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Safety and efficacy of pembrolizumab in combination with S-1 plus oxaliplatin as a first-line treatment in patients with advanced gastric/gastroesophageal junction cancer: Cohort 1 data from the KEYNOTE-659 phase IIb study
Corresponding author: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwa, Chiba, 277-8577, Japan. Fax: +81 47 134 6928.
This study was conducted for gastric/gastroesophageal junction (G/GEJ) cancer.
•
Efficacy and safety of S-1 + oxaliplatin (SOX) with pembrolizumab were assessed.
•
Overall response rate assessed by blinded independent central review was 72.2%.
•
No increase in treatment-related adverse events occurred with this combination.
•
First-line SOX with pembrolizumab warrants further evaluation for G/GEJ cancer.
Abstract
Aim
The KEYNOTE-659 study evaluated the efficacy and safety of pembrolizumab in combination with chemotherapy as the first-line treatment in Japanese patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer. In this paper, we report results from cohort 1 (S-1 plus oxaliplatin [SOX] with pembrolizumab).
Methods
This was a non-randomised, multicentre, open-label phase IIb study in patients with advanced programmed death-ligand 1 (PD-L1)-positive, human epidermal growth factor receptor 2-negative G/GEJ tumours. The primary endpoint was the objective response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses were performed based on the PD-L1 combined positive score (CPS) status.
Results
Fifty-four patients were evaluated. The median follow-up was 10.1 months. ORR and DCR by BICR were 72.2% (95% confidence interval [CI] 58.4–83.5) and 96.3% (95% CI 87.3–99.5), respectively. Median DOR, TTR, PFS and OS were as follows: not reached, 1.5 months, 9.4 months and not reached. The ORR was 73.9% in patients with CPS ≥1 to <10 and 71.0% in those with CPS ≥10. Grade ≥3 treatment-related adverse events (TRAEs) were reported by 57.4% of patients. The most common grade ≥3 TRAEs were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%).
Conclusions
SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of advanced G/GEJ cancer.
Gastric/gastroesophageal junction (G/GEJ) cancer is the fifth most common cause of new cancer cases and the third leading cause of cancer death worldwide [
]. Notably, G/GEJ cancer is more common in East Asia than in the United States or Europe; in Japan, G/GEJ cancer is the second most common cancer type and the third leading cause of cancer mortality [
Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO–ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2–positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC—a randomised phase III trial.
Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study.
Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial.
Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study.
]; to date, only trastuzumab has significantly improved overall survival of patients with human epidermal growth factor receptor 2 (HER2)-positive G/GEJ cancer [
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
]. Thus, further improvements in the treatment for advanced G/GEJ cancer are clearly needed.
Immune checkpoint inhibitors targeting programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) have shown promising activity in several types of malignancies. In patients with G/GEJ cancer, PD-L1 expression was identified in 8.4–17.3% of tumour cells and 34.5–65.3% of immune cells [
Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.
]. Therefore, the PD-1/PD-L1 pathway could play a critical role in tumour immune evasion for G/GEJ cancer, making it an attractive target for therapeutic intervention. Pembrolizumab, a humanised IgG4 monoclonal antibody against PD-1, demonstrated anti-tumour activity with an acceptable safety profile in phase II and III studies in patients with PD-L1-positive advanced G/GEJ cancer [
Pembrolizumab alone or in combination with chemotherapy as first line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.
Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study.
Several preclinical and clinical research studies suggested that anti-cancer agents can stimulate tumour-specific immune responses either by inducing the immunogenic death of tumour cells or by engaging immune effector mechanisms [
]. The addition of immune checkpoint inhibitors to standard chemotherapy has been demonstrated to improve overall survival (OS) in several cancer types [
Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
]. In the KEYNOTE-059 study, encouraging anti-tumour responses and manageable safety profile were suggested with pembrolizumab in combination with capecitabine or 5-fluorouracil plus cisplatin in patients with advanced G/GEJ cancer [
Pembrolizumab alone or in combination with chemotherapy as first line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.
Here, we report the efficacy results of pembrolizumab with S-1 plus oxaliplatin (SOX) in the phase IIb KEYNOTE-659 study to investigate pembrolizumab plus SOX or S-1 plus cisplatin (SP) as the first-line therapy in Japanese patients with advanced G/GEJ cancer.
2. Materials and methods
2.1 Study design and patients
KEYNOTE-659 (NCT03382600/JapicCTI-183829) was a non-randomised, multicentre, open-label phase IIb study to evaluate the efficacy and safety of SOX (cohort 1) or SP (cohort 2) with pembrolizumab, as first-line treatment in patients with advanced G/GEJ cancer which was PD-L1 positive and HER2-negative. PD-L1 expression was centrally assessed during screening using the PD-L1 IHC 22C3 pharm assay (Agilent, Santa Clara, CA, USA) [
Pembrolizumab alone or in combination with chemotherapy as first line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.
Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study.
]. PD-L1-positive was defined as a combined positive score of 1 or more (CPS ≥1), calculated as the number of PD-L1-positive cells (tumour cells, macrophages and lymphocytes) divided by the total number of tumour cells multiplied by 100.
In cohort 1, the key inclusion criteria were as follows: aged ≥18 to ≤75 years; histologically or cytologically confirmed advanced G/GEJ cancer and PD-L1-positive (CPS ≥1) status [
Pembrolizumab alone or in combination with chemotherapy as first line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.
Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study.
]; HER2 negative status; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; no previous chemotherapy; at least one measurable lesion assessed per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 by the investigator and adequate organ function. The key exclusion criteria were as follows: squamous cell or undifferentiated tumour type; radiotherapy within 14 days of enrolment; active autoimmune disease requiring systemic treatment in the past 2 years (excluding hormonal replacement therapy such as thyroxine, insulin or physiologic dose of corticosteroids for adrenal or pituitary insufficiency); history of non-infectious pneumonitis that required steroids or current pneumonitis; active infection requiring systemic therapy and grade ≥2 peripheral sensory neuropathy.
This study was approved by the institutional review board/independent ethics committee at each study centre (sites are listed in Supplementary Appendix A) and was conducted in accordance with International Conference on Harmonization Good Clinical Practice Guidelines and with the ethical principles outlined in the Declaration of Helsinki.
2.2 Treatment
Pembrolizumab 200 mg was administered as a 30-min intravenous (IV) infusion every 3 weeks. Oxaliplatin 130 mg/m2 was administered IV every 3 weeks. S-1 was given orally twice daily for the first 2 weeks of each 3-week cycle. The S-1 dose was 40 mg for body surface area (BSA) < 1.25 m2, 50 mg for BSA 1.25 to <1.5 m2 and 60 mg for BSA ≥1.5 m2. For each patient, pembrolizumab was administered first, followed sequentially by the oxaliplatin infusion and then S-1. SOX with pembrolizumab treatment was continued until progressive disease (PD), unacceptable toxicity or withdrawal of consent occurred or until patients had received 35 cycles of pembrolizumab. Patients who discontinued SOX or pembrolizumab could continue pembrolizumab monotherapy or SOX, respectively, if they had not met discontinuation criteria.
As prophylactic treatment against nausea and vomiting, patients were managed with palonosetron plus steroids; additionally, the use of (fos)aprepitant was also allowed. Additional details about the treatment protocol are provided in Supplementary Appendix B.
2.3 Assessment
Computed tomography was done every 6 weeks. The anti-tumour response was assessed according to RECIST version 1.1 by blinded independent central review (BICR) as well as by the investigator. Tumour imaging to confirm partial response (PR) or complete response (CR) was performed at least 4 weeks after the first evidence of response was observed. In clinically stable participants, PD was confirmed based on iRECIST between 4 and 8 weeks after the first PD [
]. Adverse events (AEs) were monitored until 30 days after the last dose of treatment (90 days for serious AEs and events of clinical interest) and graded by severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events version 4.0.
2.4 Study endpoints
The primary endpoint was the objective response rate (ORR) assessed by BICR. The secondary endpoints were duration of response (DOR), disease control rate (DCR), time to response (TTR) and progression-free survival (PFS) assessed by BICR, as well as OS, and safety. DOR was defined as the time from the date of first response (CR or PR) until the date at which PD was first documented or death occurred; TTR was defined as the time from the date of enrolment to the date at which CR or PR was first documented; PFS was defined as the time from the date of enrolment to the first documented PD or death due to any cause, whichever occurred first and OS was defined as the time from the date of enrolment to death due to any cause. Additionally, exploratory subgroup analyses by the PD-L1 CPS status were performed.
2.5 Statistical analysis
Planned sample size was 90 patients in total (45 in cohort 1 for SOX with pembrolizumab and 45 patients in cohort 2 for SP with pembrolizumab), considering 10% drop-off rate before treatment. Although there were no specific hypothesis to be tested, these sample sizes allowed the estimation of exact effect of pembrolizumab with SOX or SP based on the point estimate and 95% confidence interval (CI) according to the exact binomial method. For example, ORR was estimated as 70.0% with CI of 53.5–83.4% if 28 of 40 patients achieved objective response. The All Subjects as Treated (ASaT) population was used for all analyses; this consisted of all patients who received at least one dose of study treatment. DOR was calculated using ASaT patients who had a best response of CR or PR. For DOR, PFS, TTR and OS, the Kaplan–Meier method was used to estimate median value. SAS version 9.4 or later (SAS Institute, Cary, NC, USA) was used for statistical analyses.
3. Results
3.1 Patient characteristics
From April 2018 to September 2018, 54 patients were enroled at 18 centres in Japan and received study treatment (ASaT population). At the data cut-off date (June 21, 2019), 14 of 54 patients were still receiving study treatment and the median follow up time was 10.1 months. Table 1 shows the baseline patient characteristics. In total, 31 (57.4%) patients were defined as CPS ≥10.
Table 1Patient characteristics of cohort 1 (all subjects as treated; N = 54).
Characteristics
N = 54
Male
43 (79.6)
Age, median (years)
66 (32–75)
ECOG PS (screening phase)
0
46 (85.2)
1
8 (14.8)
Metastatic disease
No
5 (9.3)
Yes
49 (90.7)
Primary location
Gastric
46 (85.2)
Gastroesophageal junction
8 (14.8)
Histological type
Intestinal
21 (38.9)
Diffuse
32 (59.3)
Unknown
1 (1.9)
Number of metastatic sites (BICR)
<3
37 (68.5)
≥3
17 (31.5)
History of Surgery
No
49 (90.7)
Yes
5 (9.3)
CPS
<10
23 (42.6)
≥10
31 (57.4)
Values are indicated as n (%) unless otherwise stated.
The median number of pembrolizumab dose administered was 9 (range, 2–18). The median number of cycles in SOX was 6 (range, 2–13). The relative dose intensity was 89.4% for pembrolizumab, 59.8% for oxaliplatin and 72.7% for S-1, respectively. Thirty-five (64.8%) and 47 (87.0%) patients had a dose reduction of S-1 and oxaliplatin, respectively; for both agents, the most common reason for dose reduction was decreased neutrophil count. Forty patients discontinued study treatment and the reasons for that were PD in 35 patients, AEs in 2 patients (small intestine inflammation and pancreatitis/pancreatic pseudocyst) and surgery for curative intent in 2 patients. Of the 40 patients who discontinued study treatment, 30 patients (75%) received second-line treatments.
3.3 Efficacy
ORR and DCR assessed by BICR were 72.2% (95% CI 58.4–83.5) and 96.3% (95% CI 87.3–99.5), respectively (Table 2). Of the 54 patients who had a measurable lesion at baseline and at least one post-baseline tumour assessment, 52 (96.3%) experienced a decrease from baseline in the sum of their target lesions (Fig. 1A). In most patients, the tumour size decreased compared with the size in the first assessment and continued to decrease over time (Fig. 1B).
Table 2Anti-tumour responses of SOX with pembrolizumab assessed by BICR per RECIST v1.1 and duration of response (all subjects as treated; N = 54).
Category
N = 54
N (%)
95% CI
ORR
39 (72.2)
58.4–83.5
DCR
52 (96.3)
87.3–99.5
CR
2 (3.7)
–
PR
37 (68.5)
–
SD
13 (24.1)
–
PD
2 (3.7)
–
Median time to response, months
1.5
Median duration of response, months
Not reached (95% CI 5.6–not estimable)
Data cut-off: 21 June 2019.
BICR, blinded independent central review; CI, confidence interval; CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumours; SD, stable disease; SOX, S-1 plus oxaliplatin.
Fig. 1Overall tumour responses of SOX with pembrolizumab as assessed by BICR. (A) Best change from baseline in the sum of longest target lesion diameters in each patient. (B) Percent change in sum of longest diameters of target lesion from baseline in each patient. BICR, blinded independent central review; CPS, combined positive score; SOX, S-1 plus oxaliplatin.
Median DOR, TTR and PFS by BICR were as follows: not reached (95% CI 5.6–not estimable [NE]) (Fig. 2A), 1.5 months and 9.4 months (95% CI 6.6–NE) (Fig. 2B), respectively. The 6-month PFS rate was 67.0% (95% CI 52.3–78.1). The median OS was not reached. The 6-month OS rate was 87.0% (95% CI 74.7–93.6).
Fig. 2Kaplan–Meier estimates of duration of response (A) and progression-free survival (B).
In the exploratory subgroup analysis, the ORR by the PD-L1 CPS status was 73.9% (17/23) in patients with CPS ≥1 to <10 and 71.0% (22/31) in those with CPS ≥10. The median PFS was not reached (95% CI 6.6–NE) in patients with CPS ≥1 to <10 and 8.1 months (95% CI 5.5–NE) in those with CPS ≥10, respectively. The investigator-assessed ORR and PFS were 72.2% (95% CI 58.4–83.5) and 6.9 months (95% CI 5.6–8.3), respectively. Additional investigator-assessed efficacy data are shown in Supplementary Appendix C. There was no significant difference between the efficacy results based on RECIST or iRECIST (data not shown).
3.4 Safety
Table 3 shows treatment-related adverse events (TRAEs) of any grade occurring in ≥10% and of interest in this study. In total, 57.4% of patients reported grade ≥3 TRAEs, of which the most common events were decreased platelet count (14.8%), decreased neutrophil count (13.0%), colitis (5.6%) and adrenal insufficiency (5.6%). Serious TRAEs occurred in 16 patients (29.6%) and recovered with appropriate supportive care, with the exception of one patient with peripheral sensory neuropathy. TRAEs, which caused discontinuation of the study treatment, were observed in two patients with small intestine inflammation and pancreatitis/pancreatic pseudocyst. No treatment-related deaths occurred during the study period.
Table 3Treatment-related adverse events (TRAEs) of any grade occurring in ≥10% and of interest (all subjects as treated; N = 54).
This study demonstrated, for the first time, the efficacy and tolerability of SOX with pembrolizumab therapy as first-line treatment for advanced G/GEJ cancer. The ORR by BICR and median PFS were 72.2% and 9.4 months, respectively. These results are relatively favourable compared with those in previous phase II and phase III trials of SOX in Japan, which reported ORR of 56–59% and median PFS of 5.5–6.5 months [
], although cross trial comparison should be carefully interpreted because of different trial setting. Our data were also consistent with results from the phase II part of ATTRACTION-4 trial in G/GEJ cancer patients treated with SOX/CapeOX with nivolumab therapy, in which the ORR and PFS based on central review were 65.8% (95% CI 48.6–80.4) and 9.7 months (95% CI 6.8–12.5), respectively [
Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).
Recently, results of the phase III KEYNOTE-062 study were reported, which compared first-line pembrolizumab monotherapy or pembrolizumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥1 and CPS ≥10 advanced G/GEJ cancer. In the KEYNOTE-062 study, capecitabine or 5-fluorouracil plus cisplatin in combination with pembrolizumab was not superior to chemotherapy alone in terms of OS in both CPS ≥1 (12.5 versus 11.1 months, 0.85 [0.70–1.03], p = 0.046) and CPS ≥10 (12.3 versus 10.8 months, 0.85 [0.62–1.17], p = 0.158) populations, although response rate was higher in pembrolizumab plus chemotherapy (48.6% versus 37.2% in CPS≥1 and 52.5% versus 37.8% in CPS≥10) [
Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study.
]. In our exploratory analysis based on CPS, SOX with pembrolizumab therapy produced ORRs of 72.2% (CPS ≥1) and 71.0% (CPS ≥10), with no apparent association between efficacy outcomes and PD-L1 expression level. This result is generally consistent with the KEYNOTE-062 study, suggesting that the PD-L1 expression level might not be a robust predictive factor for pembrolizumab combined with chemotherapy in patients with G/GEJ cancer. The KEYNOTE-859 (NCT03675737), ATTRACTION-4 (NCT02746796) and CheckMate-649 (NCT02872116) clinical studies are currently ongoing to further evaluate the efficacy and safety of a fluoropyrimidine plus oxaliplatin in combination with nivolumab or pembrolizumab as first-line treatment for advanced G/GEJ cancer. It is anticipated that future results from these studies will clarify the association between PD-L1 expression status and treatment efficacy of chemotherapy plus nivolumab or pembrolizumab.
In the current study, the overall treatment regimen was found to be generally well-tolerated, without increasing the incidence of TRAEs in comparison with previous reports of SOX or pembrolizumab alone [
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.
]. Moreover, the immune-related AE profile in this study (SOX with pembrolizumab) was generally consistent with those from KEYNOTE-062 and ATTRACTION-4 (fluoropyrimidine plus platinum with pembrolizumab or nivolumab) [
Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study.
Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).
]. Just two patients were discontinued because of TRAEs in our study, and although grade ≥3 colitis was observed in three patients (5.6%) and adrenal insufficiency was observed in three patients (5.6%), all of these patients were recovering with appropriate prescription of treatment.
In the KEYNOTE-062 study, greater treatment effects of pembrolizumab or pembrolizumab plus chemotherapy were suggested in patients with microsatellite instability (MSI) with CPS ≥ 1 [
Pembrolizumab with or without chemotherapy vs chemotherapy in patients with advanced G/GEJ cancer (GC) including outcomes according to Microsatellite Instability-High (MSI-H) status in KEYNOTE-062.
Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
]. However, we were unable to assess the impact of SOX with pembrolizumab therapy for MSI-high patients, because MSI status was not measured in this study. A further limitation of our analysis is that the study had a non-randomised, open-label design and was conducted at a small number of sites in Japan. As such, this cannot be viewed as a confirmatory study, and further investigation may be needed before extrapolating the results to the wider G/GEJ cancer patient population.
5. Conclusions
In conclusion, SOX with pembrolizumab showed encouraging efficacy and a manageable safety profile for the first-line treatment of HER2-negative advanced G/GEJ cancer, and additional studies are warranted to further evaluate these novel combination treatment regimens.
Role of the funding source
This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Taiho Pharmaceutical Co., Ltd., Tokyo, Japan provided S-1 and collaborated in the development of this study.
Contributor statements
All authors contributed substantially to the study concept and design and data acquisition, analysis and interpretation. All authors contributed substantially to the preparation and review of the manuscript. All authors approved the final version of the manuscript.
Conflict of interest statement
Y. Negoro, M. Tsuda, S Shiratori, S.R. Han and T. Oshima, declare no conflicts of interest. A. Kawazoe reports grants and personal fees from Taiho Pharmaceutical and Ono Pharmaceutical and grants from Sumitomo Dainippon Pharma and MSD, outside the submitted work. N. Machida reports personal fees from Taiho Pharmaceutical and MSD, during the conduct of the study. K. Yamaguchi reports grants and personal fees from Taiho, grants from MSD, during the conduct of the study; grants and personal fees from Chugai Pharm, personal fees from Takeda, personal fees from Merck Serono, personal fees from Bayer, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Ono Pharm, grants and personal fees from Lilly Japan, grants from Gilliad, grants from Dainippon Sumitomo, grants from Boehringer Ingelheim, personal fees from Bristol and grants from Sanofi, outside the submitted work. H. Yasui reports personal fees from Taiho Pharmaceutical and Yakult Honsha and grants from MSD, during the conduct of the study; personal fees from Chugai Pharmaceutical, Bristol-Myers Squibb Japan and Eli Lilly Japan; grants and personal fees from Daiichi Sankyo and grants from Ono Pharmaceutical, outside the submitted work. M. Azuma reports grants and personal fees from Taiho Pharmaceutical during the conduct of the study and grants and personal fees from Ono Pharmaceutical, outside the submitted work. K. Amagai reports grants from MSD, during the conduct of the study; grants from MSD, Taiho Pharmaceutical, Bayer, Hisamitsu and Daiichi Sankyo, outside the submitted work. H. Hara reports grants from Japan Agency for Medical Research and Development (AMED) during the conduct of the study; grants from AstraZeneca, Sumitomo Dainippon Pharma, Merck Serono, Eisai, LSK BioPharma, Incyte, Pfizer, Boehringer-Ingelheim and BeiGene; grants and personal fees from Daiichi Sankyo, MSD, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical and BMS and personal fees from Eli Lilly, Yakult Honsha, Sanofi and Takeda Pharmaceutical, outside the submitted work. H. Baba reports grants, personal fees and non-financial support from Taiho Pharmaceutical, during the conduct of the study; grants, personal fees and non-financial support from Ono Pharmaceutical and Eli Lilly Japan; grants and personal fees from Takeda Pharmaceutical and Chugai Pharmaceutical; grants and non-financial support from Merck Serono, Yakult Honsha and Johnson & Johnson and grants from Shionogi & Co, Covidien Japan, Takeda Pharmaceutical, Shin Nippon Biomedical Laboratories, Novartis and Toyama Chemical, outside the submitted work. H. Hosaka reports grants from Taiho Pharmaceutical, Ono Pharmaceutical and Bristol-Myers Squibb, outside the submitted work. H. Kawakami reports personal fees from Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, MSD, AstraZeneca, Bayer and Yakult Honsha; grants and personal fees from Chugai Pharmaceutical, Daiichi Sankyo and grants from Eisai, outside the submitted work. Y. Omuro reports grants from MSD, during the conduct of the study and grants from Ono Pharmaceutical, Five Prime, Daiichi Sankyo, Astellas and BeiGene, outside the submitted work. T. Esaki reports grants from Astellas, MSD, Sumitomo Dainippon Pharma, Nihon Kayaku, Novartis and Pfizer; grants and personal fees from Daiichi-Sankyo, Ono Pharmaceutical, Merck Serono, Taiho Pharmaceutical, Eli Lilly, Bayer, Bristol-Myers Squibb; personal fees from Takeda Pharmaceutical, Kyowa Kirin, Chugai Pharmaceutical, Eisai and Sanofi, outside the submitted work. K. Yoshida reports grants and personal fees from Taiho Pharmaceutical and MSD, during the conduct of the study; grants and personal fees from Asahi Kasei Pharma, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, Johnson & Johnson, Merck Serono, Nippon Kayaku, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Tsumura and Yakult Honsha; grants from Abbott, AbbVie, Astellas, Biogen Japan, Celgene, GlaxoSmithKline, KCI, Kyowa Kirin, Meiji Seika Pharma and Toray Medical and personal fees from AstraZeneca, Bristol-Myers Squibb, Denka, EA Pharma, Olympus, Pfizer, Sanwa Kagaku Kenkyusho, SBI Pharma, Takeda Pharmaceutical, Teijin Pharmaceutical and TERUMO, outside the submitted work. T. Nishina reports grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb and Eli Lilly and grants from Daiichi Sankyo, MSD and Sumitomo Dainippon Pharma, outside the submitted work. Y. Komatsu reports grants and personal fees from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from Eli Lilly Japan K.K., Taiho Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Bayer Yakuhin, Ltd., Bristol-Myers Squibb, Sanofi S.A., Merck Biopharma, Ono Pharmaceutical, MSD K.K., Yakult Honsha, Otsuka Pharmaceutical; grants from National Cancer Center Hospital, NanoCarrier, Baxter International Inc., Clinical Co., Ltd., Quintiles and IMS Health, Sysmex Corporation, Mediscience Planning Inc., Sumitomo Dainippon Pharma, Kyowa Kirin, Asahi Kasei Pharma Corporation and Nippon Zoki Pharmaceutical, outside the submitted work. K. Shitara reports grants and personal fees from Astellas Pharma, Eli Lilly, Ono Pharmaceutical and MSD; personal fees from Bristol-Myers Squibb, Takeda Pharmaceutical, Pfizer, Novartis, AbbVie and Yakult Honsha; grants from Sumitomo Dainippon Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical and MediScience, outside the submitted work.
Acknowledgements
We thank all the patients, their families, the clinicians at the medical centres named in the supplemental data, the investigators who participated in this study and Prof. Takako Nakajima from St. Marianna University School of Medicine as a medical advisor. Medical writing support during the preparation of this paper was provided by Keisuke Nakashima of Taiho Pharmaceutical Co., Ltd. and Sally-Anne Mitchell, Ph.d., of Edanz Medical Writing, and the study was funded by Taiho Pharmaceutical., Tokyo, Japan in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3).
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer: a JSMO–ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2–positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC—a randomised phase III trial.
Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study.
Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial.
Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study.
Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.
Pembrolizumab alone or in combination with chemotherapy as first line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study.
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial.
Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study.
Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4).
Pembrolizumab with or without chemotherapy vs chemotherapy in patients with advanced G/GEJ cancer (GC) including outcomes according to Microsatellite Instability-High (MSI-H) status in KEYNOTE-062.
Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
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