . [Table: see text]