At NCCN 2026 (NCCN Annual Conference 2026), Mary F. Mulcahy, MD, presented an updated overview of the treatment landscape for gastric, esophageal, and esophagogastric junction cancers, highlighting how management is increasingly shaped by histology, disease location, and biomarker status. As the speaker emphasized, this is a complex area because these cancers span different biologic subtypes and are addressed across separate NCCN guidelines.
Although gastric cancer is not among the most common malignancies in the United States, it remains a major global burden. The presentation noted an estimated 31,510 new gastric cancer cases and 10,740 deaths in the United States in 2026. Important risk factors include Helicobacter pylori, smoking, alcohol, salt exposure, and processed meats. Esophageal cancer also remains a significant challenge, with 22,530 new cases and 16,290 deaths projected for 2026. While esophageal squamous cell carcinoma has declined over time in the United States, largely in parallel with decreased smoking, esophageal adenocarcinoma continues to rise, especially in cardia-associated disease.
A major theme of the session was tumor heterogeneity. Dr. Mulcahy noted that adenocarcinomas of the stomach, esophagus, and EGJ can arise through several molecular pathways, including chromosomal instability, genomic stability, microsatellite instability, and Epstein-Barr virus–associated disease, whereas squamous cell carcinoma is biologically more uniform. This distinction is clinically important because modern treatment selection depends heavily on biomarker evaluation. Current NCCN principles recommend assessment of HER2, PD-L1, MMR/MSI, and CLDN18.2, with broader molecular profiling when appropriate.
Among these biomarkers, HER2 remains one of the most clinically relevant in gastroesophageal adenocarcinoma. HER2 expression is seen in approximately 15% of gastric cancers and up to 30% of gastroesophageal junction adenocarcinomas. HER2 abnormalities may include overexpression, amplification, or mutation, and all can influence treatment decisions. The presentation also highlighted the heterogeneity of HER2 between primary and metastatic sites. In one series discussed during the talk, nearly 20% of cases showed discordance between primary and metastatic samples, reinforcing the point that these tumors evolve over time and may require repeat biopsy.
Another emerging biomarker is Claudin 18.2 (CLDN18.2), a tight-junction protein that becomes targetable when mucosal integrity is disrupted. This marker has become particularly important in HER2-negative gastric and EGJ adenocarcinoma. The presentation reviewed the development of zolbetuximab, a monoclonal antibody directed against CLDN18.2, and noted that positivity is generally defined by moderate-to-strong membranous staining in at least 75% of tumor cells. Dr. Mulcahy also emphasized that CLDN18.2 expression appears relatively consistent across geographic regions, unlike some other molecular features in gastroesophageal cancer.
The session also addressed the ongoing challenge of PD-L1 testing. Different studies have used tumor proportion score (TPS), combined positive score (CPS), or tumor area positivity (TAP), making cross-trial interpretation difficult. The speaker explained that CPS and TAP now appear sufficiently concordant to be used interchangeably in clinical decision-making, an important practical point as more immunotherapy-based regimens enter routine care.
For localized disease, treatment recommendations now differ clearly by histology. According to the NCCN slides reviewed during the session, perioperative systemic therapy is preferred for esophageal adenocarcinoma, esophagogastric adenocarcinoma, and gastric adenocarcinoma, whereas preoperative chemoradiation remains preferred for esophageal squamous cell carcinoma. Postoperative nivolumab is reserved for patients with esophageal or EGJ carcinoma who received preoperative chemoradiation, underwent R0 resection, and had residual disease on pathology.
Dr. Mulcahy reviewed the evolving data supporting these recommendations. CheckMate 577 established adjuvant nivolumab after neoadjuvant chemoradiotherapy and surgery in patients with residual disease, initially on the basis of disease-free survival benefit. However, the more recent overall survival analysis showed that although nivolumab numerically prolonged survival, the study did not meet statistical significance for overall survival, adding nuance to how clinicians interpret its role. The presentation suggested that benefit may be more pronounced in squamous cell carcinoma and in patients with PD-L1 CPS ≥1, though these subgroup findings should be interpreted cautiously.
The talk also highlighted the increasing role of perioperative FLOT in adenocarcinoma. Data comparing perioperative chemotherapy with preoperative chemoradiotherapy in esophageal cancer showed improved outcomes with FLOT, supporting a broader move toward perioperative systemic therapy for adenocarcinoma. The MATTERHORN study further strengthened this direction by demonstrating improved event-free survival with durvalumab plus FLOT in gastric and EGJ cancer. These findings helped shape the current guideline preference for perioperative therapy in localized adenocarcinoma.
For advanced adenocarcinoma, the treatment landscape is now firmly biomarker-driven. In HER2-positive disease, the foundation remains trastuzumab plus chemotherapy, based on the landmark ToGA trial. This strategy has since evolved with KEYNOTE-811, which added pembrolizumab to trastuzumab and chemotherapy in the first-line setting for HER2-positive advanced gastric or EGJ adenocarcinoma. For patients whose tumors continue to express HER2 after progression, trastuzumab deruxtecan has emerged as an important later-line option, though the presentation stressed the importance of confirming persistent HER2 positivity before using it.
In HER2-negative adenocarcinoma, immunotherapy now plays a central role, particularly in PD-L1–positive disease. Dr. Mulcahy reviewed CheckMate 649, KEYNOTE-590, and RATIONALE-305, all of which support adding a PD-1 inhibitor to chemotherapy in selected patients. Across these studies, a consistent pattern emerged: the higher the PD-L1 expression, the greater the apparent benefit from immunotherapy.
For tumors that are CLDN18.2-positive and HER2-negative, zolbetuximab-based therapy has become a major new option. The presentation reviewed the SPOTLIGHT and GLOW trials, both of which supported the addition of zolbetuximab to chemotherapy in this molecular subgroup. At the same time, the speaker noted that these regimens can be associated with substantial nausea, vomiting, and appetite loss, which must be weighed during treatment selection.
For advanced esophageal squamous cell carcinoma, the treatment algorithm is somewhat more straightforward. The session reviewed KEYNOTE-590, CheckMate 648, and RATIONALE-306, all of which support first-line PD-1 inhibitor–based therapy. In CheckMate 648, both nivolumab plus chemotherapy and nivolumab plus ipilimumab improved overall survival versus chemotherapy alone, further establishing immunotherapy as a key component of treatment in this setting.
The presentation closed with a look at emerging therapies, including zanidatamab, a bispecific HER2-targeted antibody, and bemarituzumab, which targets FGFR2b. While both remain promising, Dr. Mulcahy emphasized that the most immediate clinical lesson is the importance of recognizing tumor heterogeneity. Biomarker profiles may differ between the primary tumor and metastatic sites and may change over time under treatment pressure. As a result, repeat biopsy and repeat biomarker testing should be strongly considered whenever the clinical picture changes.
Key Takeaway
The NCCN 2026 update underscores that gastric, esophageal, and EGJ cancers are no longer managed with a one-size-fits-all approach. In localized adenocarcinoma, perioperative FLOT with or without durvalumab is increasingly central, while chemoradiation remains the standard for squamous cell carcinoma. In advanced disease, treatment is now defined by HER2, PD-L1, CLDN18.2, and MSI/MMR status, with repeat biopsy playing an increasingly important role in guiding care