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. 2025 Feb 4;7(6):101350.
doi: 10.1016/j.jhepr.2025.101350. eCollection 2025 Jun.

Second-line pembrolizumab for advanced HCC: Meta-analysis of the phase III KEYNOTE-240 and KEYNOTE-394 studies

Richard S Finn  1 , Kangsheng Gu  2 , Xi Chen  3 , Philippe Merle  4 , Kyung-Hun Lee  5 , Mohamed Bouattour  6 , Peiguo Cao  7 , Wei Wang  8 , Ann-Lii Cheng  9 , Liangjun Zhu  10 , Ho Yeong Lim  11 , Masatoshi Kudo  12 , Yueyin Pan  13 , Ting-Tsung Chang  14 , Julien Edeline  15 , Wei Li  16 , Ping Yang  17 , Chen Li  18 , Jianfeng Li  18 , Abby B Siegel  19 , Shukui Qin  20
Affiliations

Second-line pembrolizumab for advanced HCC: Meta-analysis of the phase III KEYNOTE-240 and KEYNOTE-394 studies

Richard S Finn et al. JHEP Rep. .

Abstract

Background & aims: We performed a meta-analysis of data from the KEYNOTE-240 and KEYNOTE-394 studies to obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma (HCC).

Methods: Participants with confirmed HCC and disease progression after treatment with or intolerance of sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only), Barcelona Clinic Liver Cancer stage C or B disease not amenable to or refractory to locoregional therapy, and one or more measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were randomly assigned 2:1 to receive pembrolizumab or placebo for ≤35 cycles. Data from the KEYNOTE-240 and KEYNOTE-394 intention-to-treat populations were pooled, and the treatment effect was evaluated for pembrolizumab and placebo separately.

Results: In total, 578 and 288 participants who received pembrolizumab and placebo, respectively, were included in this analysis. Compared with placebo, pembrolizumab improved overall survival (hazard ratio 0.79, 95% CI 0.67-0.93), progression-free survival (per RECIST v1.1 by blinded independent central review [BICR]; hazard ratio 0.76, 95% CI 0.64-0.89), and objective response rate (per RECIST v1.1 by BICR; 15.4% vs. 2.8%, for an estimated treatment difference of 12.5%; 95% CI 8.8-16.2). Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline participant characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region.

Conclusions: Meta-analysis of KEYNOTE-240 and KEYNOTE-394 showed that pembrolizumab provides clinically meaningful improvement in overall survival, progression-free survival, and objective response rate. This analysis expands on findings from each study individually and provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced HCC after prior sorafenib- or oxaliplatin-based therapy.

Impact and implications: To obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma, we performed a meta-analysis of efficacy using pooled participant data from the phase III KEYNOTE-240 and KEYNOTE-394 studies. Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region. This meta-analysis provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced hepatocellular carcinoma.

Clinical trials registration: Registered at ClinicalTrials.gov NCT02702401 (KEYNOTE-240) and NCT03062358 (KEYNOTE-394).

Keywords: Global; Pooled; Post hoc; Programmed cell death ligand 1; Randomized.

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Conflict of interest statement

RSF reported receiving payments for consultancy, travel, writing assistance, and article processing for the present work and grants paid to his institution for the present work, all from Merck, and grants to his institution from Adaptimmune, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Genentech, Pfizer, and Roche; consulting fees paid to him from AstraZeneca, Bayer, Bristol Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Genentech, Hengrui, Pfizer, and Roche; payment to him for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Genentech; and payments to him from AstraZeneca and Hengrui for participation on a data safety monitoring board or advisory board, outside of the present work. XC reported receiving consulting fees from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, EXE, Genentech/Roche, Ipsen Innovation, and MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen Taiwan, Bayer Yakuhin, Chugai Pharmaceutical, Novartis, and Ono Pharmaceutical; support for attending meetings and/or travel from IQVIA; and participation on a data safety monitoring board or advisory board for Abbisko Therapeutics, outside of the present work. PM reported serving in a consulting or advisory role for AstraZeneca, Bayer, Eisai, Ipsen, MSD, and Roche and receiving funding from Ipsen, outside of the present work. K-HL reported receiving honoraria from AstraZeneca, Eli Lilly, Novartis, and Pfizer and payment for expert testimony from Novartis, outside of the present work. MB reported receiving consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, Roche, and Sirtex Medical; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, Bayer Pharma, and Roche; and support for attending meetings and/or travel from AstraZeneca, Bayer, and Roche, outside of the present work. A-LC reported receiving consulting fees from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Eisai, Genentech/Roche, Ipsen Innovation, MSD, Omega Therapeutics, Ono Pharmaceutical, and Sanofi; payment or honoraria for lectures, presentations, or speakers’ bureaus from Amgen Taiwan, Ipsen Innovation, and Roche; support for attending meetings and/or travel from AstraZeneca and Roche; and participation on a data safety monitoring board or advisory board for Abbisko Therapeutics, outside of the present work. HYL reported receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bayer, Eisai, and Roche; participation on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Eisai, Ipsen, and Roche; and role as the president of the Korean Society of Medical Oncology, outside of the present work. MK reported receiving support for the present work from MSD, and grants or contracts from AbbVie, EA Pharma, Eisai, GE Healthcare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bayer, Chugai, Eli Lilly, Eisai, MSD, and Takeda, outside of the present work. JE reported receiving grants or contracts from BeiGene, Boston Scientific, and Bristol Myers Squibb; consulting fees from AstraZeneca, Basilea, Bayer, BeiGene, Boston Scientific, Bristol Myers Squibb, Eisai, Incyte, Ipsen, Merck Serono, MSD, Roche, Servier, and Taiho; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Incyte, Ipsen, Roche, and Servier; and support for attending meetings and/or travel from Amgen, outside of the present work. PY is an employee of MSD China, Shanghai, China. CL and JL are employees of MSD China, Beijing, China. ABS is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock in Merck & Co., Inc., Rahway, NJ, USA. KG, PC, WW, LZ, YP, T-TC, WL, and SQ report no disclosures. Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Overall survival in the pooled intention-to-treat population. (A) Kaplan–Meier estimates of OS in all participants. (B) Subgroup analysis of OS. For the overall pooled intention-to-treat population, the HR for OS was based on the Cox regression model with treatment as a covariate and stratified by protocol and, within each protocol, by strata used in the analysis of the respective protocol. For the subgroup analysis by protocol, the Cox regression model stratified by strata in the analysis of the respective protocol was used. For other subgroup analyses, the Cox regression model stratified by the protocol, but no other stratification variable, was used. BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival.
Fig. 2
Fig. 2
Progression-free survival in the pooled intention-to-treat population. (A) Kaplan–Meier estimates of PFS in all participants. (B) Subgroup analysis of PFS. For the overall pooled intention-to-treat population, the HR for PFS was based on the Cox regression model with treatment as a covariate and stratified by protocol and, within each protocol, by strata used in the analysis of the respective protocol. For the subgroup analysis by protocol, the Cox regression model stratified by strata in the analysis of the respective protocol was used. For other subgroup analyses, the Cox regression model stratified by the protocol, but no other stratification variable, was used. BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NA, not applicable; PFS, progression-free survival.
Fig. 3
Fig. 3
Subgroup analysis of the estimated treatment difference in objective response rate in the pooled intention-to-treat population. For the overall pooled intention-to-treat population, the 95% CI for ORR difference was based on the Miettinen and Nurminen method stratified by protocol and, within each protocol, by strata used in the analysis of the respective protocol. For the subgroup analysis by protocol, the Miettinen and Nurminen method stratified by strata the analysis of the respective protocol was used. For other subgroup analyses, the Miettinen and Nurminen method stratified by the protocol, but no other stratification variable, was used. BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, objective response rate.
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