Nivolumab Plus Chemotherapy Versus Placebo Plus Chemotherapy in Korean Patients with HER2-Negative, Untreated, Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer: Subgroup Analysis of a Randomized, Multicenter, Double-Blind Phase 3 Trial (ATTRACTION-4)

Yoon-Koo Kang; Min-Hee Ryu; Do-Youn Oh; Sang Cheul Oh; Sun Young Rha; Keun-Wook Lee; Ik Joo Chung; Sung Yong Oh; Sun Jin Sym; Won Ki Kang; Jong Gwang Kim; Byoung Yong Shim; In-Ho Kim; Jin Young Kim; Eun-Kee Song; Hyo-Jin Lee; Seok Yun Kang; Dong-Hoe Koo; So Yeon Oh

doi:10.4143/crt.2024.913

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Original Article Nivolumab Plus Chemotherapy Versus Placebo Plus Chemotherapy in Korean Patients with HER2-Negative, Untreated, Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer: Subgroup Analysis of a Randomized, Multicenter, Double-Blind Phase 3 Trial (ATTRACTION-4): Yoon-Koo Kang¹, Min-Hee Ryu¹, Do-Youn Oh², Sang Cheul Oh³, Sun Young Rha⁴, Keun-Wook Lee⁵, Ik Joo Chung⁶, Sung Yong Oh⁷, Sun Jin Sym⁸, Won Ki Kang⁹, Jong Gwang Kim¹⁰, Byoung Yong Shim¹¹, In-Ho Kim¹², Jin Young Kim¹³, Eun-Kee Song¹⁴, Hyo-Jin Lee¹⁵, Seok Yun Kang¹⁶, Dong-Hoe Koo¹⁷, So Yeon Oh¹⁸; DOI: https://doi.org/10.4143/crt.2024.913
Published online: July 2, 2025

¹Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Department of Oncology, Seoul National University Hospital, Seoul, Korea

³Department of Hematology and Oncology, Korea University Guro Hospital, Seoul, Korea

⁴Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea

⁵Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

⁶Department of Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea

⁷Department of Oncology, Dong-A University College of Medicine, Busan, Korea

⁸Department of Oncology, Gachon University Gil Hospital, Incheon, Korea

⁹Department of Hematology and Oncology, Samsung Medical Center, Seoul, Korea

¹⁰Department of Oncology, Kyungpook National University Medical Center, Daegu, Korea

¹¹Division of Medical Oncology, Department of Internal Medicine, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea

¹²Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

¹³Department of Hematology and Oncology, Keimyung University Dongsan Medical Center, Daegu, Korea

¹⁴Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Korea

¹⁵Department of Oncology, Chungnam National University Hospital, Daejeon, Korea

¹⁶Department of Hematology-Oncology, Ajou University Hospital, Suwon, Korea

¹⁷Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

¹⁸Department of Oncology, Pusan National University Yangsan Hospital, Yangsan, Korea

Correspondence: Yoon-Koo Kang, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43 gil, Sonpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-3230 E-mail: ykkang@amc.seoul.kr

• Received: September 13, 2024 • Accepted: July 1, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
We report the safety and efficacy of nivolumab+chemotherapy for first-line treatment of advanced or recurrent gastric or gastroesophageal junction cancer in the Korean subpopulation of the ATTRACTION-4 clinical trial.
Materials and Methods
ATTRACTION-4 (NCT02746796) was a double-blind, randomized, placebo-controlled clinical trial of patients aged ≥ 20 years with histologically confirmed unresectable advanced or recurrent gastric or gastroesophageal junction cancer. Patients received nivolumab or placebo, both combined with physician-choice chemotherapy (oxaliplatin plus oral S-1 [tegafur–gimeracil–oteracil] [SOX] or oral capecitabine [CAPOX]).
Results
Overall, 464 patients were initially screened in Korea and 291 were randomized to nivolumab+chemotherapy (total/SOX/CAPOX: 148/66/82 patients) or placebo+chemotherapy (total/SOX/CAPOX: 143/61/82 patients). Centrally assessed progression-free survival (median, 14.75 vs. 8.34 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.39 to 0.73; p < 0.001), overall survival (19.7 vs. 14.9 months; HR, 0.78; 95% CI, 0.60 to 1.02; p=0.065), overall response rate (54.7% vs. 47.6%), and duration of response (16.03 vs. 9.86 months) favored nivolumab+chemotherapy vs. placebo+chemotherapy. Grade ≥ 3 treatment-related adverse events (TRAEs) (56.1% vs. 44.1%), and any-grade endocrine (9.5% vs. 4.2%), hepatic (23.0% vs. 14.7%), hypersensitivity and infusion reactions (15.5% vs. 7.0%), renal (4.1% vs. 0.7%), and skin (44.6% vs. 23.1%) TRAEs tended to be more frequent in the nivolumab+chemotherapy group.
Conclusion
These findings demonstrate the clinical benefit of nivolumab combined with chemotherapy (either SOX or CAPOX) for first-line treatment of gastric cancer/gastroesophageal junction cancer in Korean patients.
Key words: Capecitabine, Gastroesophageal junction cancer, Nivolumab, Oxaliplatin-based chemotherapy, S-1, Stomach neoplasms

Introduction

Gastric cancer is the fifth most commonly diagnosed cancer in the world and has particularly high incidence rates in Asian countries, such as South Korea (hereafter referred to as Korea) and Japan, compared with other countries [1,2]. In Korea, gastric cancer is the fourth most common cancer, and a recent study suggested that it accounted for 10.8% of patients with cancer [2-4]. In the last two decades, the 5-year survival rate of patients with gastric cancer in Korea increased from 68.4% in 2006-2010, to 75.9% in 2011-2015, and 78.0% in 2016-2020 [4], exceeding the survival times reported for patients in the United States (33.1%) and the United Kingdom (20.7%) in 2010-2014 [5]. The improved survival of patients with gastric cancer in Korea could be explained by the higher rates of early diagnosis due to a nationwide cancer screening program, which includes biannual gastroscopy from the age of > 40 years [6] and routine use of extensive lymph node dissection in patients with localized gastric cancer by experienced surgeons [7]. Despite these trends in improved survival, the 5-year overall survival rate (OS) remained low (approximately 10%) in patients with unresectable advanced gastric cancer, and the median OS times were approximately 1-2 years in clinical trials in Asian patients [8-13]. Although the prognosis of patients with human epidermal growth factor receptor 2 (HER2)–positive gastric cancer improved following the introduction of trastuzumab, there have been no marked changes in the treatment options for patients with HER2-negative unresectable gastric cancer until quite recently with the introduction of immunotherapies [14].

Nivolumab was the first immune checkpoint inhibitor (ICI) to be approved worldwide for the first-line treatment of unresectable advanced or recurrent gastric cancer/gastroesophageal junction cancer [15,16]. In Korea, nivolumab was approved in June 2021 [17] for use in combination with fluoropyrimidine and platinum-based chemotherapy. The primary clinical trials of nivolumab in this setting were CheckMate 649, which was conducted in 29 countries worldwide [18,19], and ATTRACTION-4, which was conducted in Korea, Japan, and Taiwan [20,21]. In CheckMate 649, patients were treated with nivolumab+chemotherapy (either capecitabine and oxaliplatin [XELOX/CAPOX] or fluorouracil, leucovorin, and oxaliplatin [FOLFOX]) or with chemotherapy alone. In ATTRACTION-4, patients were treated with nivolumab+chemotherapy (either CAPOX or oxaliplatin+oral S-1 [tegafur‒gimeracil‒oteracil] [SOX]) or placebo+chemotherapy. Results of the initial analysis [21] and a 3-year follow-up [20] for the overall study population have been published.

Both studies demonstrated significant improvements in progression-free survival (PFS) in the respective nivolumab+chemotherapy groups, and CheckMate 649 revealed a significant improvement in OS in the nivolumab+chemotherapy group compared with the chemotherapy group [18,19], whereas no difference in OS was observed between the two groups in ATTRACTION-4 [20,21]. These contrasting OS results might be due to differences in the subsequent anticancer treatments, since ICIs were commonly used post-progression in the placebo group in ATTRACTION-4. In stratified analyses of ATTRACTION-4, there were signs that PFS and OS were more favorable in Korean patients treated with nivolumab+chemotherapy than in those treated with placebo+chemotherapy, relative to those observed in Japanese and Taiwanese patients [20,21].

To provide further insight into these findings in Korean patients, we performed post hoc analyses of 3-year follow-up data from ATTRACTION-4 to investigate the survival outcomes, tumor responses, and safety of nivolumab+chemotherapy versus placebo+chemotherapy in this group of patients. Results of the CheckMate 649 study were used as the basis for the approval of nivolumab+chemotherapy for unresectable advanced or recurrent gastric cancer/gastroesophageal junction cancer in Korea [17]. However, the study included limited patients in Korea. Therefore, these subanalyses of the ATTRACTION-4 study were intended to provide reference data for the outcomes of nivolumab+chemotherapy for these cancer types in Korean patients.

Materials and Methods

1. Study design

ATTRACTION-4 was a combined Phase II/III, double-blind, randomized controlled clinical trial, the design of which is described in more detail in the prior publications [20,21]. The study was registered on ClinicalTrials.gov (NCT02746796). Briefly, patients aged ≥ 20 years with histologically confirmed unresectable advanced or recurrent gastric or gastroesophageal junction cancer were enrolled across 130 centers across Japan, Korea, and Taiwan and randomized 1:1 to receive either nivolumab or placebo, both in combination with oxaliplatin-based chemotherapy.

Patients in both groups received open-label chemotherapy, which comprised intravenous SOX or oral CAPOX. The chemotherapy regimen was selected by the investigator. After selection of the chemotherapy regimen, patients were randomized to the study groups using a web-based system with stratification by tumor cell programmed death-ligand 1 (PD-L1) expression (≥ 1% vs. < 1%/undetermined), Eastern Cooperative Oncology Group performance status (ECOG PS) (0 vs. 1), disease status (unresectable advanced vs. recurrent), and region (Japan vs. Korea or Taiwan). Treatments were to be continued until investigator-determined progressive disease (per Response Evaluation Criteria in Solid Tumor [RECIST] ver. 1.1 guidelines), unacceptable toxicity, or consent withdrawal. If either the investigational product (i.e. nivolumab or placebo) or chemotherapy were discontinued, the patient could continue the other treatment if they satisfied the criteria for continuation. Nivolumab or placebo could be continued following the first event of progressive disease at the investigator’s discretion, if the patient provided written informed consent to continue treatment. Dose reductions of chemotherapy were permitted, but the doses of nivolumab or placebo could not be reduced. Subsequent therapies were at the investigator’s discretion.

The study assessments and outcomes are described in more detail in the previous articles. The primary endpoints of the study were PFS (centrally assessed) and OS. Secondary endpoints included PFS (investigator assessed), investigator-assessed response rates (overall response rate [ORR] and disease control rate [DCR]), duration of response (DOR), and safety. Responses were evaluated according to RECIST ver. 1.1. ORR was determined as the sum of complete response (CR)+partial response (PR). DCR was calculated as the sum of CR+PR+stable disease.

2. Statistical analyses

We performed post hoc analyses of data for Korean patients enrolled in ATTRACTION-4, using data obtained through to the 3-year cutoff (data cutoff date: May 10, 2021). Statistical analyses are similar to those in the previous articles [20,21], using the intention-to-treat (ITT) population (all randomly assigned patients) for efficacy outcomes and the safety analysis set for safety data.

The Kaplan-Meier method was used to plot PFS, OS, and DOR and to determine the median survival times and median DOR. These survival outcomes were also compared using the stratified log-rank test with the stratification factors (tumor PD-L1 expression, ECOG PS, disease status, and geographical region). Stratified Cox proportional hazards model was used to determine hazard ratios (HR) with 95% confidence intervals (CIs). PFS, OS, and DOR were determined in all Korean patients according to treatment group (nivolumab+chemotherapy or placebo+chemotherapy) and in subgroups according to the treatment group and chemotherapy regimen (i.e. SOX or CAPOX). Investigator-assessed tumor responses were also evaluated for 3-year survivors and non-3-year survivors in both treatment groups.

Safety was assessed in terms of adverse events (AEs) and treatment-related adverse events (TRAEs), as in the previous articles. We also report the incidences of select TRAEs (endocrine, gastrointestinal, hepatic, hypersensitivity and infusion reactions, pulmonary, renal, and skin). AEs and TRAEs were determined in all Korean patients according to treatment group and the type of chemotherapy used.

3. Data availability

Qualified researchers may request Ono Pharmaceutical to disclose individual patient-level data from clinical studies through the following website: https://www.clinicalstudydatarequest.com/. For more information on Ono Pharmaceutical’s Policy for the Disclosure of Clinical Study Data, please see the following website: https://www.ono-pharma.com/en/company/policies/clinical_trial_data_transparency_policy.html.

Results

1. Patients

A total of 464 patients were initially screened in Korea, of which 291 were randomized to either nivolumab+chemotherapy (148 patients) or placebo+chemotherapy (143 patients), all of whom received the assigned treatment and were included in the ITT and safety analysis populations (Fig. 1). Treatment was discontinued by 139 patients in the nivolumab+chemotherapy group and 140 in the placebo+chemotherapy group; the majority being due to disease progression. Patients were well balanced in both treatment groups (Table 1). The chemotherapy regimen was SOX and CAPOX in 66 and 82 patients, respectively, in the nivolumab+chemotherapy group, and in 61 and 82 patients, respectively, in the placebo+chemotherapy group.

2. Progression-free survival

Centrally assessed PFS was longer in the nivolumab+chemotherapy group than in the placebo+chemotherapy group, with median PFS of 14.75 vs. 8.34 months (HR, 0.53; 95% CI, 0.39 to 0.73; p < 0.001) (Fig. 2A). The 1-, 2-, and 3-year PFS rates were greater in the nivolumab+chemotherapy group (53.4%, 33.4%, and 31.8%, respectively) compared with the placebo+chemotherapy group (32.3%, 18.7%, and 11.5%, respectively). In the overall study population (Fig. 2B) [20], the median PFS was significantly longer in the nivolumab+chemotherapy group compared with the placebo+chemotherapy group (10.94 vs. 8.48 months; HR, 0.67; 95% CI, 0.55 to 0.82; p < 0.001). Interestingly, the median PFS was numerically longer in the Korean population than in the overall population in the nivolumab+chemotherapy groups, but was numerically similar between the Korean population and the overall population in the placebo+chemotherapy groups.

PFS was also compared between nivolumab and placebo according to the chemotherapy regimen used. The median PFS was prolonged when nivolumab was used in combination with SOX (14.75 vs. 9.59 months; HR, 0.60; 95% CI, 0.37 to 0.99) (S1A Fig.) or with CAPOX (12.45 vs. 8.31 months; HR, 0.50; 95% CI, 0.33 to 0.75) (S1B Fig.).

Fig. 3 shows the forest plot analyses of PFS for all Korean patients, and S2 Fig. shows the results of subgroup analyses stratified by chemotherapy regimen. Supporting the Kaplan-Meier analysis and log-rank test, the forest plot indicated more favorable PFS in the nivolumab+chemotherapy group in nearly all of the subgroups assessed, including patients with tumor cell PD-L1 expression < 1% or indeterminate (Fig. 3). These trends were apparent when nivolumab was combined with either SOX or CAPOX (S2 Fig.).

3. Overall survival

As shown in Fig. 4A, median OS was numerically longer in the nivolumab+chemotherapy group than in the placebo+chemotherapy group, although this did not reach statistical significance (19.71 vs. 14.88 months; HR, 0.78; 95% CI, 0.60 to 1.02; p=0.065) (Fig. 4A). The 1-, 2-, and 3-year OS rates were also greater in the nivolumab+chemotherapy group (69.0%, 39.7%, and 25.1%, respectively) compared with the placebo+chemotherapy group (55.8%, 29.7%, and 18.6%, respectively). This differs from the overall study population, where the median OS was numerically similar between the two groups (17.45 vs. 17.15 months; HR, 0.89; 95% CI, 0.75 to 1.05; p=0.156) (Fig. 4B).

Among Korean patients treated with SOX, median OS was numerically greater in the nivolumab group (21.13 vs. 16.59 months; HR, 0.89; 95% CI, 0.59 to 1.34) (S3A Fig.), with numerically greater survival rates at 1 year (70.2% vs. 57.0%) and 2 years (39.0% vs. 35.6%), but not at 3 years (23.5% vs. 26.7%). When combined with CAPOX, nivolumab was also associated with more favorable median OS compared with placebo (17.41 vs. 14.65 months; HR, 0.71; 95% CI, 0.50 to 1.01) (S3B Fig.), with numerically greater OS rates at 1 year (68.1% vs. 54.9%), 2 years (40.3% vs. 25.5%), and 3 years (26.4% vs. 12.8%).

The forest plot analysis indicated more favorable OS in the following nivolumab+chemotherapy subgroups: age < 65 years (HR, 0.69; 95% CI, 0.50 to 0.94), males (HR, 0.72; 95% CI, 0.53 to 0.99), patients with an ECOG PS of 1 (HR, 0.71; 95% CI, 0.51 to 0.99), patients with no previous pharmacotherapy for cancer (HR, 0.34; 95% CI, 0.20 to 0.61), and patients with no peritoneal metastasis (HR, 0.60; 95% CI, 0.41 to 0.88) (Fig. 5). These trends did not differ between the chemotherapy regimens (S4 Fig.).

4. Response rates

The ORR was 54.7% in the nivolumab+chemotherapy group vs. 47.6% in the placebo+chemotherapy group (Table 2). Among patients treated with SOX, the ORR was comparable between the nivolumab and placebo groups (53.0% vs. 52.5%). However, among patients treated with CAPOX, the ORR was numerically greater in the nivolumab group (56.1% vs. 43.9%). The DCR and median time to response were comparable between the nivolumab+chemotherapy and placebo+chemotherapy groups, regardless of whether SOX or CAPOX were used. As shown in S5 Table, the investigator-assessed ORR was more favorable in the nivolumab+chemotherapy group (61.5% vs. 46.9%).

We also compared the ORR and DCR among 3-year survivors and non-3-year survivors. As shown in S5 Table, the ORR was numerically greater among 3-year survivors than in non-3-year survivors in the nivolumab+chemotherapy group (84.4% vs. 55.2%) and in the placebo+chemotherapy group (75.0% vs. 41.2%). DCR was also numerically greater in the 3-year survivors (nivolumab+chemotherapy: 100.0% vs. 78.4%; placebo+chemotherapy: 100.0% vs. 75.6%).

5. Duration of response

The median DOR was longer in the nivolumab+chemotherapy group than in the placebo+chemotherapy group (16.03 vs. 9.86 months) (Fig. 6). When divided by the chemotherapy regimen, the median DOR tended to be more favorable in the nivolumab group than in the placebo group, in the SOX (16.66 vs. 9.46 months) (S6A Fig.) and CAPOX (14.16 vs. 9.89 months) (S6B Fig.) subgroups.

6. Safety

Table 3 shows the incidence of AEs, TRAEs, and selected TRAEs in the nivolumab+chemotherapy and placebo+chemotherapy groups. AEs and TRAEs occurred in most (≥ 94%) of patients in both groups. Grade ≥ 3 TRAEs occurred in 56.1% of patients in the nivolumab+chemotherapy group and in 44.1% of patients in the placebo+chemotherapy group. Grade 5 TRAEs occurred in one patient in each group (one case of hepatic failure in the nivolumab+chemotherapy group and one case of hemolytic anemia in the placebo+chemotherapy group). Endocrine (9.5% vs. 4.2%), hepatic (23.0% vs. 14.7%), hypersensitivity and infusion reactions (15.5% vs. 7.0%), renal (4.1% vs. 0.7%), and skin (44.6% vs. 23.1%) TRAEs tended to be more frequent in the nivolumab+chemotherapy group than in the placebo+chemotherapy group. AEs and TRAEs according to the chemotherapy regimen are shown in S7 Table for the nivolumab group and S8 Table for the placebo group. The incidence of AEs and TRAEs tended to be slightly higher among patients treated with SOX than in those treated with CAPOX.

7. Subsequent therapies

Subsequent therapies in the nivolumab+chemotherapy and placebo+chemotherapy groups consisted of radiotherapy (13.5% vs. 8.4%), surgery (10.1% vs. 6.3%), anticancer drugs (54.7% vs. 55.9%), and ICIs (8.1% vs. 11.2%) (S9 Table).

Discussion

This post hoc analysis of the Korean population of patients enrolled in ATTRACTION-4 revealed that nivolumab+chemotherapy tended to improve both PFS and OS compared with placebo in all randomly assigned patients, regardless of tumor cell PD-L1 expression, and had a tolerable safety profile. Interestingly, we observed more favorable OS in the nivolumab+chemotherapy group in the Korean population than in the overall population. Nivolumab+chemotherapy was also associated with more favorable DOR and ORR (CR+PR) compared with placebo+chemotherapy. These benefits were generally observed when nivolumab was combined with either SOX or CAPOX. Overall, these findings demonstrate the clinical benefit of first-line nivolumab+chemotherapy in Korean patients with previously untreated gastric cancer or gastroesophageal junction cancer, supplementing the results in the overall ATTRACTION-4 population [20,21] and in CheckMate 649 [18,19]. The approval of nivolumab+chemotherapy in this setting in Korea was based on results of CheckMate 649, which enrolled relatively few patients in this country; our study provides further evidence supporting the effectiveness and safety of this regimen in Korean patients with previously untreated gastric cancer or gastroesophageal junction cancer.

We should acknowledge that median OS in the placebo+chemotherapy group was numerically shorter in the Korean patients (14.9 months) than in the overall population (17.15 months) [20]. One possible reason might be the greater use of subsequent therapies, especially other drugs (69.6%) and ICIs (32.7%), in the overall population than in Korean patients (55.9% and 11.2%, respectively) [20]. However, this may not explain the difference in median OS in the nivolumab+chemotherapy group between the Korean and overall populations (19.7 vs. 17.45 months) since smaller proportions of Korean patients were subsequently treated with other drugs (54.7% vs. 67.1%) or ICIs (8.1% vs. 13.1%) [20]. We speculate that the longer OS in the nivolumab+chemotherapy group in the Korean population could be driven by the longer PFS (14.75 vs. 10.45 months in the overall population). Additionally, Korea has many large hospitals, with small differences in the clinical practices between facilities, which may have an impact on the overall care of patients. Considering the favorable, but non-statistically significant, difference in the HR for OS between the two treatment groups in the Korean population, we wonder whether a larger sample size would have led to a more meaningful clinical or statistical difference. However, the reason cannot be fully ascertained from the current data, and further investigation may be necessary.

The chemotherapy regimens were CAPOX (referred to as XELOX) or FOLFOX in CheckMate 649 versus CAPOX or SOX in ATTRACTION-4. SOX is a chemotherapy regimen comprising intravenous oxaliplatin plus oral S-1 that is available as first-line palliative systematic treatment for HER2-negative gastric cancer in East Asian countries [22-24]. In stratified analyses by chemotherapy regimen, the median OS was prolonged in both the nivolumab+SOX (21.13 vs. 16.59 months) and nivolumab+CAPOX (17.41 vs. 14.65 months) subgroups compared with the corresponding placebo subgroups. Although the median OS values tended to be longest in the nivolumab+SOX subgroup, the HR was 0.71 (95% CI, 0.50 to 1.01) for nivolumab+CAPOX and 0.89 (95% CI, 0.59 to 1.34) for nivolumab+SOX. The reason why the nivolumab+SOX subgroup had a longer median OS but weaker HR compared with the nivolumab+CAPOX subgroup is unclear.

We also examined the safety of nivolumab+chemotherapy in Korean patients. The incidence of TRAEs in Korean patients was similar to that in the overall population. Some categories of select TRAEs tended to be more frequent in the nivolumab+chemotherapy group than in the placebo+chemotherapy group, including skin (44.6% vs. 23.1%), hepatic (23.0% vs. 14.7%), hypersensitivity and infusion reactions (15.5% vs. 7.0%), and endocrine (9.5% vs. 4.2%) TRAEs. In Korean patients, the findings were generally consistent with those of the overall study population [20,21] and the findings reported in CheckMate 649 [18,19]. We found that the frequencies of grade 3-4 TRAEs, serious TRAEs, and selected TRAEs (endocrine, gastrointestinal, and hepatic) were numerically greater in the nivolumab+SOX group than in the nivolumab+CAPOX group. Although the reason for this is unclear, the greater frequencies may be related to the S-1 and its constituents. Nevertheless, the types and frequencies of TRAEs in the nivolumab+SOX and nivolumab+CAPOX groups were generally similar to those of the corresponding placebo groups.

1. Limitations

Limitations of ATTRACTION-4 are described in more detail in the previous publications [20,21,25]. Particular limitations that warrant discussion are that the current analysis was conducted in a post hoc manner, and the study was not specifically powered for the present analyses. Furthermore, the comparisons between the Korean population and the overall population should be interpreted cautiously because Korean patients accounted for ~40% of the overall population. Additionally, OS may be influenced by post-progression treatments, including the use of other drugs and ICIs, and these treatments were not considered in the analyses of OS.

2. Conclusions

Overall, these findings demonstrate the clinical benefit, albeit with an increased risk of side effects, of nivolumab+chemotherapy as first-line treatment of gastric cancer/gastroesophageal junction cancer in Korean patients. Although OS tended to be longer in the Korean patients than in the overall ATTRACTION-4 study, the reason remains unclear. This clinical benefit of nivolumab was apparent when it was combined with either SOX or CAPOX. Thus, nivolumab combined with SOX or CAPOX represents a clinically effective first-line treatment option for HER2-negative, untreated, unresectable advanced or recurrent gastric or gastroesophageal junction cancer. The current findings could be useful as a reference when using nivolumab+chemotherapy to treat these types of cancer in Korean patients in actual clinical practice.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

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NOTES

Ethical Statement

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. This study was reviewed and approved by the Institutional Review Board and Ethics Committee of the National Cancer Center Hospital (approval number: T4293) and the local committees of all other participating centers. All patients provided written informed consent prior to enrollment.

Author Contributions

Conceived and designed the analysis: Kang YK.

Collected the data: Kang YK, Ryu MH, Oh DY, Oh SC, Rha SY, Lee KW, Chung IJ, Oh SY (Sung Yong Oh), Sym SJ, Kang WK, Kim JG, Shim BY, Kim IH, Kim JY, Song EK, Lee HJ, Kang SY, Koo DH, Oh SY (So Yeon Oh).

Contributed data or analysis tools: Kang YK.

Performed the analysis: Kang YK.

Wrote the paper: Kang YK.

Reviewed the paper: Kang YK, Ryu MH, Oh DY, Oh SC, Rha SY, Lee KW, Chung IJ, Oh SY (Sung Yong Oh), Sym SJ, Kang WK, Kim JG, Shim BY, Kim IH, Kim JY, Song EK, Lee HJ, Kang SY, Koo DH, Oh SY (So Yeon Oh).

Conflicts of Interest

All authors reported research funding to their institution from Ono Pharmaceutical in relation to this manuscript. Byoung Yong Shim also reported grants from Yuhan; consulting fees from Takeda, AstraZeneca, BMS, and Pfizer; payments or honoraria from Pfizer and Yuhan; and participation on data safety monitoring boards or advisory boards for Guardant, Takeda, and Roche. Do-Youn Oh also reported grants or contracts from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok; and participation on data safety monitoring or advisory boards for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, AbbVie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, and Idience. Keun-Wook Lee also reported research funding to his institution for conducting clinical trials from MSD, AstraZeneca, Roche, Merck KGaA, BeiGene, Astellas Pharma, Amgen, Daiichi Sankyo, ALX Oncology, Leap Therapeutics, GlaxoSmithKline, Macrogenics, Taiho Pharmaceutical, Seagen, Y-BIOLOGICS, Bolt Biotherapeutics, Trishula Therapeutics, InventisBio, MedPacto, Ildong Pharmaceutical, Genome & Company, Arcus Biosciences, Elevar Therapeutics, Jazz Pharmaceuticals, TRIO Oncology, Exelixis, IgM Biosciences, Panolos Bioscience, Metafines, Wellmarker Bio, Medicenna, and Erasca; consulting fees from Daiichi Sankyo, MSD, Astellas Pharma, AbbVie, and Metafines; honoraria for lectures or presentations from Sanofi/Aventis, Astellas Pharma, Bayer, Daiichi Sankyo, and Merck KGaA; and an uncompensated relationship with ALX Oncology for participation on a data safety monitoring or advisory board. Min-Hee Ryu also reported grants or contracts from AstraZeneca; consulting fees from BMS, Ono Pharmaceutical, Novartis, Daiichi Sankyo, AstraZeneca, Lilly, MSD, Taiho, and Dae-Hwa Pharmaceutical; and payments or honoraria from BMS, Ono Pharmaceutical, Novartis, Daiichi Sankyo, AstraZeneca, Lilly, MSD, Astellas, Taiho, and Dae-Hwa Pharmaceutical. Sun Young Rha also reported grants or contracts from Amgen, Merck, BMS, MSD, Lilly, Daiichi Sankyo, BeiGene, Eisai, and AstraZeneca; payments or honoraria from Amgen, Astellas, BMS, MSD, Eisai, and Daiichi Sankyo; participation on data safety monitoring or advisory boards for Amgen, MSD, BMS, Merck, Indivumed, BeiGene, Eisai, and Daiichi Sankyo. Yoon-Koo Kang also declared medical writing support and study funding from Astellas Pharma and consulting fees from Amgen, Novartis, Roche, Daehwa, Zymeworks, Blueprint, Surface Oncology, ALX Oncology, Macrogenics, BMS, Merck, and Liscure. Dong-Hoe Koo, Eun-Kee Song, Hyo Jin Lee, Ik-Joo Chung, In-Ho Kim, Jin Young Kim, Jong Gwang Kim, Sang Cheul Oh, Seok Yun Kang, So Yeon Oh, Sun Jin Sym, Sung Yong Oh, and Won Ki Kang had no additional disclosures to declare.

Funding

This study was funded by Ono Pharmaceutical Co., Ltd. and BristolMyers Squibb K.K. The authors thank Nicholas D. Smith (LESPEDEZA, a division of EMC K.K.) for medical writing support, which was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb K.K.

Fig. 1.

Disposition of patients enrolled in Korea. ITT, intention-to-treat. ^a)Multiple reasons may apply.

Fig. 2.

Centrally assessed progression-free survival (PFS) in the Korean population (A) and the overall study population (B). CI, confidence interval; HR, hazard ratio. Fig. 2B was modified under a CC-BY 4.0 license from Boku et al. Gastric Cancer. 2024;27:1287-301 [20].

Fig. 3.

Forest plot of progression-free survival (PFS) in the Korean population. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NR, not reached; PD-L1, programmed death ligand 1.

Fig. 4.

Overall survival (OS) in the Korean population (A) and the overall study population (B). CI, confidence interval; HR, hazard ratio. Fig. 4B was modified under a CC-BY 4.0 license from Boku et al. Gastric Cancer 2024;27:1287-301 [20].

Fig. 5.

Forest plot of overall survival (OS) in the Korean population. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NR, not reached; PD-L1, programmed death ligand 1.

Fig. 6.

Duration of response (DOR) in the Korean population. CI, confidence interval; NR, not reached.

Table 1.

Patient characteristics

	Nivolumab+chemotherapy			Placebo+chemotherapy
	All patients	SOX	CAPOX	All patients	SOX	CAPOX
No.	148	66	82	143	61	82
Age (yr), median (range)	57.0 (27-86)	58.5 (34-86)	56.5 (27-78)	58.0 (29-80)	58.0 (30-80)	60.0 (29-77)
Sex
Male	101 (68.2)	51 (77.3)	50 (61.0)	111 (77.6)	48 (78.7)	63 (76.8)
Female	47 (31.8)	15 (22.7)	32 (39.0)	32 (22.4)	13 (21.3)	19 (23.2)
ECOG PS
0	51 (34.5)	21 (31.8)	30 (36.6)	50 (35.0)	18 (29.5)	32 (39.0)
1	97 (65.5)	45 (68.2)	52 (63.4)	93 (65.0)	43 (70.5)	50 (61.0)
Disease status
Advanced	105 (70.9)	40 (60.6)	65 (79.3)	100 (69.9)	37 (60.7)	63 (76.8)
Recurrent	43 (29.1)	26 (39.4)	17 (20.7)	43 (30.1)	24 (39.3)	19 (23.2)
Perioperative chemotherapy, yes	37 (25.0)	20 (30.3)	17 (20.7)	36 (25.2)	24 (39.3)	12 (14.6)
No. of organs with metastases
≤ 1	48 (32.4)	23 (34.8)	25 (30.5)	40 (28.0)	21 (34.4)	19 (23.2)
≥ 2	100 (67.6)	43 (65.2)	57 (69.5)	103 (72.0)	40 (65.6)	63 (76.8)
Histologic type
Intestinal	56 (37.8)	23 (34.8)	33 (40.2)	61 (42.7)	33 (54.1)	28 (34.1)
Diffuse	80 (54.1)	35 (53.0)	45 (54.9)	65 (45.5)	20 (32.8)	45 (54.9)
Other	6 (4.1)	4 (6.1)	2 (2.4)	7 (4.9)	4 (6.6)	3 (3.7)
Unknown	6 (4.1)	4 (6.1)	2 (2.4)	10 (7.0)	4 (6.6)	6 (7.3)
Tumor cell PD-L1 expression (%)
< 1	122 (82.4)	56 (84.8)	66 (80.5)	121 (84.6)	55 (90.2)	66 (80.5)
≥ 1	26 (17.6)	10 (15.2)	16 (19.5)	22 (15.4)	6 (9.8)	16 (19.5)
Chemotherapy regimen
SOX	66 (44.6)	66 (100)	-	61 (42.7)	61 (100)	-
CAPOX	82 (55.4)	-	82 (100)	82 (57.3)	-	82 (100)

Values are number (%) unless otherwise stated. CAPOX, capecitabine plus oxaliplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death ligand 1; SOX, S-1 (tegafur–gimeracil–oteracil potassium) plus oxaliplatin.

Table 2.

Objective response rates (centrally assessed)

	Nivolumab+chemotherapy			Placebo+chemotherapy
	All patients	SOX	CAPOX	All patients	SOX	CAPOX
No.	148	66	82	143	61	82
ORR (CR+PR)	81 (54.7)	35 (53.0)	46 (56.1)	68 (47.6)	32 (52.5)	36 (43.9)
95% CI	46.3-62.9	40.3-65.4	44.7-67.0	39.1-56.1	39.3-65.4	33.0-55.3
Best overall response
CR	31 (20.9)	16 (24.2)	15 (18.3)	26 (18.2)	13 (21.3)	13 (15.9)
PR	50 (33.8)	19 (28.8)	31 (37.8)	42 (29.4)	19 (31.1)	23 (28.0)
SD	20 (13.5)	14 (21.2)	6 (7.3)	26 (18.2)	12 (19.7)	14 (17.1)
PD	8 (5.4)	2 (3.0)	6 (7.3)	22 (15.4)	5 (8.2)	17 (20.7)
NE	39 (26.4)	15 (22.7)	24 (29.3)	27 (18.9)	12 (19.7)	15 (18.3)
DCR (CR+PR+SD)	101 (68.2)	49 (74.2)	52 (63.4)	94 (65.7)	44 (72.1)	50 (61.0)
95% CI	60.1-75.6	62.0-84.2	52.0-73.8	57.3-73.5	59.2-82.9	49.6-71.6
TTR (mo), median (range)	1.4 (1.0-5.8)	1.4 (1.0-5.8)	1.3 (1.2-5.4)	1.3 (1.1-8.3)	1.3 (1.1-8.3)	1.3 (1.1-5.6)

Values are presented as number (%) unless otherwise stated. CAPOX, capecitabine plus oxaliplatin; CI, confidence interval; CR, complete response; DCR, disease-control rate; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; SOX, S-1 (tegafur–gimeracil–oteracil potassium) plus oxaliplatin; TTR, time to response.

Table 3.

Comparison of AEs between nivolumab plus chemotherapy and placebo plus chemotherapy

	Nivolumab+chemotherapy (n=148)			Placebo+chemotherapy (n=143)
	Any grade	Grade 3-4	Grade 5	Any grade	Grade 3-4	Grade 5
AEs
Any AEs	147 (99.3)	106 (71.6)	5 (3.4)	142 (99.3)	91 (63.6)	5 (3.5)
Serious AEs	56 (37.8)	44 (29.7)	5 (3.4)	55 (38.5)	39 (27.3)	5 (3.5)
AEs leading to discontinuation^a)	15 (10.1)	7 (4.7)	2 (1.4)	12 (8.4)	4 (2.8)	3 (2.1)
AEs leading to dose delay or reduction^b)	119 (80.4)	78 (52.7)	3 (2.0)	116 (81.1)	66 (46.2)	1 (0.7)
TRAEs
Any TRAEs	142 (95.9)	82 (55.4)	1 (0.7)	135 (94.4)	62 (43.4)	1 (0.7)
Serious TRAEs	26 (17.6)	21 (14.2)	1 (0.7)	12 (8.4)	5 (3.5)	1 (0.7)
TRAEs leading to discontinuation^a)	8 (5.4)	2 (1.4)	1 (0.7)	4 (2.8)	1 (0.7)	1 (0.7)
TRAEs leading to dose delay or reduction^b)	115 (77.7)	67 (45.3)	0	101 (70.6)	49 (34.3)	0
Selected TRAEs
Endocrine	14 (9.5)	4 (2.7)	0	6 (4.2)	0	0
Gastrointestinal	37 (25.0)	5 (3.4)	0	38 (26.6)	3 (2.1)	0
Hepatic	34 (23.0)	6 (4.1)	1 (0.7)	21 (14.7)	5 (3.5)	0
Hypersensitivity and infusion reactions	23 (15.5)	5 (3.4)	0	10 (7.0)	2 (1.4)	0
Pulmonary	3 (2.0)	1 (0.7)	0	0	0	0
Renal	6 (4.1)	0	0	1 (0.7)	0	0
Skin	66 (44.6)	10 (6.8)	0	33 (23.1)	1 (0.7)	0

Values are presented as number (%). AE, adverse event; TRAE, treatment-related adverse event.

^a) AEs/TRAEs that led to discontinuation of study treatment due to the discontinuation of at least one medication (nivolumab, placebo, oxaliplatin, capecitabine, or tegafur–gimeracil–oteracil [S-1]),

^b) AEs/TRAEs that led to delayed administration or a reduction in the dose of at least one medication (nivolumab, placebo, oxaliplatin, capecitabine, or tegafur–gimeracil–oteracil [S-1]).

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REFERENCES

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Nivolumab Plus Chemotherapy Versus Placebo Plus Chemotherapy in Korean Patients with HER2-Negative, Untreated, Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer: Subgroup Analysis of a Randomized, Multicenter, Double-Blind Phase 3 Trial (ATTRACTION-4)

DOI: https://doi.org/10.4143/crt.2024.913

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Fig. 1. Disposition of patients enrolled in Korea. ITT, intention-to-treat. a)Multiple reasons may apply.

Fig. 2. Centrally assessed progression-free survival (PFS) in the Korean population (A) and the overall study population (B). CI, confidence interval; HR, hazard ratio. Fig. 2B was modified under a CC-BY 4.0 license from Boku et al. Gastric Cancer. 2024;27:1287-301 [20].

Fig. 3. Forest plot of progression-free survival (PFS) in the Korean population. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NR, not reached; PD-L1, programmed death ligand 1.

Fig. 4. Overall survival (OS) in the Korean population (A) and the overall study population (B). CI, confidence interval; HR, hazard ratio. Fig. 4B was modified under a CC-BY 4.0 license from Boku et al. Gastric Cancer 2024;27:1287-301 [20].

Fig. 5. Forest plot of overall survival (OS) in the Korean population. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NR, not reached; PD-L1, programmed death ligand 1.

Fig. 6. Duration of response (DOR) in the Korean population. CI, confidence interval; NR, not reached.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

	Nivolumab+chemotherapy			Placebo+chemotherapy
	All patients	SOX	CAPOX	All patients	SOX	CAPOX
No.	148	66	82	143	61	82
Age (yr), median (range)	57.0 (27-86)	58.5 (34-86)	56.5 (27-78)	58.0 (29-80)	58.0 (30-80)	60.0 (29-77)
Sex
Male	101 (68.2)	51 (77.3)	50 (61.0)	111 (77.6)	48 (78.7)	63 (76.8)
Female	47 (31.8)	15 (22.7)	32 (39.0)	32 (22.4)	13 (21.3)	19 (23.2)
ECOG PS
0	51 (34.5)	21 (31.8)	30 (36.6)	50 (35.0)	18 (29.5)	32 (39.0)
1	97 (65.5)	45 (68.2)	52 (63.4)	93 (65.0)	43 (70.5)	50 (61.0)
Disease status
Advanced	105 (70.9)	40 (60.6)	65 (79.3)	100 (69.9)	37 (60.7)	63 (76.8)
Recurrent	43 (29.1)	26 (39.4)	17 (20.7)	43 (30.1)	24 (39.3)	19 (23.2)
Perioperative chemotherapy, yes	37 (25.0)	20 (30.3)	17 (20.7)	36 (25.2)	24 (39.3)	12 (14.6)
No. of organs with metastases
≤ 1	48 (32.4)	23 (34.8)	25 (30.5)	40 (28.0)	21 (34.4)	19 (23.2)
≥ 2	100 (67.6)	43 (65.2)	57 (69.5)	103 (72.0)	40 (65.6)	63 (76.8)
Histologic type
Intestinal	56 (37.8)	23 (34.8)	33 (40.2)	61 (42.7)	33 (54.1)	28 (34.1)
Diffuse	80 (54.1)	35 (53.0)	45 (54.9)	65 (45.5)	20 (32.8)	45 (54.9)
Other	6 (4.1)	4 (6.1)	2 (2.4)	7 (4.9)	4 (6.6)	3 (3.7)
Unknown	6 (4.1)	4 (6.1)	2 (2.4)	10 (7.0)	4 (6.6)	6 (7.3)
Tumor cell PD-L1 expression (%)
< 1	122 (82.4)	56 (84.8)	66 (80.5)	121 (84.6)	55 (90.2)	66 (80.5)
≥ 1	26 (17.6)	10 (15.2)	16 (19.5)	22 (15.4)	6 (9.8)	16 (19.5)
Chemotherapy regimen
SOX	66 (44.6)	66 (100)	-	61 (42.7)	61 (100)	-
CAPOX	82 (55.4)	-	82 (100)	82 (57.3)	-	82 (100)

	Nivolumab+chemotherapy			Placebo+chemotherapy
	All patients	SOX	CAPOX	All patients	SOX	CAPOX
No.	148	66	82	143	61	82
ORR (CR+PR)	81 (54.7)	35 (53.0)	46 (56.1)	68 (47.6)	32 (52.5)	36 (43.9)
95% CI	46.3-62.9	40.3-65.4	44.7-67.0	39.1-56.1	39.3-65.4	33.0-55.3
Best overall response
CR	31 (20.9)	16 (24.2)	15 (18.3)	26 (18.2)	13 (21.3)	13 (15.9)
PR	50 (33.8)	19 (28.8)	31 (37.8)	42 (29.4)	19 (31.1)	23 (28.0)
SD	20 (13.5)	14 (21.2)	6 (7.3)	26 (18.2)	12 (19.7)	14 (17.1)
PD	8 (5.4)	2 (3.0)	6 (7.3)	22 (15.4)	5 (8.2)	17 (20.7)
NE	39 (26.4)	15 (22.7)	24 (29.3)	27 (18.9)	12 (19.7)	15 (18.3)
DCR (CR+PR+SD)	101 (68.2)	49 (74.2)	52 (63.4)	94 (65.7)	44 (72.1)	50 (61.0)
95% CI	60.1-75.6	62.0-84.2	52.0-73.8	57.3-73.5	59.2-82.9	49.6-71.6
TTR (mo), median (range)	1.4 (1.0-5.8)	1.4 (1.0-5.8)	1.3 (1.2-5.4)	1.3 (1.1-8.3)	1.3 (1.1-8.3)	1.3 (1.1-5.6)

	Nivolumab+chemotherapy (n=148)			Placebo+chemotherapy (n=143)
	Any grade	Grade 3-4	Grade 5	Any grade	Grade 3-4	Grade 5
AEs
Any AEs	147 (99.3)	106 (71.6)	5 (3.4)	142 (99.3)	91 (63.6)	5 (3.5)
Serious AEs	56 (37.8)	44 (29.7)	5 (3.4)	55 (38.5)	39 (27.3)	5 (3.5)
AEs leading to discontinuation^a)	15 (10.1)	7 (4.7)	2 (1.4)	12 (8.4)	4 (2.8)	3 (2.1)
AEs leading to dose delay or reduction^b)	119 (80.4)	78 (52.7)	3 (2.0)	116 (81.1)	66 (46.2)	1 (0.7)
TRAEs
Any TRAEs	142 (95.9)	82 (55.4)	1 (0.7)	135 (94.4)	62 (43.4)	1 (0.7)
Serious TRAEs	26 (17.6)	21 (14.2)	1 (0.7)	12 (8.4)	5 (3.5)	1 (0.7)
TRAEs leading to discontinuation^a)	8 (5.4)	2 (1.4)	1 (0.7)	4 (2.8)	1 (0.7)	1 (0.7)
TRAEs leading to dose delay or reduction^b)	115 (77.7)	67 (45.3)	0	101 (70.6)	49 (34.3)	0
Selected TRAEs
Endocrine	14 (9.5)	4 (2.7)	0	6 (4.2)	0	0
Gastrointestinal	37 (25.0)	5 (3.4)	0	38 (26.6)	3 (2.1)	0
Hepatic	34 (23.0)	6 (4.1)	1 (0.7)	21 (14.7)	5 (3.5)	0
Hypersensitivity and infusion reactions	23 (15.5)	5 (3.4)	0	10 (7.0)	2 (1.4)	0
Pulmonary	3 (2.0)	1 (0.7)	0	0	0	0
Renal	6 (4.1)	0	0	1 (0.7)	0	0
Skin	66 (44.6)	10 (6.8)	0	33 (23.1)	1 (0.7)	0

Table 1. Patient characteristics

Table 2. Objective response rates (centrally assessed)

Table 3. Comparison of AEs between nivolumab plus chemotherapy and placebo plus chemotherapy

Values are presented as number (%). AE, adverse event; TRAE, treatment-related adverse event.

AEs/TRAEs that led to discontinuation of study treatment due to the discontinuation of at least one medication (nivolumab, placebo, oxaliplatin, capecitabine, or tegafur–gimeracil–oteracil [S-1]),

AEs/TRAEs that led to delayed administration or a reduction in the dose of at least one medication (nivolumab, placebo, oxaliplatin, capecitabine, or tegafur–gimeracil–oteracil [S-1]).