Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update: J Clin Oncol | Feb. 2026 | DOI: 10.1200/JCO-25-02958

Introduction

Advanced gastroesophageal cancers (gastric, GEJ, oesophagal adenocarcinoma, and ESCC) have entered a biomarker-led era. This ASCO update reframes first-line choices around four core actionable domains—PD-L1, HER2, dMMR/MSI-H, and CLDN18.2—and then clarifies second/third-line options when disease progresses. The practical message is simple: get key biomarkers early, start chemotherapy without delay if needed, and layer immunotherapy/targeted therapy only where the signal is strongest.

20 Key Takeaways for Clinicians (ASCO 2026)

Test early, treat smart: For gastroesophageal adenocarcinoma, ASCO recommends upfront testing for HER2, PD-L1, dMMR/MSI-H, and CLDN18.2; for ESCC, test PD-L1 and dMMR/MSI-H. Consider broad NGS where feasible.

Do not delay chemotherapy while waiting for biomarker results if the patient is symptomatic or unwell—start the backbone and add targeted/IO once results return.

PD-L1 matters, and “higher is better”: The likelihood of benefit from adding immunotherapy increases with higher PD-L1 expression (largest signal at higher cutoffs such as CPS ≥10 in trials).

DPYD testing before fluoropyrimidines: ASCO includes a safety note—screen for DPYD variants before 5-FU/capecitabine; avoid fluoropyrimidines in complete DPD deficiency and individualise dose in partial deficiency.

pMMR/MSS, HER2-negative adenocarcinoma + PD-L1 ≥1 (and CLDN18.2 negative): Doublet chemo + immunotherapy is recommended as a reasonable first-line option.

pMMR/MSS, HER2-negative + PD-L1 <1 + CLDN18.2 positive: Chemo + zolbetuximab should be offered.

Dual-positive PD-L1 ≥1 and CLDN18.2 positive (HER2-negative): Either chemo + immunotherapy or chemo + zolbetuximab may be used—shared decision-making is explicitly advised.

pMMR/MSS, HER2-negative + PD-L1 <1 + CLDN18.2 negative: Chemo alone remains the standard default.

HER2-positive gastric/GEJ adenocarcinoma (pMMR/MSS): Trastuzumab + doublet chemo is standard; if PD-L1 ≥1, add pembrolizumab.

dMMR/MSI-H disease (any histology in scope): Immunotherapy is central—ASCO supports immunotherapy with chemo and also allows immunotherapy alone in selected patients (case-by-case).

ESCC (unresectable/advanced): If PD-L1 ≥1, offer immunotherapy + chemo; nivolumab + ipilimumab is another option in appropriate patients.

ESCC with PD-L1 <1: Chemo alone is acceptable; immunotherapy benefit is less certain at very low PD-L1.

Second-line adenocarcinoma backbone: Ramucirumab + paclitaxel remains a key recommended option after progression on first-line therapy.

Second-line alternative when taxanes are problematic: Ramucirumab + FOLFIRI can be considered for patients previously exposed to docetaxel or those with troublesome neurotoxicity.

Second-line for HER2-positive after progression: Trastuzumab deruxtecan (T-DXd) should be offered.

Re-test HER2 after progression on HER2-directed first-line therapy—HER2 can be lost, and treatment should match current biology.

Later-line ESCC immunotherapy: If a patient did not receive immunotherapy upfront and has PD-L1 ≥1, nivolumab or tislelizumab may be used; pembrolizumab is a stronger consideration at higher PD-L1 thresholds (e.g., ≥10 in the evidence base).

Zolbetuximab toxicity is predictable and manageable: expect nausea/vomiting early, use proactive antiemetics, adjust infusion strategies, and maintain hydration—don’t abandon an effective drug prematurely.

Actionable biomarkers are not mutually exclusive: A meaningful minority will have >1 target (e.g., PD-L1 + CLDN18.2). The guideline emphasises patient-centred choice based on PD-L1 level, symptom burden, toxicity profiles, comorbidities, and patient preference.

If no actionable biomarker or patient is not a candidate for IO/targeted therapy, fluoropyrimidine + platinum doublet chemotherapy remains the universal fallback—still the most practical global standard.