Summary
Background
While immunotherapy plus chemotherapy is the current first-line standard for gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), subgroup analyses in patients with peritoneal metastasis are limited and show inconsistent benefits across trials (e.g., ATTRACTION-4, CheckMate 649). This post-hoc analysis evaluated the efficacy of immunotherapy plus chemotherapy in patients with or without peritoneal metastases.
Methods
This is an exploratory post-hoc analysis of the randomised, double-blind, phase 3 RATIONALE-305 trial. Treatment-naïve patients aged ≥18 years with advanced GC/GEJC were enrolled across 13 countries from December 13, 2018, to February 9, 2021. Patients were randomised (1:1) to tislelizumab (200 mg intravenous every 3 weeks) plus chemotherapy or placebo plus chemotherapy until disease progression or unacceptable toxicity. Patients with or without peritoneal metastasis at baseline were identified and reanalysed. Outcomes included overall survival (OS) and progression-free survival (PFS) in the intention-to-treat population, and safety in all patients who received at least one dose of study drug. RATIONALE-305 is registered with ClinicalTrials.gov, NCT03777657.
Findings
Among the 997 randomised patients, 434 (43.5%) had peritoneal metastases at baseline. Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy irrespective of peritoneal metastasis status, with consistent benefits observed in patients with peritoneal metastases (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64–0.96) and those without peritoneal metastases (HR, 0.79; 95% CI, 0.65–0.95). The OS benefits were greater in patients with a programmed death ligand-1 tumour area positivity score of ≥5%, regardless of peritoneal metastasis status. Significant PFS benefit was also observed with tislelizumab plus chemotherapy in both patients with peritoneal metastasis (HR, 0.80; 95% CI, 0.64–0.98) and without peritoneal metastasis (HR, 0.77; 95% CI, 0.64–0.94). The safety profile was similar between treatment arms and consistent across subgroups.
Interpretation
Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy in patients with GC/GEJC, irrespective of the presence of peritoneal metastases, with a comparable safety profile between treatment arms. Further dedicated prospective studies are warranted to validate these findings in this population.
Funding
This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, Cancer Innovative Research Program of Sun Yat-sen University Cancer Center, Young Talents Program of Sun Yat-sen University Cancer Center, and Sanming Project of Medicine in Shenzhen.
Keywords: Gastric or gastroesophageal junction adenocarcinoma, Tislelizumab plus chemotherapy, Overall survival, Peritoneal metastasis
Research in context.
Evidence before this study
We searched PubMed, Embase, and Web of Science up to January 2026 using terms such as “gastric cancer”, “gastroesophageal junction adenocarcinoma”, “peritoneal metastasis”, “programmed death-ligand 1 (PD-L1)”, “immune checkpoint inhibitor”, and “post-hoc analysis”. Phase 3 trials (e.g., CheckMate-649, KEYNOTE-859, RATIONALE-305) have established anti-programmed death-1 (PD-1) inhibitors plus chemotherapy as the standard first-line treatment for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), with overall survival (OS) improvements versus chemotherapy alone, particularly in PD-L1-positive subgroups. Peritoneal metastasis is a common poor-prognostic feature associated with worse survival, and data on immunotherapy in this subgroup remain limited and inconsistent. The RATIONALE-305 trial (the only one stratified by peritoneal metastasis at randomisation) showed superior OS with tislelizumab plus chemotherapy versus placebo plus chemotherapy in the overall population, but dedicated analyses for patients with peritoneal metastasis were absent prior to this post-hoc evaluation.
Added value of this study
This post-hoc analysis of the phase 3 RATIONALE-305 trial provides the first dedicated evaluation of immunotherapy plus chemotherapy in patients with or without peritoneal metastases. The results suggest that the survival benefit of tislelizumab plus chemotherapy is consistent across these subgroups, irrespective of peritoneal metastases status, with a manageable safety profile. Greater magnitude of benefit was observed in patients with PD-L1 tumour area positivity score ≥5%. These findings address a key evidence gap regarding the efficacy of PD-1 inhibitor-based therapy in this high-risk, historically challenging subgroup of advanced GC/GEJC, extending the RATIONALE-305 trial results.
Implications of all the available evidence
Combined with evidence from RATIONALE-305 and other PD-1 inhibitor trials, this post-hoc analysis suggests that tislelizumab plus chemotherapy provides a significant survival benefit in patients with advanced GC/GEJC, irrespective of peritoneal metastasis status. These findings support its use across clinically relevant subgroups, including high-risk patients with peritoneal metastases. Further research is warranted to explore additional prognostic factors and optimise therapeutic strategies in patients with GC/GEJC.
Introduction
Gastric cancer (GC) is the fifth most common malignancy worldwide, with more than 968,000 new cases resulting in approximately 660,000 deaths in 2022 and making GC the fifth most prevalent cause of cancer-related mortality.1 East Asia and Eastern Europe continue to bear a disproportionate global burden, where GC is one of the most commonly diagnosed cancers in Japan and Korea and a leading cause of cancer-related deaths in China.2, 3, 4 Peritoneal metastasis is the most common site of metastasis in GC,5 occurring in 55%–60% of patients during the disease course.6 Patients with peritoneal metastasis have a poor prognosis, with median overall survival (OS) ranging from 2 to 9 months.7 Compared to patients with liver metastasis only, patients with peritoneal metastasis alone have a statistically significant decrease in median OS and a 2.87-fold increase in hazard of mortality.8
Current first-line standard of care for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative GC patients includes immune checkpoint inhibitors (ICIs) combined with chemotherapy.9 The therapeutic strategy has demonstrated improved OS over placebo plus chemotherapy in multiple clinical trials. However, immunotherapy benefits have not been adequately explored or consistently established among patients with peritoneal metastasis. Most studies did not include specific subgroup analyses on peritoneal metastasis10, 11, 12, 13, 14, 15 or failed to demonstrate a survival benefit among this population of patients.16,17 In the context of chemoimmunotherapy, RATIONALE-305 is the only global phase 3 trial to stratify patients by peritoneal metastasis status at randomisation, uniquely positioning it to evaluate treatment effects in this subgroup.18,19 In this trial, tislelizumab, a humanised immunoglobulin G4 anti-programmed death-1 (PD-1) antibody, was investigated in patients with gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJC), and the primary analysis revealed statistically significant OS benefits with tislelizumab plus chemotherapy compared to placebo plus chemotherapy in the overall population. Notably, the study also demonstrated a significant survival benefit in the subgroup of patients with peritoneal metastasis.
Given the prevalence of peritoneal metastatic disease, the lack of compelling evidence for ICI efficacy in this population, and the innovative design of RATIONALE-305, we conducted a post-hoc analysis on RATIONALE-305 to further evaluate the long-term efficacy and safety of tislelizumab plus chemotherapy in patients with advanced GC/GEJC, with or without peritoneal metastasis.
Methods
Study design and patients
This is an exploratory post-hoc analysis on RATIONALE-305 study. Patients with or without peritoneal metastasis at baseline were identified in two cohorts from the RATIONALE-305 study and reanalysed. The detailed methodology information of the RATIONALE-305 study has been previously published.18 In brief, RATIONALE-305 is a randomised, double-blind, global, phase 3 clinical trial that enrolled patients from December 13, 2018, to February 9, 2021 at 146 medical centres across Asia, Europe, and North America. Patients aged ≥18 years with histologically confirmed locally advanced unresectable or metastatic GC/GEJC and no previous systemic therapy for advanced disease were recruited. Patients with HER2-positive tumours were excluded.
Ethics
This original RATIONALE-305 study was approved by the relevant institutional review board or independent ethics committee for each study site (Supplementary Table S1). The study was done in accordance with the International Conference on Harmonisation E6 guideline for Good Clinical Practice, the principles of Declaration of Helsinki, and all applicable local laws and regulations. All patients provided written informed consent before enrolment.
Randomisation and masking
Eligible patients were randomised 1:1 to receive either tislelizumab (200 mg intravenous every 3 weeks) plus investigator-chosen chemotherapy (capecitabine and oxaliplatin, or 5-fluorouracil and cisplatin) or placebo plus investigator-chosen chemotherapy. Randomisation was stratified according to region (China [including Taiwan] vs. Japan and South Korea vs. Europe/North America), programmed death-ligand 1 (PD-L1) expression (PD-L1 tumour area positivity [TAP] score ≥5% vs. <5%), peritoneal metastases (yes vs. no), and investigator's choice of chemotherapy (capecitabine and oxaliplatin, vs. 5-fluorouracil and cisplatin). As a double-blind design, all investigators, participants, site staff, and funder staff were masked to the treatment allocation.
Outcomes
In the RATIONALE-305 study, the primary endpoint was OS, assessed in patients with a PD-L1 TAP score of ≥5% and in all randomised patients. Secondary endpoints included progression-free survival (PFS), confirmed objective response rate (ORR), disease control rate, clinical benefit rate, time to response, and duration of response (DOR), evaluated in patients with a PD-L1 TAP score of ≥5% and in all randomised patients; safety and tolerability, assessed based on the incidence and severity of adverse events.
The final analysis of the RATIONALE-305 study has been published (data cutoff [DCO]: February 28, 2023), along with the subgroup analysis on patients with or without peritoneal metastasis.18 The median follow-up was 24.6 months. The long-term survival follow-up with a minimum 3-year (DCO: February 28, 2024) results were also published,19 further evaluating the OS in subgroup analysis, including patients with or without peritoneal metastasis.
This post-hoc analysis was performed after unblinding, using the same DCO (February 28, 2024) as in the long-term follow-up publication of the RATIONALE-305 study.19 The outcomes measured included OS and PFS in all randomised patients with or without peritoneal metastasis. Given the well-established association between PD-L1 expression and the efficacy of ICIs, efficacy outcomes were also analysed using different PD-L1 cutoffs, including TAP score of ≥5% (the prespecified stratification factor) and ≥1%. ORR, DOR, and safety were also evaluated in all randomised patients by peritoneal metastasis status. Tumour responses were assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for all patients. Target lesions were strictly selected according to RECIST v1.1 criteria. Response analysis included all patients, regardless of the presence of target lesions.
Statistical analysis
In this post-hoc analysis, all subgroup analyses were exploratory, non-prespecified, and not prospectively powered. No adjustments were made for multiple comparisons; thus, results should be interpreted as hypothesis-generating. Effect sizes and corresponding 95% confidence intervals (CIs) are presented to facilitate interpretation rather than formal hypothesis testing. Baseline characteristics and safety data were summarised descriptively. Continuous variables were presented as median (range), and categorical variables were presented as frequency (percentages). Median OS, PFS, and DOR were estimated by the Kaplan–Meier method with 95% CIs estimated through the method of Brookmeyer and Crowley. Hazard ratios (HRs) with corresponding 95% CIs for OS and PFS were estimated using an unstratified Cox regression model with treatment as a covariate. P values of one-side log-rank test for each survival outcomes were reported. Unstratified models were used because some subgroups (e.g., PD-L1 TAP ≥1%) were not prespecified stratification factors in the parent trial, allowing consistent estimation of treatment effects across subgroups in this exploratory analysis. ORR was calculated, along with two-sided 95% CIs using the Clopper–Pearson method. Odds ratio (OR) for ORR was calculated using an unstratified Cochran–Mantel–Haenszel test, accompanied by 95% CIs. All statistical analyses were done using R software (version 4.4).
Role of the funding source
The funders had no involvement in study design, data collection, data analyses, data interpretation, or the writing of the report.
Results
Patients
In RATIONALE-305, 997 patients were randomised (tislelizumab plus chemotherapy, n = 501; placebo plus chemotherapy, n = 496), among whom 434 (43.5%) patients had peritoneal metastases at baseline, with 220 patients in the tislelizumab plus chemotherapy arm and 214 in the placebo plus chemotherapy arm (Fig. 1). In accordance, 563 (56.4%) patients were without peritoneal metastases at baseline, with 281 in the tislelizumab plus chemotherapy arm and 282 in the placebo plus chemotherapy arm. The baseline characteristics were balanced between treatment arms in patients with or without peritoneal metastases (Table 1; Supplementary Table S2). In total, the median age was 59 (range, 23–84) years in patients with peritoneal metastasis and 61 (range, 30–86) years in patients without peritoneal metastasis. Compared to the group without peritoneal metastasis, the group with peritoneal metastasis had a lower proportion of males (58.8% vs. 77.6%), gastro-oesophageal junction primary (13.4% vs. 24.6%), PD-L1 TAP score ≥5% (50.0% vs. 58.4%), liver metastasis (24.9% vs. 48.0%), microsatellite instability-high (2.5% vs. 5.2%) and previous adjuvant or neoadjuvant therapy (17.3% vs. 23.4%), and a higher proportion of metastatic sites ≥3 (49.1% vs. 20.1%).
Fig. 1.
CONSORT diagram.
Table 1.
Baseline characteristics.
| Characteristics, n (%) | Patients with peritoneal metastasis |
Patients without peritoneal metastasis |
||||
|---|---|---|---|---|---|---|
| Tislelizumab plus chemotherapy (n = 220) | Placebo plus chemotherapy (n = 214) | Total (n = 434) | Tislelizumab plus chemotherapy (n = 281) | Placebo plus chemotherapy (n = 282) | Total (n = 563) | |
| Age-years, median (range) | 59 (49–66) | 59 (48–66) | 59 (23–84) | 60 (54–67) | 62 (56–69) | 61 (30–86) |
| Sex | ||||||
| Female | 84 (38.2) | 95 (44.4) | 179 (41.2) | 71 (25.3) | 55 (19.5) | 126 (22.4) |
| Male | 136 (61.8) | 119 (55.6) | 255 (58.8) | 210 (74.7) | 227 (80.5) | 437 (77.6) |
| Region | ||||||
| East Asia | 165 (75.0) | 160 (74.8) | 325 (74.9) | 211 (75.1) | 212 (75.2) | 423 (75.1) |
| Rest of World | 55 (25.0) | 54 (25.2) | 109 (25.1) | 70 (24.9) | 70 (24.8) | 140 (24.9) |
| ECOG PS | ||||||
| 0 | 82 (37.3) | 66 (30.8) | 148 (34.1) | 87 (31.0) | 88 (31.2) | 175 (31.1) |
| 1 | 138 (62.7) | 148 (69.2) | 286 (65.9) | 194 (69.0) | 194 (68.8) | 388 (68.9) |
| Primary tumour location | ||||||
| Stomach | 196 (89.1) | 180 (84.1) | 376 (86.6) | 209 (74.4) | 215 (76.2) | 424 (75.4) |
| Gastro-oesophageal junction | 24 (10.9) | 35 (15.9) | 58 (13.4) | 72 (25.6) | 66 (23.4) | 138 (24.6) |
| PD-L1 Score | ||||||
| PD-L1 TAP <5% | 110 (50.0) | 107 (50.0) | 217 (50.0) | 117 (41.6) | 117 (41.5) | 234 (41.6) |
| PD-L1 TAP ≥5% | 110 (50.0) | 107 (50.0) | 217 (50.0) | 164 (58.4) | 165 (58.5) | 329 (58.4) |
| Chemotherapy regimen | ||||||
| FP | 16 (7.3) | 11 (5.1) | 27 (6.2) | 19 (6.8) | 20 (7.1) | 39 (6.9) |
| CAPEOX | 204 (92.7) | 203 (94.9) | 407 (93.8) | 262 (93.2) | 262 (92.9) | 524 (93.1) |
| Metastatic sites | ||||||
| 0–2 | 112 (50.9) | 109 (50.9) | 221 (50.9) | 223 (79.4) | 226 (80.1) | 449 (79.9) |
| ≥3 | 108 (49.1) | 105 (49.1) | 213 (49.1) | 58 (20.6) | 55 (19.5) | 113 (20.1) |
| Peritoneal metastasis | 220 (100) | 214 (100) | 434 (100) | 0 | 0 | 0 |
| Liver metastasis | 55 (25.0) | 53 (24.8) | 108 (24.9) | 135 (48.0) | 135 (47.9) | 270 (48.0) |
| MSI/MMR | ||||||
| MSI-H/dMMR | 6 (2.7) | 5 (2.3) | 11 (2.5) | 10 (3.6) | 19 (6.7) | 29 (5.2) |
| MSI-L/MSS/pMMR | 194 (88.2) | 193 (90.2) | 387 (89.1) | 254 (90.4) | 246 (87.2) | 500 (88.8) |
| Unknown | 20 (9.1) | 16 (7.5) | 36 (8.3) | 17 (6.0) | 17 (6.0) | 34 (6.0) |
| Previous adjuvant or neoadjuvant therapy | 38 (17.3) | 37 (17.3) | 75 (17.3) | 69 (24.6) | 63 (22.3) | 132 (23.4) |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death-ligand 1; TAP, tumour area positivity; FP, 5-fluorouracil plus cisplatin; CAPEOX, capecitabine plus oxaliplatin; MSI, microsatellite instability; MMR, mismatch repair; MSI-H, microsatellite instability-high; dMMR, mismatch repair-deficient; MSI-L, microsatellite instability-low; MSS, microsatellite stable; pMMR, mismatch repair-proficient.
Efficacy
As of the data cutoff (28 February 2024), the median follow-up (defined as time from randomisation to data cutoff) was 46.7 (range, 36.6–62.5) months. The median OS was 12.0 (95% CI, 11.1–13.3) months in patients with peritoneal metastasis and 15.3 (95% CI, 14.1–16.9) months in patients without peritoneal metastasis. Consistent with previous reports, patients with peritoneal metastasis had poorer prognosis than those without (median OS, 12.0 vs. 15.3 months), regardless of treatment assignment.
In patients with peritoneal metastases, OS was significantly improved with tislelizumab plus chemotherapy compared to placebo plus chemotherapy (median OS, 12.3 vs. 11.8 months; HR, 0.78 [95% CI, 0.64–0.96]) (Table 2 and Fig. 2). Significant OS improvement was also observed in the tislelizumab plus chemotherapy versus placebo plus chemotherapy in peritoneal metastasis patients with a PD-L1 TAP score of ≥5% (HR, 0.71 [95% CI, 0.53–0.95]) and ≥1% (HR, 0.79 [95% CI, 0.64–0.98]) (Table 2 and Fig. 2). As expected, the treatment benefit appeared attenuated in patients with a PD-L1 TAP score <5% (HR, 0.88 [95% CI, 0.67–1.17]; data not shown).
Table 2.
Efficacy outcomes of tislelizumab plus chemotherapy versus placebo plus chemotherapy in patients with or without peritoneal metastasis.
| Efficacy outcomes | Patients with peritoneal metastasis |
Patients without peritoneal metastasis |
||
|---|---|---|---|---|
| Tislelizumab plus chemotherapy (n = 220) | Placebo plus chemotherapy (n = 214) | Tislelizumab plus chemotherapy (n = 281) | Placebo plus chemotherapy (n = 282) | |
| OS | ||||
| Overall population | ||||
| Median (95% CI), months | 12.3 (10.6–14.3) | 11.8 (10.6–13.0) | 17.3 (15.0–20.3) | 14.0 (12.6–16.0) |
| HR (95% CI) | 0.78 (0.64–0.96) | 0.79 (0.65–0.95) | ||
| P value | 0.009 | 0.006 | ||
| PD-L1 TAP score ≥1% | ||||
| Median (95% CI), months | 12.2 (10.4–14.1) | 11.9 (10.9–13.1) | 18.0 (15.0–21.3) | 13.7 (12.5–15.5) |
| HR (95% CI) | 0.79 (0.64–0.98) | 0.76 (0.62–0.92) | ||
| P value | 0.017 | 0.003 | ||
| PD-L1 TAP score ≥5% | ||||
| Median (95% CI), months | 11.7 (9.7–15.3) | 11.3 (9.8–12.3) | 20.8 (16.9–24.7) | 14.5 (12.7–16.4) |
| HR (95% CI) | 0.71 (0.53–0.95) | 0.71 (0.56–0.91) | ||
| P value | 0.011 | 0.004 | ||
| PFS | ||||
| Overall population | ||||
| Median (95% CI), months | 5.8 (5.6–7.3) | 5.7 (5.3–6.9) | 7.0 (5.8–8.4) | 6.9 (5.7–7.1) |
| HR (95% CI) | 0.80 (0.64–0.98) | 0.77 (0.64–0.94) | ||
| P value | 0.018 | 0.005 | ||
| PD-L1 TAP score ≥1% | ||||
| Median (95% CI), months | 5.8 (5.6–7.3) | 5.7 (5.3–6.9) | 7.0 (5.7–8.3) | 6.9 (5.6–7.1) |
| HR (95% CI) | 0.79 (0.63–0.99) | 0.77 (0.63–0.94) | ||
| P value | 0.021 | 0.006 | ||
| PD-L1 TAP score ≥5% | ||||
| Median (95% CI), months | 7.0 (5.7–8.3) | 5.5 (4.2–6.8) | 7.4 (5.8–9.7) | 6.9 (5.7–8.1) |
| HR (95% CI) | 0.65 (0.48–0.89) | 0.72 (0.56–0.93) | ||
| P value | 0.003 | 0.006 | ||
| DOR | ||||
| Median (95% CI), months | 6.0 (4.4–8.1) | 5.1 (4.2–7.2) | 8.7 (6.8–12.4) | 7.2 (6.0–9.3) |
| ORR | ||||
| % (95% CI) | 43.6 (37.0–50.5) | 32.2 (26.0–39.0) | 50.2 (44.2–56.2) | 46.8 (40.9–52.8) |
| OR (95% CI) | 1.63 (1.10–2.41) | 1.14 (0.82–1.59) | ||
Abbreviations: OS, overall survival; PFS, progression-free survival; DOR, duration of response; ORR, overall response rate; PD-L1, programmed death-ligand 1; TAP, tumour area positivity; CI, confidence interval; HR, hazard ratio; OR, odds ratio.
Fig. 2.
Kaplan–Meier estimates of overall survival in patients with peritoneal metastasis, stratified by treatment arm. (A) In all patients. (B) In patients with a PD-L1 TAP score of ≥1%. (C) In patients with a PD-L1 TAP score of ≥5%. Censored data are indicated by tick marks. HRs and associated 95% CIs were estimated using an unstratified Cox regression model with treatment as a covariate. Abbreviations: HR, hazard ratio; CI, confidence interval; PD-L1, programmed death-ligand 1; TAP, tumour area positivity.
In patients without peritoneal metastases, OS was also significantly improved with tislelizumab plus chemotherapy compared to placebo plus chemotherapy (median OS, 17.3 vs. 14.0 months; HR, 0.79 [95% CI, 0.65–0.95]). The OS benefit was greater in patients with a PD-L1 TAP score of ≥5% (median OS, 20.8 vs. 14.5 months; HR, 0.71 [95% CI, 0.56–0.91]) and a PD-L1 TAP score of ≥1% (median OS, 18.0 vs. 13.7 months; HR, 0.76 [95% CI, 0.62–0.92]) (Table 2 and Fig. 3).
Fig. 3.
Kaplan–Meier estimates of overall survival in patients without peritoneal metastasis, stratified by treatment arm. (A) In all patients. (B) In patients with a PD-L1 TAP score of ≥1%. (C) In patients with a PD-L1 TAP score of ≥5%. Censored data are indicated by tick marks. HRs and associated 95% CIs were estimated using an unstratified Cox regression model with treatment as a covariate. Abbreviations: HR, hazard ratio; CI, confidence interval; PD-L1, programmed death-ligand 1; TAP, tumour area positivity.
PFS was significantly improved with tislelizumab plus chemotherapy versus placebo plus chemotherapy in patients with (median PFS, 5.8 vs. 5.7 months; HR, 0.80 [95% CI, 0.64–0.98]) and without peritoneal metastasis (median PFS, 7.0 vs. 6.9 months; HR, 0.77 [95% CI, 0.64–0.94]). Consistent results were observed in patients with a PD-L1 TAP score of ≥5% and ≥1% (Table 2 and Figs. 4 and 5).
Fig. 4.
Kaplan–Meier estimates of progression-free survival in patients with peritoneal metastasis, stratified by treatment arm. (A) In all patients. (B) In patients with a PD-L1 TAP score of ≥1%. (C) In patients with a PD-L1 TAP score of ≥5%. Censored data are indicated by tick marks. HRs and associated 95% CIs were estimated using an unstratified Cox regression model with treatment as a covariate. Abbreviations: HR, hazard ratio; CI, confidence interval; PD-L1, programmed death-ligand 1; TAP, tumour area positivity.
Fig. 5.
Kaplan–Meier estimates of progression-free survival in patients without peritoneal metastasis, stratified by treatment arm. (A) In all patients. (B) In patients with a PD-L1 TAP score of ≥1%. (C) In patients with a PD-L1 TAP score of ≥5%. Censored data are indicated by tick marks. HRs and associated 95% CIs were estimated using an unstratified Cox regression model with treatment as a covariate. Abbreviations: HR, hazard ratio; CI, confidence interval; PD-L1, programmed death-ligand 1; TAP, tumour area positivity.
The ORR was numerically higher in the tislelizumab plus chemotherapy arm versus the placebo plus chemotherapy arm, in patients with (43.6% vs. 32.2%; OR, 1.63 [95% CI, 1.10–2.41]) and without peritoneal metastases (50.2% vs. 46.8%; OR, 1.14 [95% CI, 0.82–1.59]), though the difference was not statistically significant in the latter group. Similarly, the median DOR was also numerically longer in the tislelizumab plus chemotherapy compared with placebo plus chemotherapy in patients with (6.0 vs. 5.1 months) and without (8.7 vs. 7.2 months) peritoneal metastases.
The median duration of treatment was similar between tislelizumab plus chemotherapy group and placebo plus chemotherapy group, which was 5.6 (range, 0.1–59.0) months and 5.5 (range, 0.3–48.7) months in patients with peritoneal metastasis, respectively, and was 6.4 (range, 0.6–53.1) months and 5.9 (range, 0.5–47.0) months in patients without peritoneal metastasis. After study treatment discontinuation, 132 (59.2%) patients in the tislelizumab plus chemotherapy arm and 129 (61.1%) patients in the placebo plus chemotherapy arm received the subsequent systemic anticancer treatment for patients with peritoneal metastasis. There were 141 (50.2%) and 171 (60.6%) patients in the two treatment arms receiving subsequent systemic anticancer treatment for patients without peritoneal metastasis (Supplementary Table S3).
Safety
Among patients with peritoneal metastases, the incidence of treatment-related adverse events (TRAEs) at any grade were 96.8% in the tislelizumab plus chemotherapy arm and 94.8% in the placebo plus chemotherapy arm. Grade ≥3 TRAEs were reported in 57.5% of patients in the tislelizumab plus chemotherapy and 49.3% in the placebo plus chemotherapy. Treatment-emergent adverse events (TEAEs) leading to treatment discontinuation occurred in 49 (22.4%) patients of tislelizumab plus chemotherapy versus 30 (14.1%) patients of placebo plus chemotherapy, and dose modification in 76.3% versus 74.2% patients, respectively (Table 3). The safety was also comparable between tislelizumab plus chemotherapy and placebo plus chemotherapy in patients without peritoneal metastases. The most commonly occurring TRAEs (≥10%) in the tislelizumab plus chemotherapy and placebo plus chemotherapy arms are listed in Supplementary Tables S4 and S5.
Table 3.
Summary of adverse events in patients with or without peritoneal metastasis.
| Adverse events, n (%) | Patients with peritoneal metastasis |
Patients without peritoneal metastasis |
||
|---|---|---|---|---|
| Tislelizumab plus chemotherapy (n = 219) | Placebo plus chemotherapy (n = 213) | Tislelizumab plus chemotherapy (n = 279) | Placebo plus chemotherapy (n = 281) | |
| TRAEs | 212 (96.8) | 202 (94.8) | 271 (97.1) | 274 (97.5) |
| Grade ≥3 | 126 (57.5) | 105 (49.3) | 143 (51.3) | 141 (50.2) |
| SAEs | 53 (24.2) | 37 (17.4) | 60 (21.5) | 35 (12.5) |
| Leading to death | 4 (1.8) | 2 (0.9) | 7 (2.5) | 2 (0.7) |
| TEAEs | ||||
| Leading to discontinuation | 49 (22.4) | 30 (14.1) | 68 (24.4) | 38 (13.5) |
| Leading to dose modification | 167 (76.3) | 158 (74.2) | 214 (76.7) | 217 (77.2) |
| Infusion-related reaction | 11 (5.0) | 11 (5.2) | 11 (3.9) | 6 (2.1) |
Abbreviations: TRAEs, treatment-related adverse events; SAEs, serious adverse event; TEAEs, treatment-emergent adverse events.
Discussion
The incorporation of ICIs into first-line treatment regimens has revolutionised the management of advanced GC/GEJC. However, while immunotherapy has become an established standard in this setting, its efficacy in patients with peritoneal metastases, a subgroup characterised by particularly poor prognosis, has remained uncertain until now. RATIONALE-305 is the only study to stratify patients based on the presence of peritoneal metastases, uniquely positioning it to evaluate the efficacy of tislelizumab in this subgroup. To our knowledge, this post-hoc analysis is the first study to investigate both the efficacy and safety of ICI-based therapy in patients with GC/GEJC, with or without peritoneal metastases.
In this post-hoc analysis, we confirmed that patients with peritoneal metastases had poorer survival compared with those without peritoneal metastases (12.0 vs. 15.3 months), reinforcing the identification of this subgroup as historically refractory.7 More importantly, we found that tislelizumab plus chemotherapy consistently demonstrated a statistically significant OS improvement over placebo plus chemotherapy in patients with peritoneal metastases, yielding a HR of 0.78 (95% CI, 0.64–0.96). Consistent with other anti-PD-1 trials,11,17 the magnitude of OS benefit with tislelizumab plus chemotherapy was even greater among those whose tumours exhibited PD-L1 TAP score ≥5%, with nearly 30% reduction in the risk of death versus control (HR, 0.71 [95% CI, 0.53–0.95]), whereas the benefit appeared attenuated in PD-L1 TAP <5% populations. Similarly, tislelizumab plus chemotherapy also resulted in statistically significant OS benefits over placebo plus chemotherapy in patients without peritoneal metastases, especially in patients with PD-L1 TAP score ≥5% (HR, 0.71 [95% CI, 0.56–0.91]). Another noteworthy point is that while the absolute OS improvement of 0.5 months in the peritoneal metastasis population was modest, the HR of 0.78 represents a 22% relative risk reduction, which is particularly important in this historically refractory subgroup with median OS under 12 months.11,16,17 Therefore, even modest improvements may be clinically meaningful in this challenging population, especially when accompanied by improved PFS (HR, 0.80 [95% CI, 0.64–0.98]), higher response rates (44% vs. 32%), and more durable responses (6.0 vs. 5.1 months), without compromising safety.
There are multiple landmark trials with ICI-based therapy in GC/GEJC, but only a few studies (RATIONALE-305, ATTRACTION-4, and CheckMate-649) investigating the efficacy on this subgroup, with only the RATIONALE-305 study stratified by peritoneal metastases (yes or no). In ATTRACTION-4, nivolumab combined with chemotherapy failed to bring an OS improvement for patients harbouring peritoneal metastases, with a HR of 1.20 (95% CI, 0.94–1.53).16 Similarly, CheckMate 649 established no OS benefit for nivolumab plus chemotherapy in patients with peritoneal metastases (median OS, 9.3 vs. 10.0 months; HR, 0.95), whereas an OS advantage in patients with peritoneal metastases and PD-L1 combined positive score (CPS) ≥5 (median OS, 10.9 vs. 8.0 months; HR, 0.70) and ≥10 (median OS, 9.7 vs. 7.9 months; HR, 0.69).17 To date, tislelizumab is the only PD-1 inhibitor that has demonstrated a statistically significant OS improvement in the overall population of patients with peritoneal metastases, without PD-L1–based patient selection. However, direct cross-trial comparison should be interpreted with caution due to differences in therapeutic regimen and the use of different PD-L1 scoring systems across trials. Nevertheless, although TAP and CPS are different scoring algorithms, both assess PD-L1 expression on tumour and/or immune cells and have shown good correlation in this disease.20 Additionally, the structural advantage of tislelizumab may partly account for the discrepancies observed across trials. Preclinical studies have suggested that tislelizumab's engineered Fc region minimises FcγR binding and may reduce antibody-dependent cellular phagocytosis-mediated depletion of PD-1+ effector T cells—a mechanism that could be particularly relevant in the tumour-associated macrophage-rich peritoneal metastatic microenvironment.21,22 These observations provide a biological rationale for our clinical findings and warrant dedicated translational investigation.
The safety profile was comparable between the tislelizumab and placebo arms, irrespective of the presence of peritoneal metastases. The duration of treatment was similar in both arms, and the incidence rates of TRAEs, grade ≥3 TRAEs, and TEAEs leading to treatment discontinuation were also similar between arms. No new safety signals were observed during extended follow-up periods.
There are several limitations that warrant consideration. Firstly, this is an exploratory, non-prespecified post-hoc subgroup analysis, with relatively small sample sizes in certain subgroups, which may reduce statistical power and randomisation benefits. In addition, hypothesis testing for OS and PFS in subgroups was conducted without multiplicity adjustment and stratified Cox models were not applied; unstratified estimates were considered acceptable given the exploratory nature. Therefore, these findings should be interpreted with caution and warrant validation in further studies specifically designed for patients with peritoneal metastases. Secondly, although the efficacy and safety were evaluated separately in patients with and without peritoneal metastasis, the underlying mechanisms contributing to the poorer prognosis in patients with peritoneal metastases remain unclear and warrant further investigation. Thirdly, stratified efficacy analysis by histological type is not feasible due to incomplete histological data, as these were not mandatory for all patients. Additionally, the reported ORR may primarily reflect responses in measurable extraperitoneal lesions, as peritoneal metastases are often non-measurable, potentially introducing bias in efficacy assessment. Finally, although post-progression treatments were generally balanced between arms, the potential impact of subsequent therapies (e.g., a higher rate of subsequent immunotherapy in the placebo arm) on the observed OS benefit cannot be fully excluded, which is a limitation inherent to first-line trials. Further studies are needed to identify molecular biomarkers and prognostic factors that may influence outcomes in patients with advanced GC/GEJC.
In conclusion, in this exploratory, post-hoc analysis, tislelizumab plus chemotherapy demonstrated a statistically significant OS benefit compared with placebo plus chemotherapy in patients with advanced GC/GEJC with or without peritoneal metastasis. The safety profile was comparable between tislelizumab and placebo arms, irrespective of the presence of peritoneal metastases, with no new safety signals. These findings provide supportive evidence for chemoimmunotherapy in this high-risk subgroup, while warranting further confirmation in dedicated studies.
Contributors
MZQ, MM and RHX conceived and conceptualised the study. MZQ, KWL, HYL, HH, TZ, FHW, YB, SYR, FW, and MMH performed the investigation and curated the data. SX developed the methodology and software. XP drafted the original manuscript. All authors reviewed and edited the manuscript. All authors read and approved the final version of the manuscript. MZQ, MM and RHX accessed and verified the underlying data.
Data sharing statement
The trial protocol, statistical analysis plan, and data that support the findings of this study are available from the corresponding author upon reasonable request.
Editor note
The Lancet Group takes a neutral position with respect to territorial claims in published content and institutional affiliations.
Declaration of interests
KWL reports research funding to his institution from BeOne; grants or contracts from MSD, AstraZeneca, Ono Pharmaceutical, Merck KGaA, Pfizer, Astellas Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Celltrion, ALX Oncology, Bolt Biotherapeutics, Leap Therapeutics, MedPacto, Ildong Pharmaceutical, Roche, Amgen, Arcus Biosciences, Jazz Pharmaceuticals, Exelixis, IgM Biosciences, GlaxoSmithKline, Panolos Bioscience, Metafines, Wellmarker Bio, Medicenna, Hanmi, Torl Biotherapeutics, Bayer, Boehringer Ingelheim, Yuhan, Avelos Therapeutics, IDRx, Jiangsu Hengrui Pharmaceuticals, ImmuneOncia, and Aptabio; consulting fees from Astellas Pharma, AstraZeneca, Daiichi Sankyo, MSD, ONO pharmaceutical, BeOne, Abbvie, Takeda, Pin Therapeutics, and ImmuneOncia; honoraria for lectures or presentations from Astellas Pharma, Ono Pharmaceutical, BeOne, Sanofi-Aventis, AstraZeneca, Bayer, MSD, Merck KGaA, and Celltrion; and participation on an advisory board for ALX Oncology (uncompensated).
MM reports grants or contracts to his institution from Amgen, Leap Therapeutics, Merck Serono, AstraZeneca, MSD, and Taiho Pharmaceutical; consulting fees from Bayer, MSD, Merck Serono, Amgen, Taiho Pharmaceutical, Lilly, Servier, BeOne, BMS, Astra-Zeneca, Daiichi Sankyo Europe GmbH, Takeda, and Astellas Pharma; honoraria for lectures or presentations from Amgen, Merck Serono, MSD Oncology, Bristol-Myers Squibb, AstraZeneca/MedImmune, Pierre Fabre, Transcenta, Idience, Triptych Health Partners, Daiichi Sankyo Europe GmbH, Astellas Pharma, and Bayer Schering Pharma; and support for attending meetings or travel from Amgen, Merck Serono, Roche, Bayer, ASCO, German Cancer Society, MSD, ESMO, BeOne, and Sanofi Pasteur.
HH reports grants or contracts to his institution from PPD, Daiichi Sankyo, Nippon Boehringer Ingelheim, ALX Oncology, BeOne, Novartis, Amgen, Bristol-Myers Squibb, Taiho Pharmaceutical, Seagen, and Janssen Pharmaceutical; and honoraria for lectures or presentations from Astellas, Taiho Pharmaceutical, Novartis, Bristol-Myers Squibb, Ono Pharmaceutical, and Daiichi Sankyo.
SYR reports grants or contracts to him and his institution from MSD Oncology, Bristol-Myers Squibb, Eisai, Roche/Genentech, ASLAN Pharmaceuticals, Sillajen, Bayer, Daiichi Sankyo, Eli Lilly, AstraZeneca, BeOne, Astellas Pharma, Indivumed, Amgen, Boehringer Ingelheim, and Jazz Pharmaceuticals; consulting fees from MSD Oncology, Daiichi Sankyo, Eisai, LG chemical Ltd., Astellas Pharma, Indivumed, AstraZeneca, Ono Pharmaceutical, Amgen, Toray Industries, Arcus Biosciences, and BeOne; and honoraria for lectures or presentations from Eisai, MSD Oncology, BMS/Ono, Amgen, Daiichi Sankyo/UCB Japan, AstraZeneca, Astellas Pharma, Arcus Biosciences, and BeOne.
RHX reports consulting fees from Hutchison, Hengrui, Junshi, Qilu, CPPC, F Hoffmann-La Roche, and Merck Serono; and participation on a data safety monitoring board or advisory board for Astellas, Merck Sharp and Dohme, AstraZeneca, Junshi, Hengrui, BeOne, Innovent, CPPC, and Keymed Biosciences.
All other authors declare no competing interests.
Acknowledgements
This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0543800), National Natural Science Foundation of China (82321003), the Guangdong Basic and Applied Basic Research Foundation (2024B1515020120), Cancer Innovative Research Program of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0004), Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-PT22142001) and Sanming Project of Medicine in Shenzhen (SZSM202211017).
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2026.103980.
Contributor Information
Miao-Zhen Qiu, Email: qiumzh@sysucc.org.cn.
Rui-Hua Xu, Email: xurh@sysucc.org.cn.
Appendix A. Supplementary data
References
- 1.Bray F., Laversanne M., Sung H., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
- 2.Stomach Cancer Collaborators G.B.D. The global, regional, and national burden of stomach cancer in 195 countries, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):42–54. doi: 10.1016/S2468-1253(19)30328-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Torre L.A., Siegel R.L., Ward E.M., Jemal A. Global cancer incidence and mortality rates and Trends--An update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16–27. doi: 10.1158/1055-9965.EPI-15-0578. [DOI] [PubMed] [Google Scholar]
- 4.Zhao J.K., Wu M., Kim C.H., et al. Jiangsu Four Cancers Study: a large case-control study of lung, liver, stomach, and esophageal cancers in Jiangsu Province, China. Eur J Cancer Prev. 2017;26(4):357–364. doi: 10.1097/CEJ.0000000000000262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Society of Gastric Cancer of China Anti-Cancer A CACA guidelines for holistic integrative management of gastric cancer. Holist Integr Oncol. 2022;1(1):3. doi: 10.1007/s44178-022-00007-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Yao X., Ajani J.A., Song S. Molecular biology and immunology of gastric cancer peritoneal metastasis. Transl Gastroenterol Hepatol. 2020;5:57. doi: 10.21037/tgh.2020.02.08. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Rijken A., Lurvink R.J., Luyer M.D.P., et al. The burden of peritoneal metastases from gastric cancer: a systematic review on the incidence, risk factors and survival. J Clin Med. 2021;10(21):4882. doi: 10.3390/jcm10214882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Shablak A., Zar L., Abdalhadi A., et al. Comparison of survival between liver-only metastasis and other metastatic sites in patients with de novo stage 4 gastric cancer: nationwide data from a single institute. J Clin Oncol. 2025;43(16_suppl):e16044. [abstract] [Google Scholar]
- 9.Ajani J.A., D'Amico T.A., Bentrem D.J., et al. Gastric cancer, version 2.2025, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2025;23(5):169–191. doi: 10.6004/jnccn.2025.0022. [DOI] [PubMed] [Google Scholar]
- 10.Janjigian Y.Y., Shitara K., Moehler M., et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27–40. doi: 10.1016/S0140-6736(21)00797-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Rha S.Y., Oh D.Y., Yanez P., et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(11):1181–1195. doi: 10.1016/S1470-2045(23)00515-6. [DOI] [PubMed] [Google Scholar]
- 12.Shen L., Zhang Y., Li Z., et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat Med. 2025;31(4):1163–1170. doi: 10.1038/s41591-024-03450-4. [DOI] [PubMed] [Google Scholar]
- 13.Shitara K., Van Cutsem E., Bang Y.J., et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571–1580. doi: 10.1001/jamaoncol.2020.3370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Xu J., Jiang H., Pan Y., et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial. JAMA. 2023;330(21):2064–2074. doi: 10.1001/jama.2023.19918. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zhang X., Wang J., Wang G., et al. First-line sugemalimab plus chemotherapy for advanced gastric cancer: the GEMSTONE-303 randomized clinical trial. JAMA. 2025;333(15):1305–1314. doi: 10.1001/jama.2024.28463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kang Y.K., Chen L.T., Ryu M.H., et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23(2):234–247. doi: 10.1016/S1470-2045(21)00692-6. [DOI] [PubMed] [Google Scholar]
- 17.Janjigian Y.Y., Shitara K., Ajani J.A., et al. Nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 5-year follow-up results from CheckMate 649. Ann Oncol. 2026 doi: 10.1016/j.annonc.2026.02.003. https://www.sciencedirect.com/science/article/pii/S0923753426000591 Available at: [DOI] [PubMed] [Google Scholar]
- 18.Qiu M.Z., Oh D.Y., Kato K., et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024;385 doi: 10.1136/bmj-2023-078876. [DOI] [PubMed] [Google Scholar]
- 19.Cruz-Correa M., Oh D.Y., Kato K., et al. 1437P Tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in HER2-negative advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJC): RATIONALE-305 study minimum 3-year survival follow-up. Ann Oncol. 2024;35:S893–S894. [abstract] [Google Scholar]
- 20.Moehler M., Oh D.Y., Kato K., et al. 397MO Tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in HER2-negative advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma (GC/GEJC): PD-L1 biomarker analysis from RATIONALE-305. Ann Oncol. 2024;35:S160–S161. [abstract] [Google Scholar]
- 21.Mantovani A., Allavena P., Marchesi F., Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov. 2022;21(11):799–820. doi: 10.1038/s41573-022-00520-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Zhang T., Song X., Xu L., et al. The binding of an anti-PD-1 antibody to FcgammaRIota has a profound impact on its biological functions. Cancer Immunol Immunother. 2018;67(7):1079–1090. doi: 10.1007/s00262-018-2160-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
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