What question did this study set out to answer?

The study aims to investigate regional heterogeneity in biomarkers predictive of clinical efficacy outcomes in advanced gastric and esophageal cancers.

May 29, 2026

Heterogeneity in biomarkers for advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC) across regions: Insights from CheckMate-649.

Key Points

The study aims to investigate regional heterogeneity in biomarkers predictive of clinical efficacy outcomes in advanced gastric and esophageal cancers.
Conducted post hoc exploratory analyses using whole-exome sequencing and RNA-seq of baseline tumor tissue.
Grouped patients by region: China, Asia (including China), U.S. + Canada + EU, and Latin America.
Characterized genomic subtypes and gene expression signatures associated with various pathways.
Of 1512 patients randomized, 647 were WES-evaluable and 769 RNA-evaluable across regions.
Noted a lower proportion of chromosomal instability subtype and higher proportion of EBV subtype in Latin America.
Gene alterations showed regional variability, with specific alterations like FGFR2 more prevalent in China and altered TP53 in U.S. + Canada + EU.

Abstract

4056 Background: In CheckMate 649, first-line nivolumab plus chemotherapy showed improved clinical efficacy vs chemotherapy in patients (pts) with advanced GC/GEJC/EAC, with varied benefit across regions in a subgroup analysis. To identify biomarkers predictive of differential efficacy outcomes, we did post hoc exploratory biomarker analyses by region. Methods: Post hoc exploratory analyses were done with whole-exome sequencing (WES) and RNA-seq of baseline tumor tissue. Pts were grouped by region: China (CN), Asia (including CN), United States + Canada + European Union (UCE), Latin America (LA). For WES-evaluable pts, gene alterations were profiled and pts grouped into genomic subtypes: chromosomal instability (CIN), genomically stable (GS), hypermutated (H), and Epstein–Barr virus (EBV)-positive. Gene expression signatures (GES) related to mitogen-activated protein kinase (MAPK) pathway, stroma, and angiogenesis were assessed by RNA-seq, and pts were stratified into tertiles based on GES score: high, medium, or low. Results: Of 1512 pts randomized, 647 were WES-evaluable (79, 141, 351, 155 in CN, Asia, UCE, and LA, respectively) and 769 RNA-evaluable (50, 106, 423, 240, respectively). A numerically lower proportion of CIN subtype and higher proportion of EBV subtype was seen in LA vs other regions (Table). Percentage (%) of select gene alterations was generally comparable across regions: of note, there was numerically higher % of altered FGFR2 (10%) in CN, altered TP53 (58%) , KRAS (16%) , CDKN2A (11%), and CDH1 (7%) in UCE, and altered PIK3CA (10%) and ERBB2 (22%) in LA. By contrast, there was numerically lower % of altered EGFR (4%) in Asia and altered ARID1A (8%) in LA. GES profile was broadly similar across regions, with numerically higher % of MAPK-high subgroup in UCE, stroma-medium/low subgroup in LA, and angiogenesis-low subgroup in CN (Table). Conclusions: While the biomarker profile was largely comparable across regions, differential features were noted for certain subgroups; clinical utility of these biomarkers requires validation in future trials. Clinical trial information: NCT02872116 . Regions CN Asia(including CN) UCE LA Genomic subtypes CIN 53 (67) 86 (61) 223 (64) 81 (52) GS 22 (28) 47 (33) 99 (28) 49 (32) H 4 (5) 6 (4) 18 (5) 6 (4) EBV 0 2 (1) 11 (3) 19 (12) GES 5-gene MAPK HighMediumLow 15 (30)13 (26)22 (44) 31 (29)29 (27)46 (43) 145 (34)153 (36)125 (30) 74 (31)79 (33)87 (36) 15-gene stroma HighMediumLow 20 (40)11 (22)19 (38) 38 (36)34 (32)34 (32) 151 (36)138 (33)134 (32) 70 (29)79 (33)91 (38) 5-gene angiogenesis HighMediumLow 15 (30)14 (28)21 (42) 35 (33)34 (32)37 (35) 137 (32)138 (33)148 (35) 81 (34)89 (37)70 (29) Data are n (%). % was calculated as events divided by number of WES- or RNA-seq–evaluable pts.

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