Gastric cancer and gastroesophageal junction cancer collectively represent one of the most significant oncological challenges globally, with gastric cancer ranking as the fifth most common cancer diagnosis and the fourth leading cause of cancer death worldwide. The geographical distribution of gastric cancer is markedly non uniform, with substantially higher incidence rates in East Asia, Eastern Europe, and parts of South America compared to North America and Western Europe, reflecting the differential prevalence of Helicobacter pylori infection, dietary risk factors, and genetic susceptibility across populations. Gastroesophageal junction cancers, which arise at or within five centimeters of the anatomical junction between the esophagus and stomach, share molecular and clinical characteristics with both esophageal adenocarcinoma and gastric adenocarcinoma, creating a classification challenge that has been approached differently across oncological disciplines and regulatory jurisdictions.
The molecular heterogeneity of gastric and gastroesophageal junction cancers is substantial, encompassing tumors driven by HER2 amplification, microsatellite instability, Epstein Barr virus infection, and chromosomal instability as major genomic subtypes with distinct biological behaviors and treatment sensitivities. HER2 amplification, present in approximately 15 to 20 percent of gastric and gastroesophageal junction adenocarcinomas, was the first targetable molecular alteration to yield an approved targeted therapy when trastuzumab demonstrated an overall survival benefit in combination with chemotherapy. Microsatellite instability, present in approximately 5 to 10 percent of gastric cancers, predicts exceptional sensitivity to immune checkpoint inhibition and is now a biomarker that guides first line treatment selection. EBV positive gastric cancers, comprising approximately 10 percent of cases, display high PD L1 expression and may represent another particularly immunotherapy responsive subgroup.
PD L1 Expression and Biomarker Landscape
PD L1 expression in gastric and gastroesophageal junction cancers is assessed using the combined positive score, which accounts for expression on both tumor cells and immune cells within the tumor microenvironment. The combined positive score shows substantial variability across gastric cancer tumors, with higher scores associated with greater immunotherapy responsiveness in clinical trials. The KEYNOTE 590 and KEYNOTE 811 trials established PD L1 combined positive score as a key biomarker for pembrolizumab treatment decisions in upper gastrointestinal malignancies, with patients with CPS of ten or greater deriving the most pronounced survival benefit from pembrolizumab addition to standard chemotherapy regimens.
Tumor mutational burden has also been evaluated as a predictive biomarker in gastric and gastroesophageal junction cancer, with high mutational burden identified as an independent predictor of pembrolizumab response in the KEYNOTE 158 basket trial that evaluated pembrolizumab across multiple solid tumor types. MSI high status, which is associated with exceptionally high tumor mutational burden, has been established as a biomarker for pembrolizumab across all solid tumor types through the accelerated histology agnostic approval of pembrolizumab for MSI high solid tumors, making comprehensive molecular profiling of gastric and gastroesophageal junction cancers at diagnosis essential for optimal treatment selection.
Pembrolizumab in First Line Gastric Cancer Treatment
The KEYNOTE 590 trial evaluated pembrolizumab combined with fluorouracil and cisplatin for the first line treatment of locally advanced or metastatic esophageal cancer including gastroesophageal junction tumors with squamous histology or adenocarcinoma. The trial demonstrated significant overall survival benefits for pembrolizumab across the overall population, with particularly pronounced benefits in patients with high PD L1 combined positive scores. Building on these results, the KEYNOTE 811 trial addressed gastric and gastroesophageal junction adenocarcinomas specifically, evaluating pembrolizumab added to trastuzumab and fluoropyrimidine platinum chemotherapy for HER2 positive tumors. The trial demonstrated significant objective response rate improvements and subsequently confirmed progression free survival benefits, establishing Keytruda as part of the standard first line regimen for HER2 positive gastric and gastroesophageal junction cancers.
For HER2 negative gastric and gastroesophageal junction adenocarcinoma, the KEYNOTE 859 trial evaluated pembrolizumab combined with fluoropyrimidine and platinum chemotherapy, demonstrating significant overall survival improvement in the overall patient population and particularly strong benefits in patients with high PD L1 combined positive scores. These results have expanded the indication for pembrolizumab in gastric cancer beyond HER2 positive disease to encompass HER2 negative adenocarcinomas with PD L1 expression, establishing checkpoint inhibition as a component of standard first line treatment across a broad population of gastric and gastroesophageal junction cancer patients.
Second Line and Subsequent Therapy
Prior to pembrolizumab approval, second line options for platinum refractory gastric cancer included ramucirumab with paclitaxel, taxane monotherapy, and irinotecan, none of which produced substantial response rates or meaningfully extended overall survival. The KEYNOTE 061 trial evaluated pembrolizumab versus paclitaxel as second line therapy for gastric or gastroesophageal junction adenocarcinoma with PD L1 combined positive scores of one or greater, demonstrating a trend toward improved overall survival that did not reach statistical significance in the overall population but suggested benefit in patients with higher PD L1 scores. These results highlighted the importance of biomarker driven patient selection for immunotherapy in later lines of gastric cancer treatment and the greater benefit achievable when pembrolizumab is used in the first line setting where patients are less heavily pretreated.
The treatment of MSI high gastric cancer deserves particular attention, as this molecular subgroup demonstrates exceptional sensitivity to PD 1 blockade across treatment lines. Pembrolizumab achieves objective response rates exceeding 40 to 50 percent in MSI high gastric cancer, substantially higher than in microsatellite stable disease, and produces complete responses and durable remissions at rates that are rare with conventional chemotherapy in this disease. The accelerated approval of pembrolizumab for any MSI high or mismatch repair deficient solid tumor has made pembrolizumab available for MSI high gastric cancer patients regardless of prior treatment history, providing an important treatment option for a molecular subgroup with otherwise limited effective options.
Perioperative and Adjuvant Strategies
The investigation of perioperative immunotherapy for resectable gastric and gastroesophageal junction cancer builds on the established benefit of perioperative chemotherapy demonstrated in the FLOT4 and MAGIC trials. Multiple phase III trials are evaluating the addition of pembrolizumab or other checkpoint inhibitors to perioperative chemotherapy, with the goal of improving pathological complete response rates at surgery and event free survival outcomes compared to chemotherapy alone. Pathological complete response, achieved in 8 to 15 percent of patients with standard perioperative chemotherapy, may be substantially higher with immunotherapy containing regimens based on phase II data, and achieving pathological complete response in gastric cancer is strongly associated with improved long term survival outcomes.
The rationale for perioperative immunotherapy in gastric cancer is supported by the inflammatory and immunologically active nature of many gastric cancers, the potential for neoadjuvant immunotherapy to reduce tumor bulk and facilitate more complete surgical resection, and the opportunity for adjuvant continuation of pembrolizumab to address microscopic residual disease following surgery. Patient selection based on PD L1 expression, MSI status, and other molecular markers will be essential for identifying the patient populations most likely to benefit from the addition of pembrolizumab to perioperative treatment, as the molecular heterogeneity of gastric cancer means that the benefits of immunotherapy are likely to be concentrated in specific biomarker defined subgroups.
Conclusion
Gastric and gastroesophageal junction cancer treatment has been meaningfully advanced by the integration of pembrolizumab into first line chemotherapy regimens, delivering survival benefits that extend the modest improvements previously achievable with HER2 targeted therapy and anti angiogenic agents. Keytruda has established itself as a component of standard first line treatment across HER2 positive and HER2 negative gastric adenocarcinomas with PD L1 expression, and as an exceptional option for the MSI high subgroup regardless of PD L1 status. Continued investigation in the perioperative setting and the development of rational combination strategies will further expand the clinical impact of pembrolizumab in this globally significant malignancy.
