---
title: "First-line immunotherapy for advanced gastric cancer: article content not available on source page"
id: "frontiers-in-immunology-17-efficacy-hierarchy-and-absolute-survival-benefit-of-first-line-immunotherapy-in"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-efficacy-hierarchy-and-absolute-survival-benefit-of-first-line-immunotherapy-in"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1866848"
published_at: "2026-08-17T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# First-line immunotherapy for advanced gastric cancer: article content not available on source page
## Provenance & Clinical Metadata
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- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1866848)
- **Published At:** 2026-08-17T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The provided Frontiers in Immunology page did not include the article text for the meta-analysis titled on **first-line immunotherapy** in **advanced gastric cancer**; only site navigation and journal metadata were present. - Key study elements such as objectives, inclusion criteria, search strategy, number and identity of trials, patient populations, and intervention details were not reported on the captured source. - No numerical results were available for pooled overall survival, progression-free survival, hazard ratios, absolute survival benefit, or ranking/evidence hierarchy of immunotherapy regimens. - Details on subgroup analyses (for example by PD-L1 status, MSI, tumor histology, geographic region, or chemotherapy backbone) were not reported in the source capture. - Methods for meta-analysis including statistical models, heterogeneity assessment, risk-of-bias evaluation, and sensitivity analyses were not available from the page content provided. - Safety and adverse-event data, treatment discontinuation rates, or quality-of-life outcomes were not accessible in the captured content. - Any authorship, institutional affiliations, trial identifiers, publication date, figures, tables, and full references were absent from the provided page snapshot. - Because the source capture lacks the article body, no evidence-based clinical conclusions, numerical effect sizes, or guideline implications can be extracted or summarized from this source alone. - To obtain the missing clinical and quantitative details, consultation of the full article on the Frontiers website or access to the published PDF is required; the source page includes navigation links but did not display the article text in the captured content. - This summary reports only what was present (site navigation and journal sections) and what was not reported; no additional data or outcomes have been inferred or invented.
## Clinical Analysis & Structured Key Points
Frontiers | Efficacy hierarchy and absolute survival benefit of first-line immunotherapy in advanced gastric cancer: a meta-analysis and pooled survival analysis SYSTEMATIC REVIEW article Front. Immunol. , 17 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1866848 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Checkpoint immunotherapy: Reshaping the landscape of gastrointestinal cancer treatment - Volume III Submission open 6170 views 9 articles Editor & Reviewers Edited by S P Stavros P. Papadakos Reviewed by A H Atsushi Horiuchi G A Gülin Alkan Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Table 1 Characteristics of the included studies. View in article SYSTEMATIC REVIEW article Front. Immunol. , 17 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1866848 Efficacy hierarchy and absolute survival benefit of first-line immunotherapy in advanced gastric cancer: a meta-analysis and pooled survival analysis J L Jialun Lv 1,2 K T Krishnapriya Thangaretnam 1,2 M O Md Obaidul Islam 1,2 J T Jason Tang 3 S D Sabine Denize 4 N B Nadeem Bhat 1,2 S Z Shoumin Zhu 1,2 H L Heng Lu 1,2 D P Dunfa Peng 1,2 W E Wael El-Rifai 1,2,5 +2 more Z C Zheng Chen 1,2 * 1. Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States 2. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States 3. American Heritage Schools, Broward Campus, Plantation, Florida, FL, United States 4. Doctors Charter School of Miami Shores, Miami shores, FL, United States 5. Department of Veterans Affairs, Miami Healthcare System, Miami, FL, United States See more Article metrics View details Abstract Background: While immune checkpoint inhibitors (ICIs) have revolutionized first-line treatment for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, outcomes across phase III trials remained heterogeneous. This study aimed to determine the efficacy and safety of ICI plus chemotherapy, and to define a clinically meaningful PD-L1 expression threshold through a meta-analysis. Methods: We systematically searched PubMed, Embase, and Cochrane for phase III randomized controlled trials (up to November 2025) comparing ICI-chemotherapy combinations against chemotherapy alone in patients with advanced gastric or GEJ adenocarcinoma. The combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. Safety was assessed through the combined risk ratio (RR) of grade ≥3 adverse events (AEs) and serious adverse events (SAEs). Results: Eight trials involving 7,127 patients with previously untreated, HER2-negative, advanced gastric or GEJ adenocarcinoma were included. The pooled analysis showed a significant improvement in OS (HR = 0.79) and PFS (HR = 0.71) with immunochemotherapy versus chemotherapy alone. Immunochemotherapy was associated with longer median OS (14.4 vs 12.6 months) and PFS (7.3 vs 6.2 months). Treatment benefit increased with higher PD-L1 combined positive score (CPS): OS HRs were 0.90 (CPS < 1), 0.76 (CPS ≥ 1), 0.74 (CPS ≥ 5), and 0.65 (CPS ≥ 10). Combination therapy modestly increased grade ≥3 AEs (RR = 1.16) and SAEs (RR = 1.54) compared with chemotherapy alone. Conclusions: Our results supported the strategy of first-line immunochemotherapy, which significantly prolongs OS and PFS in advanced gastric and GEJ adenocarcinoma with manageable toxicity. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251180445 , identifier CRD420251180445. Introduction Gastric and gastroesophageal junction (GEJ) adenocarcinomas impose a substantial global burden, ranking fifth in incidence and fourth in cancer mortality worldwide ( 1 ). Despite advances in surgery and systemic therapy, outcomes in advanced settings remain poor. Median overall survival (OS) with fluoropyrimidine–platinum doublets rarely exceeds 12 months ( 2 ). Hence, developing systemic strategies that deliver meaningful survival gains has become a central aim in contemporary gastric cancer research. Immune checkpoint inhibitors (ICIs) directed against programmed cell death-1 (PD-1) or its ligand PD-L1 have fundamentally changed the treatment landscape for several solid tumors, including gastric and GEJ adenocarcinoma ( 3 ). Introducing ICIs into first-line therapy rests on a biological advantage: cytotoxic chemotherapy may increase tumor antigen release and presentation, enhance T-cell infiltration, and mitigate tumor-driven immunosuppression, thereby augmenting PD-1 blockade ( 4 ). Multiple large phase III randomized controlled trials (RCTs), including CheckMate-649, ATTRACTION-4, KEYNOTE-062, ORIENT-16, and RATIONALE-305—have tested PD-1 inhibitors such as nivolumab, pembrolizumab, sintilimab, and tislelizumab in combination with chemotherapy for advanced patients ( 3 , 5 – 8 ). The findings of these pivotal trials have been inconsistent. CheckMate-649 showed clinically meaningful improvements in OS and progression-free survival (PFS), particularly in tumors with a PD-L1 combined positive score (CPS) ≥5, whereas ATTRACTION-4 improved PFS without an OS advantage in an all-Asian cohort ( 5 , 6 ). KEYNOTE-062 reported mixed results, with limited benefit for pembrolizumab plus chemotherapy over chemotherapy alone in patients with PD-L1 CPS ≥1 tumor ( 9 ). These discrepancies may stem from variations in PD-L1 testing assays, CPS thresholds, chemotherapy backbones, or ethnic composition of the enrolled patients ( 10 ). However, the predictive role of PD-L1 remains unsettled. Although CPS is widely used, the optimal clinical cut-off has not been firmly defined ( 11 ). Emerging subgroup analyses also suggest that age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), liver metastases, and tumor location may influence treatment effects ( 12 , 13 ). A rigorous synthesis of phase III data is therefore needed to quantify the magnitude and consistency of benefits from ICI-based regimens and to identify patient groups most likely to derive a survival advantage. Consequently, we conducted a systematic review and meta-analysis of phase III RCTs comparing first-line ICI plus chemotherapy versus chemotherapy alone in advanced gastric and GEJ adenocarcinoma. The primary objectives were to: (1) estimate pooled effects on OS and PFS; (2) examine effect modification by PD-L1 CPS and key clinicopathologic subgroups; and (3) characterize the safety profile of ICI-based combinations. Methods Search strategy and selection criteria This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( 14 ). The research protocol was registered on the International Prospective Register of Systematic Reviews (CRD420251180445). A comprehensive search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) was performed up to November 2025, using the following keywords and Medical Subject Headings (MeSH) terms: (“gastric cancer” OR “gastroesophageal junction cancer” OR “stomach neoplasms”) AND (“immune checkpoint inhibitor” OR “PD-1” OR “PD-L1” OR “nivolumab” OR “pembrolizumab” OR “sintilimab” OR “tislelizumab” OR “cadonilimab” OR “sugemalimab”) AND “randomized controlled trial” . Only phase III randomized controlled trials (RCTs) comparing ICI plus chemotherapy versus chemotherapy alone as the first-line treatment for advanced or metastatic gastric or GEJ adenocarcinoma were included. Inclusion and exclusion criteria Eligible studies met the following criteria: (1) randomized phase III design; (2) patients with histologically confirmed, unresectable or metastatic gastric or GEJ adenocarcinoma; (3) Intervention: PD-1 or PD-L1 inhibitor in combination with platinum–fluoropyrimidine chemotherapy; (4) comparator: chemotherapy alone; (5) reported hazard ratios (HRs) and 95% confidence intervals (CIs) for OS or PFS. The exclusion criteria were as follows: (1) phase I/II trials, (2) neoadjuvant or adjuvant settings, (3) single-arm studies, or (4) duplicated datasets. Data extraction and quality assessment Two reviewers independently abstracted the trial-level characteristics using a standardized extraction form: study design, sample size, follow-up duration, PD-L1 testing platform, and HRs for OS and PFS. Where reported, we also captured subgroup HRs stratified by CPS threshold, age, sex, Eastern Cooperative Oncology Group performance status, liver metastases, tumor location, and geographic region. Disagreements were reconciled through discussion. The methodological quality of each trial was appraised using the Cochrane Risk of Bias 2.0 tool ( 15 ), covering random sequence generation, allocation concealment, blinding, completeness of outcome data, and selective outcome reporting. Statistical analysis We pooled HRs and 95% CIs for OS and PFS using the DerSimonian–Laird random-effects model to accommodate between-trial heterogeneity. For binary safety outcomes—grade ≥3 adverse events (AEs) and serious adverse events (SAEs)—risk ratios (RRs) were synthesized via the Mantel–Haenszel random-effects approach. The DerSimonian–Laird random-effects model was selected as the primary pooling method because it provides conservative variance estimates and facilitates comparisons with prior meta-analyses in gastric cancer. Although restricted maximum-likelihood (REML) estimation can offer less biased between-study variance estimates, particularly with a large number of trials, simulation studies suggest that the DerSimonian–Laird method performs comparably when the number of included studies is small (n < 10). Given that this meta-analysis incorporated eight phase III trials, the DerSimonian–Laird approach was considered statistically appropriate and ensured methodological consistency with previously published immunotherapy meta-analyses. Heterogeneity was quantified using Cochran’s Q test (significance threshold P < 0.10) and the I 2 statistic, interpreted as low (25%), moderate (50%), or high (≥75%). When ten or more studies were available, we examined small-study effects and potential publication bias through Egger’s regression and funnel plots. Prespecified subgroup analyses examined effect modification by PD-L1 CPS (<1, ≥1, ≥5, ≥10), age (<65 versus ≥65 years), sex, ECOG PS (0 versus 1), presence of liver metastases, tumor location (gastric versus GEJ), and geographic region (Asia versus non-Asia). Sensitivity analyses sequentially omitted individual trials to test the robustness of the summary estimates. We reconstructed individual patient data (IPD) from published Kaplan–Meier curves using a two-stage algorithmic framework described by Guyot et al., implemented through the R package IPDfromKM ( 16 ). In the first stage, we digitized each curve and extracted the time points and the corresponding survival probabilities for each treatment arm. In the second stage, we integrated the extracted coordinates with reported numbers at risk and total sample sizes at each specified time point to estimate event and censoring patterns, thereby generating patient-level time-to-event data. The reconstructed IPD from all eligible trials were pooled into a unified analysis dataset. Reconstruction accuracy was assessed by comparing the reproduced risk tables, hazard ratios, and overall shapes of the regenerated Kaplan–Meier curves with the values reported in the original publications. All computations were performed in R (version 4.5.0) using the meta and meta for packages. Forest, funnel, and Galbraith radial plots were generated using custom scripts built on a meta-framework. Network meta-analysis To ascertain the comparative efficacy of various immune checkpoint inhibitors, a network meta-analysis was formulated within a frequentist framework utilizing the netmeta package in R. The network geometry was primarily star-shaped, predicated on chemotherapy as the common comparator node. Treatment hierarchies were quantitatively evaluated employing P-scores, a frequentist analog to the surface under the cumulative ranking curve (SUCRA). P-scores measure the extent of certainty that a specific intervention encompasses superior efficacy relative to competing regimens, bounded between 0 and 1. Outcomes The primary outcome was OS. Secondary outcomes included PFS, subgroup efficacy across prespecified clinical and biomarker strata, and treatment-related toxicity (grade ≥3 AEs and SAEs). Results Study selection and characteristics of included studies A total of 161 records were identified through the initial database search, of which eight phase III randomized controlled trials met the inclusion criteria and were included in the final analysis ( 5 – 9 , 17 – 19 ) ( Supplementary Figure 1 ). These trials collectively enrolled 7,127 patients with previously untreated, HER2-negative, advanced or metastatic gastric or GEJ adenocarcinoma. All trials compared PD-1 inhibitor plus platinum-fluoropyrimidine chemotherapy with chemotherapy alone. The ICIs included nivolumab (CheckMate-649; ATTRACTION-4), pembrolizumab (KEYNOTE-062; KEYNOTE-859), sintilimab (ORIENT-16), tislelizumab (RATIONALE-305), cadonilimab (COMPASSION-15), and sugemalimab (GEMSTONE-303). All studies were double-blind, except for CheckMate-649, an open-label study. Baseline patient characteristics were well balanced across treatment arms, with median ages ranging from 60 to 63 years and approximately 72% of patients being male. The proportion of participants with a PD-L1 CPS ≥1 ranged from 40% to 85%. Individual study details, including the trial design, population, and reported HRs for OS and PFS, are summarized in Table 1 . Table 1 Study Year Design Intention-to-treat population Experimental arm Control arm Population characteristics OS (95% CI) PFS (95% CI) ATTRACTION-4 2022 Phase 2-3, double-blind RCT ICI+CT: 362 CT: 362 Nivolumab plus CT Placebo plus CT HER2 negative, untreated, unresectable advanced or recurrent G/GEJ adenocarcinoma. 0.90 (0.75-1.08) 0.68 (0.51-0.90) CHECKMATE 649 2021 Phase 3, open label RCT ICI+CT: 789 CT: 792 Nivolumab plus CT CT Untreated, unresectable, non-HER2-positive G/GEJ cancer, and esophageal adenocarcinoma. 0.80 (0.68-0.94) 0.77 (0.68-0.87) COMPASSION- 15 2025 Phase 3, double-blind RCT ICI+CT: 305 CT: 305 Cadonilimab plus CT Placebo plus CT Untreated, HER2 negative unresectable locally advanced or metastatic G/GEJ adenocarcinoma. 0.62 (0.50-0.78) 0.53 (0.44-0.65) GEMSTONE- 303 2025 Phase 3, double-blind RCT ICI+CT:241 CT: 248 Sugemalimab plus CT Placebo plus CT Untreated, no known HER2-positive status, PD-L1 expression ≥ 5%, unresectable advanced or metastatic G/GEJ adenocarcinoma. 0.75 (0.61-0.92) 0.66 (0.54-0.81) KEYNOTE-062 2020 Phase 3, double-blind RCT ICI+CT: 257 CT: 250 Pembrolizumab plus CT Placebo plus CT PD-L1 CPS ≥ 1, HER2 negative, untreated, locally advanced, unresectable, or metastatic G/GEJ adenocarcinoma. 0.85 (0.70-1.03) 0.84 (0.70-1.02) KEYNOTE-859 2023 Phase 3, double-blind RCT ICI+CT: 790 CT: 789 Pembrolizumab plus CT Placebo plus CT Untreated, locally advanced or metastatic HER2 negative G/GEJ adenocarcinoma. 0.78 (0.70-0.87) 0.76 (0.67-0.85) ORIENT-16 2023 Phase 3, double-blind RCT ICI+CT: 327 CT: 323 Sintilimab plus CT Placebo plus CT Unresectable, no known HER2 positive status, locally advanced or metastatic G/GEJ adenocarcinoma. 0.77 (0.63-0.94) 0.64 (0.52-0.77) RATIONALE-305 2024 Phase 3, double-blind RCT ICI+CT: 501 CT: 496 Tislelizumab plus CT Placebo plus CT HER2 negative locally advanced unresectable or metastatic G/GEJ adenocarcinoma. 0.80 (0.70-0.92) 0.78 (0.67-0.90) Characteristics of the included studies. Efficacy in intention-to-treat (ITT) population In the pooled analysis, ICI plus chemotherapy significantly improved OS compared with chemotherapy alone (HR = 0.79, 95% CI 0.75–0.83; p < 0.001; I² = 0%, p_heterogeneity = 0.54) ( Figure 1A ). Similarly, a significant benefit was observed in PFS (HR = 0.71, 95% CI 0.65–0.79; p < 0.001; I²= 62.1%, p_heterogeneity = 0.01) ( Figure 1B ). Figure 1 Forest plots and Kaplan-Meier estimates depicting pooled efficacy outcomes in the intention-to-treat (ITT) population: (A) overall survival (OS) and (B) progression-free survival (PFS) for immune checkpoint inhibitors plus chemotherapy (ICIs + CT) versus chemotherapy (CT) alone. (C) Kaplan-Meier curves for OS (D) Kaplan-Meier curves for PFS. The red line represents the immune checkpoint inhibitor plus chemotherapy (ICI+CT) group, and the blue line represents the chemotherapy (CT) group. Shaded areas indicate the 95% confidence intervals (CI). Vertical tick marks on the curves represent censored data. The reconstructed IPD yielded internally consistent patient-level time-to-event profiles across trials and enabled an integrated assessment of treatment effects. For OS, immunochemotherapy produced a median survival of 14.4 months compared with 12.6 months for chemotherapy alone. The corresponding 12-month OS rates were 57.16% and 50.81%, respectively. The hazard ratio for death was 0.79, reflecting a 21% relative reduction in mortality risk ( Figure 1C ). For PFS, the immunochemotherapy group achieved a median PFS of 7.3 months versus 6.2 months in the chemotherapy group, with 12-month PFS rates of 32.35% and 21.04%, respectively. The hazard ratio for progression or death was 0.74, indicating a 26% reduction in risk ( Figure 1D ). Collectively, these findings demonstrate a consistent survival benefit associated with immunochemotherapy following reconstruction and pooling of the original Kaplan–Meier data. The temporal dynamics of survival benefit were further elucidated via RMST analysis. For overall survival, the absolute mean survival gain (ΔRMST) conferred by immunochemotherapy expanded from 0.38 months at the 12-month landmark to 1.42 months at the 24-month truncation horizon. A congruent pattern was observed for progression-free survival, with the ΔRMST incrementing from 0.88 to 2.13 months over the identical temporal span, corroborating the durable efficacy elicited by PD-1 blockade. There was low-to-moderate heterogeneity among the trials (I² = 0% for OS; 62.1% for PFS). Funnel plots and Egger’s regression tests revealed no significant publication bias (Egger’s p = 0.83 for OS; p = 0.15 for PFS) ( Supplementary Figures 2A , S3A ). Galbraith (radial) plots showed that most studies clustered within 95% confidence limits ( Supplementary Figures 2B , S3B ). Sensitivity analyses confirmed the robustness of these results, with no single study unduly influencing the pooled estimates ( Supplementary Figures 2C , S3C ). Safety in ITT population The safety population included all the patients who received at least one dose of the assigned treatment. Combination therapy with ICI significantly increased the risk of grade ≥ 3 AEs (RR = 1.16, 95% CI 1.09–1.23; p < 0.001; I²= 50.6%, p_heterogeneity = 0.05) and SAEs (RR = 1.54, 95% CI 1.35–1.77; p < 0.001; I²= 33.0%, p_heterogeneity = 0.21) compared with chemotherapy alone ( Figures 2A, B ). Figure 2 Forest plots illustrating safety outcomes in the intention-to-treat (ITT) population: (A) grade 3–5 adverse events (AEs) and (B) serious adverse events (SAEs) reported as relative risk (RR) for immune checkpoint inhibitors plus chemotherapy (ICIs + CT) versus chemotherapy (CT) alone. The most frequently reported high-grade AEs included neutropenia, anemia, and nausea, while immune-related AEs such as thyroid dysfunction, rash, and hepatitis were more common in the ICI group, but were generally manageable with corticosteroids. No significant heterogeneity was detected across safety outco
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