ASCO 2026 Living Guideline for Immunotherapy & Targeted Therapy for Advanced Gastroesophageal Cancer: J Clin Oncol.| August 2026
Introduction
Management of advanced gastroesophageal cancer has moved rapidly from a largely chemotherapy-based approach toward biomarker-driven treatment selection. HER2, PD-L1, mismatch-repair status/MSI, and CLDN18.2 can now determine first-line therapy, while broad next-generation sequencing may identify additional actionable alterations. ASCO therefore recommends obtaining predictive biomarkers early enough to guide treatment decisions.
This 2026.1.2 Living Guideline is particularly important because it updates first-line management of HER2-positive advanced or unresectable gastroesophageal adenocarcinoma following the phase III HERIZON-GEA-01 trial.
The central clinical message: Advanced gastroesophageal cancer should no longer be treated as one disease—biomarker profiling should precede therapeutic selection whenever feasible.
20 Key Takeaways
- Biomarker testing should come first.
For gastroesophageal adenocarcinoma, ASCO recommends testing HER2, PD-L1, dMMR/MSI-H and CLDN18.2. For esophageal squamous cell carcinoma (ESCC), PD-L1 and dMMR/MSI-H should be assessed. Broad-based NGS, including pan-tumor biomarkers, should also be considered.
- Do not unnecessarily delay chemotherapy while waiting for biomarkers.
Although biomarker results should be available as early as possible, the clinical condition matters. In symptomatic or rapidly progressive disease, chemotherapy should not automatically be withheld while awaiting results.
- DPYD testing should precede fluoropyrimidine therapy.
Approximately 4%–8% of patients may have partial DPD deficiency associated with DPYD variants and increased fluoropyrimidine toxicity. ASCO recommends testing before treatment; dosing should be modified for partial deficiency, while fluoropyrimidines should be avoided in complete DPD deficiency.
- HER2-negative, PD-L1 ≥1 disease can receive chemo-immunotherapy.
For pMMR/MSS, HER2-negative gastric/GEJ or esophageal adenocarcinoma with PD-L1 ≥1 and absent CLDN18.2 expression, fluoropyrimidine/platinum chemotherapy plus immunotherapy may be recommended.
- The magnitude of immunotherapy benefit increases with PD-L1 expression.
ASCO emphasizes that benefit correlates positively with increasing PD-L1 expression, with greater benefit particularly evident at higher levels such as PD-L1 ≥10. The optimal universal cutoff remains uncertain.
- Pembrolizumab, nivolumab and tislelizumab are reasonable PD-1 options.
The guideline considers these agents to have broadly similar efficacy; choice can therefore incorporate dosing, administration, toxicity, availability and cost.
- CLDN18.2 creates another first-line therapeutic pathway.
For pMMR/MSS, HER2-negative gastric/GEJ adenocarcinoma with PD-L1 <1 and CLDN18.2 positivity, fluoropyrimidine/platinum chemotherapy plus zolbetuximab should be offered—a strong recommendation.
- When both PD-L1 and CLDN18.2 are positive, treatment must be individualized.
In HER2-negative disease with PD-L1 ≥1 and CLDN18.2 positivity, either chemotherapy + immunotherapy or chemotherapy + zolbetuximab may be considered. PD-L1 level, toxicity, symptom burden, comorbidities and previous treatment history should guide the decision.
- Biomarker-negative HER2-negative disease remains a chemotherapy domain.
For pMMR/MSS, HER2-negative gastroesophageal adenocarcinoma with PD-L1 <1 and absent CLDN18.2, fluoropyrimidine/platinum chemotherapy alone remains the recommended first-line treatment.
- The major 2026 change concerns HER2-positive disease.
For pMMR/MSS, HER2-positive gastroesophageal adenocarcinoma with PD-L1 ≥1, ASCO now strongly recommends a HER2-targeting antibody + immunotherapy + fluoropyrimidine/platinum chemotherapy.
- HER2-directed therapy is no longer synonymous with trastuzumab alone.
Following HERIZON-GEA-01, ASCO deliberately broadened its wording from specific trastuzumab-based regimens to a “HER2-targeting antibody”, thereby accommodating newer HER2-directed strategies such as zanidatamab.
- HERIZON-GEA-01 provides the evidence driving this change.
The phase III trial randomized 914 previously untreated HER2-positive patients to zanidatamab + tislelizumab + chemotherapy, zanidatamab + chemotherapy, or trastuzumab + chemotherapy.
- Zanidatamab + tislelizumab produced a clinically important survival improvement.
Median OS was 26.4 months versus 19.2 months with trastuzumab + chemotherapy (HR 0.72), while median PFS was 12.4 versus 8.1 months (HR 0.63).
- Zanidatamab without immunotherapy also improved PFS.
Zanidatamab + chemotherapy achieved median PFS of 12.4 months versus 8.1 months with trastuzumab + chemotherapy. However, its OS advantage did not reach statistical significance at the reported analysis.
- PD-L1 <1 HER2-positive disease is different: immunotherapy is not routinely recommended.
For pMMR/MSS, HER2-positive disease with PD-L1 <1, ASCO recommends a HER2-targeting antibody + fluoropyrimidine/platinum chemotherapy. The evidence is currently insufficient to routinely add immunotherapy.
- Do not overinterpret the provocative PD-L1 <1 HERIZON result.
Although the HERIZON-GEA-01 subgroup analysis appeared to show substantial benefit from the triplet in PD-L1 TAP <1 disease, ASCO regards these findings as exploratory: PD-L1 assessment was retrospective, the cutoff was not prespecified, confidence intervals were not adjusted for multiplicity, and the biological explanation remains uncertain.
- Toxicity matters when choosing the HER2-directed regimen.
Grade ≥3 diarrhea occurred more frequently with zanidatamab-containing regimens: approximately 25% with zanidatamab + tislelizumab, 20% with zanidatamab alone, versus 13% with trastuzumab. Hypokalemia was also more frequent with zanidatamab-based treatment.
- dMMR/MSI-H disease is an immunotherapy-driven subgroup.
For dMMR/MSI-H gastric/GEJ or esophageal adenocarcinoma or ESCC, immunotherapy combined with fluoropyrimidine/oxaliplatin chemotherapy may be offered; immunotherapy alone is also an option in selected patients on a case-by-case basis.
- Second-line therapy depends strongly on HER2 status.
For pMMR/MSS HER2-negative gastroesophageal adenocarcinoma progressing after first-line therapy, ramucirumab + paclitaxel remains an option; ramucirumab + FOLFIRI can be considered in selected patients. Importantly, zolbetuximab has not been established as second-line therapy.
- HER2 should be reassessed before second-line trastuzumab deruxtecan.
For HER2-positive gastric/GEJ adenocarcinoma progressing after first-line treatment, trastuzumab deruxtecan should be offered. However, ASCO specifically recommends repeat tumor testing after progression on trastuzumab to confirm that HER2 expression has been retained.
