First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50)

Ken Kato, Yuichiro Doki, Takashi Ogata, Satoru Motoyama, Hisato Kawakami, Masaki Ueno, Takashi Kojima, Yasuhiro Shirakawa, Morihito Okada, Ryu Ishihara, Yutaro Kubota, Carlos Amaya-Chanaga, Tian Chen, Yasuhiro Matsumura, Yuko Kitagawa, Ken Kato, Yuichiro Doki, Takashi Ogata, Satoru Motoyama, Hisato Kawakami, Masaki Ueno, Takashi Kojima, Yasuhiro Shirakawa, Morihito Okada, Ryu Ishihara, Yutaro Kubota, Carlos Amaya-Chanaga, Tian Chen, Yasuhiro Matsumura, Yuko Kitagawa

Abstract

Background: Programmed cell death 1 (PD-1)-based treatments are approved for several cancers. CheckMate 648, a global, phase 3 trial, showed that first-line nivolumab (anti-PD-1 antibody) plus ipilimumab (NIVO + IPI) or nivolumab plus chemotherapy (NIVO + Chemo) significantly increased survival in advanced esophageal squamous cell carcinoma (ESCC) without new safety signals versus chemotherapy alone (Chemo).

Methods: We evaluated the Japanese subpopulation of CheckMate 648 (n = 394/970), randomized to receive first-line NIVO + IPI, NIVO + Chemo, or Chemo. Efficacy endpoints included overall survival (OS) and progression-free survival assessed by blinded independent central review in Japanese patients with tumor-cell programmed death-ligand 1 (PD-L1) expression ≥ 1% and in all randomized Japanese patients.

Results: In the Japanese population, 131, 126, and 137 patients were treated with NIVO + IPI, NIVO + Chemo, and Chemo, and 66, 62, and 65 patients had tumor-cell PD-L1 ≥ 1%, respectively. In patients with tumor-cell PD-L1 ≥ 1%, median OS was numerically longer with NIVO + IPI (20.2 months; hazard ratio [95% CI], 0.46 [0.30-0.71]) and NIVO + Chemo (17.3 months; 0.53 [0.35-0.82]) versus Chemo (9.0 months). In all randomized patients, median OS was numerically longer with NIVO + IPI (17.6 months; 0.68 [0.51-0.92]) and NIVO + Chemo (15.5 months; 0.73 [0.54-0.99]) versus Chemo (11.0 months). Grade 3-4 treatment-related adverse events were reported in 37%, 49%, and 36% of all patients in the NIVO + IPI, NIVO + Chemo, and Chemo arms, respectively.

Conclusion: Survival benefits with acceptable tolerability observed for NIVO + IPI and NIVO + Chemo treatments strongly support their use as a new standard first-line treatment in Japanese patients with advanced ESCC.

Gov id: NCT03143153.

Keywords: Esophageal squamous cell carcinoma; First-line treatment; Ipilimumab; Japanese population; Nivolumab.

Conflict of interest statement

Ken Kato has received research grants from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Merck & Co., Oncolys BioPharma Inc., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., and Taiho Pharmaceuticals Co., Ltd.; received honoraria and consulting fees from Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Merck & Co., Ono Pharmaceutical Co., Ltd., and Taiho Pharmaceuticals Co., Ltd.; and received consulting fees from AstraZeneca, Bayer, and BeiGene. Yuichiro Doki has received research grants and speaker engagement fees from Abbott, Ajinomoto Pharmaceuticals, Astellas Pharma Inc., AstraZeneca, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd.; Eisai Co., Ltd., Eli Lilly & Co., Johnson & Johnson Health Care Systems Inc., Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Taiho Pharmaceuticals Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Yakult Honsha Co. Ltd.; received research grants from CSL Behring, Nestle HealthCare Nutrition Inc., Nippon Kayaku, Novartis Pharma, and Pfizer; and received speaker engagements fees from Asahi Kasei Pharma Corporation, Intuitive Surgical, Medtronic, Merck & Co., Olympus Corporation, Otsuka Pharmaceutical Co., Ltd., Sanofi, and Teijin Pharma Ltd. Takashi Ogata has received honoraria for lectures from Bristol Myers Squibb and Ono Pharmaceutical Co., Ltd. Satoru Motoyama has received institutional research grants from Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Factory Inc., Shionogi & Co., Ltd., Taiho Pharmaceuticals Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; received advisory board fees and honoraria from Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Merck & Co., and Ono Pharmaceutical Co., Ltd.; and honoraria from Kaken Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Otsuka Pharmaceutical Factory Inc. Hisato Kawakami has received institutional research grants from Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Kobayashi Pharmaceutical. Co., Ltd., and Taiho Pharmaceuticals Co., Ltd.; consulting fees from Daiichi-Sankyo Co., Ltd.; and honoraria from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Eli Lilly & Co., GlaxoSmithKline, Merck & Co., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Taiho Pharmaceuticals Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., and Yakult Honsha Co. Ltd. Takashi Kojima has received institutional research grants from Amgen Inc., BeiGene, Chugai Pharmaceutical Co., Ltd., EPS Corporation, Merck & Co., Parexel International, Shionogi & Co., Ltd., and Taiho Pharmaceuticals Co., Ltd.; received honoraria from Bristol Myers Squibb, Covidien Japan, Inc., Merck & Co., Oncolys BioPharma Inc, Ono Pharmaceutical Co., Ltd., and Taiho Pharmaceuticals Co., Ltd.; and participated on data safety monitoring or advisory board of Astellas Pharma Inc., Bristol Myers Squibb, Merck & Co., and Oncolys BioPharma Inc. Morihito Okada has received institutional research grants and honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Covidien Japan, Inc., Daiichi-Sankyo Co., Ltd., Johnson & Johnson, Kyorin Pharmaceutical Co., Ltd., Merck & Co., and Pfizer Inc.; and research grants from Clinipace, Eli Lilly & Co., Kissei Pharmaceutical Co., Ltd., Kyouwa Hakkou Kirin Co., Ltd., Mitsubishi Tanabe Pharma, Nihon Medi-Physics Co., Ltd., Ono Pharmaceutical Co., Ltd., Parexel International, and Taiho Pharmaceuticals Co., Ltd. Ryu Ishihara received honoraria from AstraZeneca, Daiichi-Sankyo Co., Ltd., EA Pharma Co., Ltd., Fujifilm, Olympus Corporation, and Ono Pharmaceutical Co., Ltd. Carlos Amaya Chanaga is an employee of Bristol Myers Squibb and has stocks of AbbVie and Bristol Myers Squibb. Tien Chen is an employee of Bristol Myers Squibb, and has stocks and a patent issued by Bristol Myers Squibb. Yasuhiro Matsumura is an employee and holds stocks of Ono Pharmaceutical Company Ltd. Yuko Kitagawa has received institutional research grants from Asahi Kasei Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., EA Pharma Co., Ltd., Eisai Co., Ltd., Kaken Pharmaceutical Co., Ltd., Kyouwa Hakkou Kirin Co., Ltd., Medicon Inc., Merck & Co., Nihon Pharmaceuticals Co. Ltd., Nippon Covidien Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Factory Inc., Taiho Pharmaceuticals Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Tsumura & Co., and Yakult Honsha Co. Ltd.; and received honoraria from Asahi Kasei Pharma Corporation, Aska Pharmaceutical Co., Ltd., AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Ethicon Inc., Kaken Pharmaceutical Co., Ltd., Merck & Co., Nippon Covidien Inc., Olympus Corporation, Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Smith & Nephew KK, and Taiho Pharmaceuticals Co., Ltd. Masaki Ueno, Yutaro Kubota, and Yasuhiro Shirakawa have nothing to disclose.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Overall survival, progression-free survival per BICR, and duration of response per BICR with NIVO + IPI versus Chemo in patients with tumor-cell PD-L1 ≥ 1% (left panel: a, c, e) and all randomized patients (right panel: b, d, f) in the Japanese subpopulation. BICR blinded independent central review, Chemo chemotherapy, DOR duration of response, HR hazard ratio, IPI ipilimumab, NIVO nivolumab, OS overall survival, PFS progression-free survival, PD-L1 programmed death-ligand 1. Note: Kaplan–Meier estimates are shown, and HRs were calculated using unstratified Cox proportional hazard regression model. DOR was calculated for patients whose best overall response was complete or partial
Fig. 2
Fig. 2
Overall survival, progression-free survival per BICR, and duration of response per BICR with NIVO + Chemo versus Chemo in patients with tumor-cell PD-L1 ≥ 1% (left panel: a, c, e) and all randomized patients (right panel: b, d, f) in the Japanese subpopulation. BICR blinded independent central review, Chemo chemotherapy, DOR duration of response, HR hazard ratio, NIVO nivolumab, OS overall survival, PFS progression-free survival, PD-L1 programmed death-ligand 1. Note: Kaplan–Meier estimates are shown, and HRs were calculated using unstratified Cox proportional hazard regression model. DOR was calculated for patients whose best overall response was complete or partial

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