Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial

Philippe Merle; Masatoshi Kudo; Julien Edeline; Mohamed Bouattour; Ann-Lii Cheng; Stephen L Chan; Thomas Yau; Marcelo Garrido; Jennifer Knox; Bruno Daniele; Valeriy Breder; Ho Yeong Lim; Sadahisa Ogasawara; Stéphane Cattan; Yee Chao; Abby B Siegel; Iván Martinez-Forero; Ziwen Wei; Chih-Chin Liu; Richard S Finn

doi:10.1159/000529636

Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial

Liver Cancer. 2023 Feb 14;12(4):309-320. doi: 10.1159/000529636. eCollection 2023 Sep.

Authors

Philippe Merle¹, Masatoshi Kudo², Julien Edeline³, Mohamed Bouattour⁴, Ann-Lii Cheng⁵, Stephen L Chan⁶, Thomas Yau⁷, Marcelo Garrido⁸, Jennifer Knox⁹, Bruno Daniele¹⁰, Valeriy Breder¹¹, Ho Yeong Lim¹², Sadahisa Ogasawara¹³, Stéphane Cattan¹⁴, Yee Chao¹⁵, Abby B Siegel¹⁶, Iván Martinez-Forero¹⁷, Ziwen Wei¹⁸, Chih-Chin Liu¹⁸, Richard S Finn¹⁹

Affiliations

¹ Department of Hepatology and Gastroenterology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France, and Centre de Recherche en Cancerologie de Lyon, Lyon, France.
² Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
³ INSERM, University Rennes, Department of Medical Oncology, CLCC Eugène Marquis, COSS (Chemistry Oncogenesis Stress Signaling) - UMR_S 1242, Rennes, France.
⁴ Department of Liver Cancer Unit, Hôpital Beaujon, Assistance Publique Hôpitaux de Paris, Clichy, France.
⁵ Department of Medical Oncology, National Taiwan University Cancer Center and National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China.
⁷ Department of Medicine, The University of Hong Kong, Hong Kong, China.
⁸ Department of Medical Oncology, Pontificia Universidad Catolica de Chile, Santiago, Chile.
⁹ Department of Medical Oncology, UHN Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Oncology, Ospedale del Mare, Naples, Italy.
¹¹ Department of Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation.
¹² Department of Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
¹³ Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
¹⁴ Department of Medical Oncology and Gastroenterology, Hôpital Claude Huriez, Centre Hospitalier Régional Universitaire de Lille, Lille, France.
¹⁵ Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁶ Department of Medical Oncology, Merck & Co., Inc., Rahway, NJ, USA.
¹⁷ Department of Medical Oncology, MSD, Luzern, Switzerland.
¹⁸ Biostatistics and Research Decision Sciences, Merck & Co., Inc., Rahway, NJ, USA.
¹⁹ Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Abstract

Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported.

Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety.

Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7-48.8) months for pembrolizumab and 39.8 (31.7-47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4-22.5%) for pembrolizumab and 11.7% (6.8-17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3-13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0-23.4%) for pembrolizumab and 4.4% (1.6-9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported.

Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.

Keywords: Hepatocellular carcinoma; Long-term follow-up; Pembrolizumab; Programmed cell death protein 1.

Grants and funding

This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA. Medical writing and editorial assistance were funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.