An exploratory biomarker analysis from the CheckMate 649 study identified patient populations with gastric, gastro-oesophageal junction and oesophageal adenocarcinoma that seem to derive greater overall survival (OS) benefit from first-line nivolumab plus chemotherapy or potential benefit from nivolumab plus ipilimumab versus chemotherapy.
KRAS alterations were associated with greater OS benefit when treated with nivolumab plus chemotherapy versus chemotherapy alone, whereas high regulatory T-cell signatures were associated with greater OS benefit when treated with nivolumab plus ipilimumab according to Prof. Yelena Y. Janjigian of the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, NY, US and colleagues, who published the findings on 7 March 2025 in the Nature Medicine.
Nivolumab plus chemotherapy demonstrated superior OS compared with chemotherapy alone in previously untreated, non-HER2-positive advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma in the CheckMate 649 study. However, treatment with nivolumab plus ipilimumab failed to meet the prespecified hierarchically tested secondary endpoint of OS versus chemotherapy in patients with PD-L1 combined positive score ≥ 5, although responses were more durable and the OS rate was higher at 24 months.
The authors wrote in the background that observed efficacy of nivolumab plus chemotherapy in CheckMate 649 may be attributed to the potentiation of chemotherapy-induced cytotoxicity and immunogenic cell death with the antitumour effects of nivolumab. Therefore, responses to nivolumab plus chemotherapy and to nivolumab plus ipilimumab are likely driven by distinct molecular or immunophenotypes of the tumour. Identification of pretreatment biomarkers associated with outcomes with nivolumab-based regimens in gastro-oesophageal adenocarcinoma may help identify patient subgroups that are likely to derive the most clinical benefit.
Among the four molecularly distinct subsets of gastro-oesophageal cancer, MSI-high tumours have the most favourable outcomes with immune checkpoint blockade, whereas studies describing tumours with chromosomal instability or that are genomically stable or EBV-positive are limited.
Select gene expression signatures related to inflammation, stroma or angiogenesis were associated with immune checkpoint blockade outcomes across tumour types; however, there has not been a comprehensive DNA or RNA analysis exploring the relationship of various pretreatment tumour characteristics with therapeutic outcomes in metastatic gastro-oesophageal adenocarcinoma.
To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed from baseline tumours from the CheckMate 649 study using whole exome sequencing (WES) and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, EBV-positive tumours compared with chromosomally unstable and genomically stable tumours.
Benefit in OS with nivolumab plus chemotherapy versus chemotherapy was generally observed regardless of gene alteration status; alterations in TP53, ARID1A and KRAS were the most common in these analyses. Within the KRAS-altered subgroup, only patients treated with nivolumab plus chemotherapy demonstrated improved OS benefit versus chemotherapy.
In RNA sequencing analyses, subgroups with low angiogenesis and low stroma gene expression signature scores were associated with OS benefit with nivolumab plus chemotherapy and nivolumab plus ipilimumab versus chemotherapy; high regulatory T cell signatures were associated with OS benefit only with nivolumab plus ipilimumab.
The authors underlined that although the biomarker-evaluable populations were generally representative of the all randomised study population with respect to demographics, baseline clinical characteristics and outcomes, the small sample sizes of each biomarker subgroup may have resulted in imbalances that are not captured by these measurements. Additionally, these retrospective biomarker analyses were exploratory and therefore were not formally tested or intended to determine statistical significance.
This study provides the largest WES and RNA sequencing datasets with first-line immune checkpoint blockade in patients with gastro-oesophageal adenocarcinoma. The pattern of biomarkers identified in this analysis suggests a role for overlapping (anti-PD1) and distinct (anti-CTLA4) mechanisms from these regimens. Additional prospective clinical studies are needed to determine if these predictive biomarkers hold clinical utility for treatment selection.
This study was supported by Bristol Myers Squibb and Ono Pharmaceutical Co.
Reference
Shitara K, Janjigian YY, Ajani J, et al. Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial. Nature Medicine; Published online 7 March 2025. DOI: https://doi.org/10.1038/s41591-025-03575-0