Clinical Trial

. 2024 Nov;27(6):1287-1301.

doi: 10.1007/s10120-024-01535-0. Epub 2024 Aug 20.

Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial

Narikazu Boku¹, Takeshi Omori², Kohei Shitara³, Shinichi Sakuramoto⁴, Kensei Yamaguchi⁵, Ken Kato⁶, Shigenori Kadowaki⁷, Kunihiro Tsuji⁸, Min-Hee Ryu⁹, Do-Youn Oh¹⁰, Sang Cheul Oh¹¹, Sun Young Rha¹², Keun-Wook Lee¹³, Ik-Joo Chung¹⁴, Sun Jin Sym¹⁵, Li-Tzong Chen^{16

17}, Jen-Shi Chen¹⁸, Li-Yuan Bai¹⁹, Takashi Nakada²⁰, Shunsuke Hagihara²¹, Reina Makino²², Eiji Nishiyama²², Yoon-Koo Kang²³

Affiliations

¹ Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
² Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.
³ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁴ Saitama Medical University International Medical Center, Hidaka, Japan.
⁵ Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
⁶ Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁷ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁸ Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
⁹ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
¹⁰ Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
¹¹ Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, South Korea.
¹² Division of Medical Oncology, Yonsei Cancer Center, Yonsei University Health System, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.
¹³ Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
¹⁴ Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, South Korea.
¹⁵ Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, South Korea.
¹⁶ National Institute of Cancer Research, National Health Research Institutes, and National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
¹⁷ Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁸ Division of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
¹⁹ Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, and China Medical University, Taichung, Taiwan.
²⁰ Department of Oncology Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²¹ Department of Statistical Analysis, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²² Department of Medical Affairs, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²³ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea. ykkang@amc.seoul.kr.

PMID: 39162872
PMCID: PMC11513732
DOI: 10.1007/s10120-024-01535-0

Clinical Trial

Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial

Narikazu Boku et al. Gastric Cancer. 2024 Nov.

. 2024 Nov;27(6):1287-1301.

doi: 10.1007/s10120-024-01535-0. Epub 2024 Aug 20.

Authors

Affiliations

¹ Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
² Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.
³ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁴ Saitama Medical University International Medical Center, Hidaka, Japan.
⁵ Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
⁶ Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁷ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁸ Department of Medical Oncology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
⁹ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
¹⁰ Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
¹¹ Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, South Korea.
¹² Division of Medical Oncology, Yonsei Cancer Center, Yonsei University Health System, Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, South Korea.
¹³ Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.
¹⁴ Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Chonnam National University College of Medicine, Hwasun, South Korea.
¹⁵ Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, South Korea.
¹⁶ National Institute of Cancer Research, National Health Research Institutes, and National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
¹⁷ Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁸ Division of Hematology and Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
¹⁹ Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, and China Medical University, Taichung, Taiwan.
²⁰ Department of Oncology Clinical Development Planning, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²¹ Department of Statistical Analysis, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²² Department of Medical Affairs, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
²³ Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro, 43-gil, Songpa-gu, Seoul, 05505, South Korea. ykkang@amc.seoul.kr.

PMID: 39162872
PMCID: PMC11513732
DOI: 10.1007/s10120-024-01535-0

Abstract

Background: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited.

Methods: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur-gimeracil-oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints-centrally assessed progression-free survival (PFS) and overall survival (OS)-and landmark analyses of OS among patients alive using 3-year follow-up data.

Results: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55-0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75-1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy.

Conclusion: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer.

Trial registration: NCT02746796.

Keywords: Chemotherapy; Gastric cancer; Nivolumab; Oxaliplatin; Randomized controlled trial.

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Conflict of interest statement

Narikazu Boku disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, and Taiho Pharma. Takeshi Omori disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Kohei Shitara disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; research funding (to the institution) from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharma, Chugai, MSD, Amgen, Eisai, PRA Health Sciences, Syneos Health; consulting fees as an advisor from Bristol-Myers Squibb, Takeda, Ono Pharmaceutical, Novartis, Daiichi Sankyo, Amgen, Boehringer Ingelheim, MSD, Astellas, Guardant Health Japan, Janssen, AstraZeneca, Zymeworks, ALX Oncology, and Bayer; and honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Janssen, Eli Lilly, Astellas, and AstraZeneca. Shinichi Sakuramoto disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Kensei Yamaguchi disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; grants from Taiho Pharma; and honoraria from Daiichi Sankyo, Chugai Pharmaceutical, Bristol-Myers Squibb, Eli Lilly, Taiho Pharma, Takeda, and Merck Biopharm. Ken Kato disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; consulting fees from Ono Pharmaceutical, Bristol-Myers Squibb, BeiGene/Novartis, AstraZeneca, Roche, Bayer, Merck & Co, Merck Bio, and Janssen; honoraria from Ono Pharmaceutical and Bristol-Myers Squibb; and payments for expert testimony from Ono Pharmaceutical and Bristol-Myers Squibb. Shigenori Kadowaki disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; research grants from Bristol-Myers Squibb, Ono Pharmaceutical, Bayer, Daiichi Sankyo, MSD, Chugai, Janssen, Nobelpharma, and Eli Lilly; and honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Bayer, Taiho Pharma, Eisai, Daiichi Sankyo, MSD, Chugai, and Otsuka Pharmaceutical. Kunihiro Tsuji disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Min-Hee Ryu disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; research grants from AstraZeneca; consulting fees from Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Eli Lilly, Taiho Pharma, Novartis, Daiichi Sankyo, AstraZeneca, Astellas, and Daehwa; and payments or honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Eli Lilly, Taiho Pharma, Novartis, and Daehwa. Do-Youn Oh disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; research grants from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok; and participation on data safety monitoring boards or advisory boards for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho Pharma, ASLAN, Halozyme, Zymeworks, Bristol-Myers Squibb, Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, and MSD. Sang Cheul Oh disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Sun Young Rha disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; grants (to the institution) from AstraZeneca, Ono Pharmaceutical, Eisai, Ipsen, MSD, Merck KGaA, Pfizer, BeiGene, Astellas Pharma, AMGEN, ALX Oncology, Zymeworks, Macrogenics, Seagen, Bold Therapeutics, MedPacto, ABLBIO, Daiichi Sankyo, Taiho Pharmaceutical, Leap therapeutics, and Arcus Biosciences for conducting clinical trials; consulting fees from LG Biochem and Indivumed; personal fees/honoraria from MSD, Eli Lilly, Daiichi Sankyo, Eisai, and Ipsen; and participation on data safety monitoring boards or advisory boards for Amgen and Toray. Keun-Wook Lee disclosed institutional research funding (to the institution) from Ono Pharmaceutical for conducting clinical trials; research funding (to the institution) for conducting clinical trials from AstraZeneca, MSD, Merck KGaA, Roche, BeiGene, Leap therapeutics, ALX Oncology, Zymeworks, Astellas, Macrogenics, Amgen, Seagen, Bolt Therapeutics, Trishula Therapeutics, MedPacto, Green Cross Corp, Y-BIOLOGICS, Daiichi Sankyo, Taiho Phama, InventisBio, Elevar Therapeutics, Metafines, Idience, Genome & Company, and Exelixis; honoraria for lectures from Ono Pharmaceutical, Boryung, Daiichi Sankyo, Astellas, and Sanofi-Aventis; and participation on data safety monitoring boards or advisory boards for ALX Oncology and Metafines. Ik-Joo Chung disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Sun Jin Sym disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Li-Tzong Chen disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; grants (to the institution) from MSD; consulting fees from AstraZeneca and MSD; honoraria from AstraZeneca, MSD, Ono Pharmaceutical, and Bristol-Myers Squibb; participation on data safety monitoring boards or advisory boards for AstraZeneca and MSD; and receipt of study drugs (to the institute) from Ono Pharmaceutical, Bristol-Myers Squibb, and Boehringer Ingelheim. Jen-Shi Chen disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Li-Yuan Bai disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial. Takashi Nakada is an employee of Ono Pharmaceutical. Shunsuke Hagihara is an employee of Ono Pharmaceutical. Reina Makino is an employee of Ono Pharmaceutical. Eiji Nishiyama is an employee of Ono Pharmaceutical. Yoon-Koo Kang disclosed research funding (to the institution) from Ono Pharmaceutical for this clinical trial; medical writing support from Astellas Pharma; and consulting fees from Amgen, Novartis, Roche, Daehwa, Zymeworks, Blueprint, Surface Oncology, ALX Oncology, Macrogenics, Bristol-Myers Squibb, Merck, and Liscure.

Figures

**Fig. 1**
a Centrally assessed PFS. b Investigator-assessed PFS. c Forest plot analysis of centrally assessed PFS. *CAPOX* capecitabine plus oxaliplatin, CI confidence interval, *ECOG PS* Eastern Cooperative Oncology Group performance status, *eCRF* electronic case report form, HR hazard ratio, *IWRS* interactive web response system, *n/c* not countable, *PD-L1* programmed death ligand 1, *PFS* progression-free survival, *SOX* S-1 (tegafur–gimeracil–oteracil potassium) plus oxaliplatin

**Fig. 2**
a OS. b Forest plot analysis of OS. c Landmark analysis of OS. *CAPOX* capecitabine plus oxaliplatin, CI confidence interval, *ECOG PS* Eastern Cooperative Oncology Group performance status, *eCRF* electronic case report form, HR hazard ratio, *IWRS* interactive web response system, *n/c* not countable, OS overall survival, *PD-L1* programmed death ligand 1, *SOX* S-1 (tegafur–gimeracil–oteracil potassium) plus oxaliplatin

**Fig. 3**
DOR in patients whose best objective response was CR or PR. CI confidence interval, CR complete response, *DOR* duration of response, PR partial response

See this image and copyright information in PMC

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Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial

Affiliations

Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial

Authors

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Abstract

Conflict of interest statement

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