SUMMARY: Gastroesophageal cancers, including gastric, esophageal, and gastroesophageal junction (GEJ) malignancies are among the most common gastrointestinal cancers worldwide. The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer and 22,530 new cases of esophagus cancer will be diagnosed in 2026, and about 10,740 and 16,290 people respectively, will die of the disease.
The burden of disease varies geographically, with gastric cancer occurring more frequently in East Asian populations, while adenocarcinoma of the gastroesophageal junction has shown a rising incidence in Western countries. Squamous cell carcinoma remains the predominant histologic subtype of esophageal cancer globally, although adenocarcinoma is increasingly common in North America and Europe.
One of the major clinical challenges associated with gastroesophageal cancers is that early-stage disease is frequently asymptomatic. As a result, many patients present with unresectable locally advanced or metastatic disease at the time of diagnosis, contributing to persistently poor long-term survival outcomes. Despite advances in multimodal therapy, the overall 5-year survival rate for advanced gastroesophageal cancer remains low.
The rapidly evolving treatment landscape for advanced gastroesophageal cancer has increasingly emphasized biomarker-driven therapy. In 2023, the American Society of Clinical Oncology published guideline recommendations for first-line treatment strategies based on biomarkers such as PD-L1 and HER2 expression, while also addressing the use of targeted agents and immunotherapy in later treatment lines. More recent updates have incorporated emerging evidence from phase III randomized controlled trials evaluating novel immunotherapeutic combinations, targeted therapies, and precision oncology approaches. These updates also highlight the importance of comprehensive biomarker testing and shared decision-making, particularly for patients whose tumors demonstrate multiple actionable biomarkers.
To support these recommendations, ASCO convened an Expert Panel that conducted a systematic review of contemporary evidence in advanced gastroesophageal malignancies. The updated guideline incorporated findings from multiple newly published and updated Phase III clinical trials involving patients with unresectable locally advanced, recurrent, or metastatic disease. Collectively, these studies reflect the continued transition toward individualized treatment strategies aimed at improving survival outcomes and quality of life for patients with advanced gastroesophageal cancer.
Mandatory Biomarker Testing
1.1. Testing to determine the presence of predictive biomarkers PD-L1, dMMR/MSI-H, CLDN18.2, and HER2 in gastroesophageal adenocarcinoma is recommended, and PD-L1 and dMMR/MSI-H status should be tested for ESCC. Clinicians should consider broad-based NGS testing, which includes pan-tumor biomarkers. The results of predictive biomarker testing should be available as soon as possible to inform treatment decision making.
First-Line Therapy
pMMR/MSS HER2-negative gastric/GEJ and esophageal adenocarcinoma
2.1. For patients with pMMR/MSS HER2-negative gastric/GEJ or esophageal adenocarcinoma with PD-L1 expression ≥1 and absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy in combination with immunotherapy may be recommended.
Qualifying statements for Recommendation 2.1:
Immunotherapy benefit has shown a positive association with higher PD-L1 expression (eg, greater benefit with PD-L1 expression ≥10). Not all possible PD-L1 cutoff scores have been assessed. Therefore, the optimal PD-L1 cutoff score balancing benefits and harms is unknown.
Recommended immunotherapy agents include Pembrolizumab, Nivolumab, or Tislelizumab. These agents are considered to have similar efficacy. Selection of a specific agent should be based on dosing schedule, cost considerations, toxicity, and method of administration.
Taking into account the clinical situation, clinicians should avoid withholding the start of chemotherapy while awaiting biomarker testing results.
2.2. For patients with pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma with PD-L1 expression <1 and positive CLDN18.2 expression, fluoropyrimidine and platinum-based chemotherapy combined with Zolbetuximab should be offered.
2.3. For patients with pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma with PD-L1 expression ≥1, and CLDN18.2 expression positivity, fluoropyrimidine and platinum-based chemotherapy combined with immunotherapy or Zolbetuximab may be offered on a case-by-case basis.
Qualifying statement for Recommendation 2.3:
Choice of therapy should take into consideration degree of PD-L1 expression, toxicity profile, burden of symptoms, and anticipated improvement in symptoms associated with response to treatment, patient comorbidities, and prior medical and treatment history.
2.4. For patients with pMMR/MSS HER2-negative gastroesophageal adenocarcinoma, PD-L1 expression <1, and absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy should be offered.
pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma
3.1. For patients with pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma with PD-L1 expression ≥1, Pembrolizumab plus Trastuzumab should be offered, in combination with fluoropyrimidine- and Oxaliplatin-based chemotherapy.
3.2. For patients with pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma with PD-L1 expression <1, Trastuzumab should be offered in combination with fluoropyrimidine and Oxaliplatin-based chemotherapy.
dMMR/MSI-H gastric/GEJ or esophageal adenocarcinoma or ESCC
4.1. Immunotherapy in combination with fluoropyrimidine and Oxaliplatin-based chemotherapy may be offered.
4.2. Immunotherapy alone is an additional treatment option that may be offered on a case-by-case basis.
ESCC that is locally advanced unresectable and not amenable to definitive chemoradiation, advanced or metastatic
5.1. For patients with pMMR/MSS ESCC and PD-L1 expression ≥1, first-line therapy with immunotherapy in combination with fluoropyrimidine and platinum-based chemotherapy or Nivolumab plus Ipilimumab may be offered.
Qualifying statement for Recommendation 5.1:
Immunotherapy benefit has shown a positive association with higher PD-L1 expression (ie, greater benefit with PD-L1 expression ≥10). Not all possible PD-L1 cutoff scores have been assessed. Therefore, the optimal PD-L1 cutoff score balancing benefits and harms is unknown.
5.2. For patients with pMMR/MSS ESCC with PD-L1 expression <1, first-line therapy with fluoropyrimidine and platinum-based chemotherapy may be offered.
Qualifying statement for Recommendations 2.1 to 5.2:
Chemotherapy alone may be offered to patients who express predictive biomarkers but are not considered candidates for targeted therapy or immunotherapy.
Second or Third Line Therapy
pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma
6.1. For patients with pMMR/MSS advanced gastroesophageal adenocarcinoma whose disease has progressed after first-line therapy, Ramucirumab plus Paclitaxel may be offered.
Qualifying statements for Recommendation 6.1:
Ramucirumab plus FOLFIRI may be an option for patients who have previously been treated with Docetaxel or experienced neurotoxicity with first-line treatment.
Although outside the scope of this review, for patients with gastric or GEJ adenocarcinoma, Trifluridine and Tipiracil may be offered after progression on second-line therapy.
Note for Recommendation 6.1:
CLDN18.2 inhibitor Zolbetuximab has not been studied as second-line therapy for previously treated patients with gastroesophageal adenocarcinoma and is therefore not recommended for this patient population.
pMMR/MSS HER2-positive gastric/GEJ adenocarcinoma
6.2. For HER2-positive patients with gastric/GEJ adenocarcinoma and progressive disease after first-line therapy, Trastuzumab Deruxtecan should be offered.
Note for Recommendation 6.2:
Repeat tumor testing after progression on Trastuzumab is recommended to ensure that the tumor maintains HER2 expression after progression on first-line HER2-directed therapy.
ESCC
6.3. For patients with ESCC whose disease has progressed after first-line combination chemotherapy without immunotherapy and with PD-L1 ≥1, Nivolumab or Tislelizumab may be offered, and for patients with PD-L1 ≥10, Pembrolizumab may be offered.
Note to Recommendation 6.3:
This is expected to be a rare circumstance as patients who are candidates for immunotherapy should receive it as first-line therapy.
Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update. Shah MA, Kennedy EB, Deighton D, et al. J Clin Oncol. 2026; 44:1145-1165.
