Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial

Yoon Koo Kang, Narikazu Boku, Taroh Satoh, Min Hee Ryu, Yee Chao, Ken Kato, Hyun Cheol Chung, Jen Shi Chen, Kei Muro, Won Ki Kang, Kun Huei Yeh, Takaki Yoshikawa, Sang Cheul Oh, Li Yuan Bai, Takao Tamura, Keun Wook Lee, Yasuo Hamamoto, Jong Gwang Kim, Keisho Chin, Do Youn OhKeiko Minashi, Jae Yong Cho, Masahiro Tsuda, Li Tzong Chen

Research output: Contribution to journalArticle

331 Citations (Scopus)

Abstract

Background Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0–1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343. Findings Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57–12·37) in the nivolumab group and 8·59 months (5·65–11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60–6·37) in the nivolumab group and 4·14 months (3·42–4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51–0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7–32·0) with nivolumab and 10·9% (6·2–17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed. Interpretation In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines. Funding Ono Pharmaceutical and Bristol-Myers Squibb.

Original languageEnglish
Pages (from-to)2461-2471
Number of pages11
JournalThe Lancet
Volume390
Issue number10111
DOIs
Publication statusPublished - 2017 Dec 2

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Esophageal Neoplasms
Stomach
Placebos
Drug Therapy
Therapeutics
nivolumab
Safety
Survival
Research Personnel
Republic of Korea
Taiwan

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Kang, Yoon Koo ; Boku, Narikazu ; Satoh, Taroh ; Ryu, Min Hee ; Chao, Yee ; Kato, Ken ; Chung, Hyun Cheol ; Chen, Jen Shi ; Muro, Kei ; Kang, Won Ki ; Yeh, Kun Huei ; Yoshikawa, Takaki ; Oh, Sang Cheul ; Bai, Li Yuan ; Tamura, Takao ; Lee, Keun Wook ; Hamamoto, Yasuo ; Kim, Jong Gwang ; Chin, Keisho ; Oh, Do Youn ; Minashi, Keiko ; Cho, Jae Yong ; Tsuda, Masahiro ; Chen, Li Tzong. / Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2) : a randomised, double-blind, placebo-controlled, phase 3 trial. In: The Lancet. 2017 ; Vol. 390, No. 10111. pp. 2461-2471.
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title = "Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial",
abstract = "Background Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0–1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343. Findings Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57–12·37) in the nivolumab group and 8·59 months (5·65–11·37) in the placebo group. Median overall survival was 5·26 months (95{\%} CI 4·60–6·37) in the nivolumab group and 4·14 months (3·42–4·86) in the placebo group (hazard ratio 0·63, 95{\%} CI 0·51–0·78; p<0·0001). 12-month overall survival rates were 26·2{\%} (95{\%} CI 20·7–32·0) with nivolumab and 10·9{\%} (6·2–17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10{\%}) of 330 patients who received nivolumab and seven (4{\%}) of 161 patients who received placebo; treatment-related adverse events led to death in five (2{\%}) of 330 patients in the nivolumab group and two (1{\%}) of 161 patients in the placebo group. No new safety signals were observed. Interpretation In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines. Funding Ono Pharmaceutical and Bristol-Myers Squibb.",
author = "Kang, {Yoon Koo} and Narikazu Boku and Taroh Satoh and Ryu, {Min Hee} and Yee Chao and Ken Kato and Chung, {Hyun Cheol} and Chen, {Jen Shi} and Kei Muro and Kang, {Won Ki} and Yeh, {Kun Huei} and Takaki Yoshikawa and Oh, {Sang Cheul} and Bai, {Li Yuan} and Takao Tamura and Lee, {Keun Wook} and Yasuo Hamamoto and Kim, {Jong Gwang} and Keisho Chin and Oh, {Do Youn} and Keiko Minashi and Cho, {Jae Yong} and Masahiro Tsuda and Chen, {Li Tzong}",
year = "2017",
month = "12",
day = "2",
doi = "10.1016/S0140-6736(17)31827-5",
language = "English",
volume = "390",
pages = "2461--2471",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
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Kang, YK, Boku, N, Satoh, T, Ryu, MH, Chao, Y, Kato, K, Chung, HC, Chen, JS, Muro, K, Kang, WK, Yeh, KH, Yoshikawa, T, Oh, SC, Bai, LY, Tamura, T, Lee, KW, Hamamoto, Y, Kim, JG, Chin, K, Oh, DY, Minashi, K, Cho, JY, Tsuda, M & Chen, LT 2017, 'Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial', The Lancet, vol. 390, no. 10111, pp. 2461-2471. https://doi.org/10.1016/S0140-6736(17)31827-5

Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2) : a randomised, double-blind, placebo-controlled, phase 3 trial. / Kang, Yoon Koo; Boku, Narikazu; Satoh, Taroh; Ryu, Min Hee; Chao, Yee; Kato, Ken; Chung, Hyun Cheol; Chen, Jen Shi; Muro, Kei; Kang, Won Ki; Yeh, Kun Huei; Yoshikawa, Takaki; Oh, Sang Cheul; Bai, Li Yuan; Tamura, Takao; Lee, Keun Wook; Hamamoto, Yasuo; Kim, Jong Gwang; Chin, Keisho; Oh, Do Youn; Minashi, Keiko; Cho, Jae Yong; Tsuda, Masahiro; Chen, Li Tzong.

In: The Lancet, Vol. 390, No. 10111, 02.12.2017, p. 2461-2471.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2)

T2 - a randomised, double-blind, placebo-controlled, phase 3 trial

AU - Kang, Yoon Koo

AU - Boku, Narikazu

AU - Satoh, Taroh

AU - Ryu, Min Hee

AU - Chao, Yee

AU - Kato, Ken

AU - Chung, Hyun Cheol

AU - Chen, Jen Shi

AU - Muro, Kei

AU - Kang, Won Ki

AU - Yeh, Kun Huei

AU - Yoshikawa, Takaki

AU - Oh, Sang Cheul

AU - Bai, Li Yuan

AU - Tamura, Takao

AU - Lee, Keun Wook

AU - Hamamoto, Yasuo

AU - Kim, Jong Gwang

AU - Chin, Keisho

AU - Oh, Do Youn

AU - Minashi, Keiko

AU - Cho, Jae Yong

AU - Tsuda, Masahiro

AU - Chen, Li Tzong

PY - 2017/12/2

Y1 - 2017/12/2

N2 - Background Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0–1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343. Findings Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57–12·37) in the nivolumab group and 8·59 months (5·65–11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60–6·37) in the nivolumab group and 4·14 months (3·42–4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51–0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7–32·0) with nivolumab and 10·9% (6·2–17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed. Interpretation In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines. Funding Ono Pharmaceutical and Bristol-Myers Squibb.

AB - Background Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0–1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2:1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343. Findings Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n=330) or placebo (n=163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8·87 months (IQR 6·57–12·37) in the nivolumab group and 8·59 months (5·65–11·37) in the placebo group. Median overall survival was 5·26 months (95% CI 4·60–6·37) in the nivolumab group and 4·14 months (3·42–4·86) in the placebo group (hazard ratio 0·63, 95% CI 0·51–0·78; p<0·0001). 12-month overall survival rates were 26·2% (95% CI 20·7–32·0) with nivolumab and 10·9% (6·2–17·0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed. Interpretation In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines. Funding Ono Pharmaceutical and Bristol-Myers Squibb.

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