We evaluated the efficacy and safety of pembrolizumab in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC).

In a double-blind, phase III trial, 453 patients with advanced HCC and progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomly assigned in a 2:1 ratio to receive pembrolizumab (200 mg) or placebo once every 3 weeks for ≤ 35 cycles plus best supportive care. The primary end point was overall survival (one-sided significance threshold, P = .0193 [final analysis]). Secondary end points included progression-free survival (PFS) and objective response rate (ORR; one-sided significance threshold, P = .0134 and .0091, respectively [second interim analysis]; RECIST version 1.1, by blinded independent central review).

Median overall survival was longer in the pembrolizumab group than in the placebo group (14.6 v 13.0 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = .0180). Median PFS was also longer in the pembrolizumab group than in the placebo group (2.6 v 2.3 months; hazard ratio for progression or death, 0.74; 95% CI, 0.60 to 0.92; P = .0032). ORR was greater in the pembrolizumab group (12.7% [95% CI, 9.1 to 17.0]) than in the placebo group (1.3% [95% CI, 0.2 to 4.6]; P < .0001). Treatment-related adverse events occurred in 66.9% of patients (grade 3, 12.0%; grade 4, 1.3%; grade 5, 1.0%) in the pembrolizumab group and 49.7% of patients (grade 3, 5.9%; grade 4, 0%; grade 5, 0%) in the placebo group.

In patients from Asia with previously treated advanced HCC, pembrolizumab significantly prolonged overall survival and PFS, and ORR was greater versus placebo.

CONTEXT

Key Objective

KEYNOTE-394 evaluated the efficacy and safety of pembrolizumab plus best supportive care versus placebo plus best supportive care in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC).

Knowledge Generated

Pembrolizumab showed statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and objective response rate compared with placebo in patients from Asia with advanced HCC and disease progression or intolerance to sorafenib or oxaliplatin-based chemotherapy. Adverse events were manageable and consistent with the known safety profile of pembrolizumab in previously treated patients with advanced HCC.

Relevance (E.M. O'Reilly)

This study adds to the body of evidence pertaining to the role of immune checkpoint blockade in HCC.*

*Relevance section written by JCO Associate Editor Eileen M. O'Reilly, MD.

Presented in part at the Gastrointestinal Cancers Symposium (ASCO-GI) annual meeting, San Francisco, CA, January 20-22, 2022.

Supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ.

KEYNOTE-394 (NCT03062358)

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Conception and design: Shukui Qin, Zhendong Chen, Ruocai Xu, Baek-Yeol Ryoo, Zhiqiang Meng, Xiufeng Liu, Juxiang Xiao, Jianfeng Li, Yu Zhou, Abby B. Siegel

Administrative support: Zhendong Chen, Juxiang Xiao, Abby B. Siegel

Provision of study materials or patients: Zhendong Chen, Weijia Fang, Ruocai Xu, Zhiqiang Meng, Xiaoming Chen, Xiufeng Liu, Juxiang Xiao, Gwo Fuang Ho, Xin Wang, Jieer Ying, Jianfeng Li

Collection and assembly of data: Shukui Qin, Zhendong Chen, Weijia Fang, Zhenggang Ren, Ruocai Xu, Baek-Yeol Ryoo, Zhiqiang Meng, Xiaoming Chen, Xiufeng Liu, Juxiang Xiao, Gwo Fuang Ho, Yimin Mao, Xin Wang, Jieer Ying, Jianfeng Li, Chunyi Hao

Data analysis and interpretation: Shukui Qin, Zhenggang Ren, Ruocai Xu, Baek-Yeol Ryoo, Xiufeng Liu, Jieer Ying, Jianfeng Li, Wenyan Zhong, Abby B. Siegel

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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Zhenggang Ren

Consulting or Advisory Role: AstraZeneca, Roche, Merck Sharp & Dohme

Gwo Fuang Ho

Honoraria: Merck, Novartis, Roche, Boehringer Ingelheim, AstraZeneca

Consulting or Advisory Role: AstraZeneca, Pfizer, Boehringer Ingelheim, Novartis, Merck Sharp & Dohme, Roche/Genentech

Research Funding: Merck Sharp & Dohme (Inst), Samsung Bioepis (Inst), Tessa Therapeutics (Inst), AB Science (Inst), Pfizer (Inst), Lilly (Inst), Regeneron (Inst), Kura Oncology (Inst), AstraZeneca (Inst), Arcus Ventures (Inst), Astellas Pharma (Inst), Roche (Inst)

Jianfeng Li

Employment: MSD, China

Wenyan Zhong

Employment: MSD, China

Yu Zhou

Employment: MSD, China

Abby B. Siegel

Employment: Merck

Stock and Other Ownership Interests: Merck

Patents, Royalties, Other Intellectual Property: I have a patent pending related to a drug combination at Merck. I received 1$ (token) for this

Travel, Accommodations, Expenses: Merck

No other potential conflicts of interest were reported.