ESMO Updates Guidelines for Gastric and Esophageal Cancer – 2026
In this article
Immunotherapy with FLOT, a New HER2 Antibody and Four Tests for Every Patient: What Has Changed in Gastric and Oesophageal Cancer?
The European Society for Medical Oncology (ESMO) published its new Clinical Practice Guideline for gastric and oesophageal cancer online in Annals of Oncology on 15 October 2026. Prepared by a 15-member expert panel led by Salah-Eddin Al-Batran (Frankfurt) and Michel Ducreux (Gustave Roussy), the guideline was approved by the ESMO Guidelines Committee in September 2026. For the first time, the separate gastric and oesophageal cancer guidelines published in 2022 have been merged into a single document. The most important changes are the addition of immunotherapy to chemotherapy in resectable gastric cancer, a new drug for HER2-positive disease, FLOT chemotherapy taking precedence over chemoradiotherapy in oesophageal adenocarcinoma, and four biomarker tests becoming mandatory for every patient at diagnosis. We have previously covered the symptoms and treatment of gastric cancer and immunotherapy in advanced gastric and oesophageal cancer; the guideline was released ahead of the ESMO 2026 Congress.
- At diagnosis: In gastric and oesophageal adenocarcinoma, HER2, MSI/dMMR, PD-L1 (CPS and TAP) and CLDN18.2 should be tested from the outset; in oesophageal squamous cell carcinoma, PD-L1 (TPS, CPS, TAP). DPD deficiency testing before fluoropyrimidines is routine.
- Resectable adenocarcinoma: Perioperative FLOT is standard; where available, adding durvalumab to FLOT (D-FLOT) is the preferred option. In MATTERHORN, 2-year event-free survival was 67.4% versus 58.5%, and overall survival improved with a 22% relative risk reduction. In oesophageal adenocarcinoma, FLOT is preferred over CROSS chemoradiotherapy (ESOPEC: median overall survival 66 versus 37 months).
- Advanced, HER2-positive: Zanidatamab + tislelizumab + chemotherapy is recommended where available (FDA-approved, not EMA-approved). Trastuzumab deruxtecan in the second or third line after trastuzumab; HER2 re-biopsy is encouraged, as HER2 positivity is lost in about 30% of patients.
- In Turkey: SGK, the national social security insurer, reimburses first-line trastuzumab and nivolumab + chemotherapy for PD-L1 CPS ≥5. D-FLOT, adjuvant nivolumab, trastuzumab deruxtecan, ramucirumab and pembrolizumab are not reimbursed in these indications; zolbetuximab and trifluridine/tipiracil are not licensed.
Why does this matter?
Gastric and oesophageal cancers are among the leading causes of cancer-related loss of life worldwide, and most patients are diagnosed at an advanced stage. Turkey is one of the countries where gastric cancer is common; we have written before that cases could rise in the coming years unless action is taken. Helicobacter pylori infection, dietary habits and hereditary factors are the main risk factors.
Treatment in this field has changed rapidly over the past five years: immunotherapy has moved from advanced disease into the perioperative setting, and new targets such as CLDN18.2 and antibody–drug conjugates have entered practice. These advances make it more important than ever to perform the right tests at diagnosis in order to select the right patient. The new guideline will shape treatment protocols at many centres in Europe and in Turkey.
Yes. Until now, ESMO had published separate guidelines for these two cancers:
- 2016 and 2022: Separate ESMO guidelines for gastric cancer and oesophageal cancer. The most recent versions were published in 2022.
- October 2026: The first joint guideline. The approach is organised by histology rather than anatomical site: oesophageal squamous cell carcinoma (OSCC) forms one group, while oesophageal, oesophagogastric junction and gastric adenocarcinomas (GOAC) together form the second.
- Recommended for the first time: Perioperative immunotherapy (D-FLOT) as the preferred option in resectable adenocarcinoma, a HER2-directed drug other than trastuzumab (zanidatamab) in the first line for HER2-positive disease, and CLDN18.2 testing joining the mandatory biomarkers.
What has changed in the ESMO gastric and oesophageal cancer guideline?
The 2026 ESMO guideline covers gastric and oesophageal cancers in a single document for the first time. In resectable adenocarcinoma, adding durvalumab to FLOT chemotherapy has become the preferred treatment. In advanced HER2-positive disease, a zanidatamab combination is recommended, with trastuzumab deruxtecan in the second line. HER2, MSI, PD-L1 and CLDN18.2 testing is mandatory at diagnosis.
Diagnosis and staging: four tests for every patient
| Test | Which patients? | What does it guide? | Guideline detail |
|---|---|---|---|
| HER2 (immunohistochemistry ± ISH) | Adenocarcinoma | Trastuzumab, zanidatamab, trastuzumab deruxtecan | Positive in 12–30% of patients; more frequent in tumours near the oesophagogastric junction and in intestinal-type tumours. The percentage of positive cells and the ISH ratio should be reported numerically. |
| MSI / dMMR | Adenocarcinoma | Immunotherapy; the benefit of preoperative chemotherapy is questioned | MSI-H tumours respond far better to immunotherapy than to chemotherapy. |
| PD-L1 (CPS, TPS, TAP) | Adenocarcinoma and squamous cell carcinoma | Which immunotherapy to use | Each drug was assessed with a different method and cut-off in its own trial; inter-observer agreement among pathologists is debated. |
| CLDN18.2 | Adenocarcinoma | Zolbetuximab | Moderate-to-strong membranous staining in at least 75% of tumour cells is considered positive (Ventana 43-14A assay). |
| DPD deficiency | Every patient due to receive 5-FU, capecitabine or S-1 | Prevention of severe drug toxicity | Should be performed routinely before treatment. |
- Biopsy: In advanced tumours, 6–10 biopsies should be taken at endoscopy to capture intratumoural heterogeneity; 1–2 biopsies are usually sufficient for early lesions.
- Imaging: CT of the chest, abdomen and pelvis is the baseline; endoscopic ultrasound can be used for T and N staging. PET-CT is recommended for patients being considered for oesophageal surgery but not routinely in gastric cancer; it may be uninformative in mucinous and diffuse-type tumours.
- Laparoscopy: Diagnostic laparoscopy is recommended in resectable stage IIA–IVA gastric cancer to exclude occult peritoneal metastases. For patients with tumour cells in peritoneal washings, the decision is made individually by the multidisciplinary board.
- Nutrition and preparation: Nutritional status and history of weight loss must be assessed, with nutritional support given when needed. Preoperative physical, psychological and nutritional preparation (prehabilitation) is recommended; exercise has been shown to improve postoperative fitness and quality of life.
- Squamous cell carcinoma: Because about 6.7% of patients have a second primary tumour in the head and neck region, this region and the lungs should be screened.
Resectable and locally advanced disease
The guideline recommends that treatment decisions always be made by a multidisciplinary tumour board, and that oesophageal and gastric surgery be performed in high-volume centres carrying out at least 20 operations per year.
Gastric and oesophageal adenocarcinoma (GOAC)
For cT2 or higher or node-positive disease, the standard is perioperative FLOT chemotherapy (docetaxel, oxaliplatin, 5-FU) with radical surgery. What is new is the addition of the immunotherapy drug durvalumab to FLOT. In the phase 3 MATTERHORN trial, 948 patients with stage II–IVA disease received perioperative FLOT with either durvalumab or placebo, followed by durvalumab or placebo maintenance.
MATTERHORN: adding durvalumab to FLOT
Percentage. Resectable gastric and oesophageal adenocarcinoma, 948 patients. Coloured bar D-FLOT, grey bar FLOT + placebo.
Event-free survival HR 0.71; overall survival HR 0.78 at the final analysis. Absolute difference: at 2 years, roughly 9 more patients out of every 100 remained event-free. Adverse event rates were similar.
With durvalumab, 2-year event-free survival rose from 58.5% to 67.4% (HR 0.71): roughly 9 more patients out of every 100 remained event-free. The pathological complete response rate more than doubled (19.2% versus 7.2%). At the final analysis, overall survival also improved significantly (HR 0.78). Rates of grade 3–4 adverse events were the same in both arms (71.6% versus 71.2%). On the basis of these data, the guideline recommends D-FLOT as the preferred perioperative treatment where durvalumab is available [I, A; ESMO-MCBS A].
For adenocarcinoma of the oesophagus and oesophagogastric junction, the second major change comes from the ESOPEC trial: perioperative FLOT extended median overall survival from 37 to 66 months compared with CROSS-type preoperative chemoradiotherapy (HR 0.70). The TOPGEAR trial, which tested the benefit of adding preoperative chemoradiotherapy to chemotherapy, showed no survival difference. FLOT is therefore preferred; preoperative chemoradiotherapy followed by postoperative nivolumab in PD-L1-positive patients remains an option for patients who are not suitable for FLOT.
ESOPEC: FLOT versus CROSS in oesophageal adenocarcinoma
Median overall survival, months. Coloured bar perioperative FLOT, grey bar CROSS-type preoperative chemoradiotherapy.
HR 0.70. On this basis, the guideline prefers FLOT in oesophageal and junctional adenocarcinoma; chemoradiotherapy remains an option for patients not suitable for FLOT.
Retrospective analyses question the benefit of perioperative chemotherapy in MSI-H gastric cancer. By contrast, preoperative immunotherapy achieves very high response rates: in the phase 2 NEONIPIGA (nivolumab + ipilimumab) and INFINITY (durvalumab + tremelimumab) trials, the pathological complete response rate was around 60%. The guideline supports investigating non-operative management in this group; we recently covered the FDA approval of a similar approach with dostarlimab in dMMR rectal cancer. For gastric cancer, this is not yet standard and remains under investigation.
Oesophageal squamous cell carcinoma (OSCC)
- Standard: CROSS chemoradiotherapy, restaging and surgery. In the CROSS trial, 10-year overall survival in squamous cell carcinoma rose from 23% to 46% (HR 0.48).
- Surgery even after a clinical complete response: In resectable squamous cell carcinoma, surgery is recommended even if a clinical complete response to preoperative treatment is achieved [I, A].
- Postoperative nivolumab: One year of nivolumab is recommended for patients with residual tumour in the surgical specimen after chemoradiotherapy and surgery. In CheckMate 577, median disease-free survival increased from 11.0 to 22.4 months (HR 0.69); however, no significant difference in overall survival was shown (HR 0.85). The numerical benefit was greatest in squamous and PD-L1-positive tumours.
- Patients unable to receive radiotherapy: Based on the Japanese NExT (JCOG1109) trial, preoperative triplet chemotherapy (5-FU, cisplatin, docetaxel) is an option; however, febrile neutropenia is markedly more frequent with the triplet (16% versus 1%).
- Definitive chemoradiotherapy: For cervical oesophageal tumours or for patients who cannot undergo or decline surgery, the standard dose is 50 Gy in 25 fractions. Despite promising results for atezolizumab after definitive chemoradiotherapy (SKYSCRAPER-07), this use is not licensed.
CheckMate 577: postoperative nivolumab
Median disease-free survival, months. Oesophageal and junctional cancer with residual tumour after chemoradiotherapy and surgery. Coloured bar nivolumab, grey bar placebo.
Disease-free survival HR 0.69; no significant difference in overall survival (HR 0.85). The guideline recommends it in squamous cell carcinoma and in PD-L1-positive adenocarcinoma in patients unable to receive FLOT.
Figure 1 · Recommended treatment pathway in locally advanced disease
Simplified; not a strict rule. Decisions are made by the multidisciplinary board.
Advanced and metastatic disease
Oesophageal squamous cell carcinoma
| Line | Recommended treatment | PD-L1 cut-off / condition |
|---|---|---|
| First line | Chemotherapy + nivolumab | TPS ≥1% |
| Chemotherapy + pembrolizumab | CPS ≥10 | |
| Chemotherapy + tislelizumab | TAP ≥5% | |
| Chemotherapy + toripalimab | CPS ≥1 | |
| Nivolumab + ipilimumab (chemotherapy-free) | TPS ≥1%; higher risk of early progression, may be considered with low tumour burden | |
| First line (PD-L1-negative) | Platinum + fluoropyrimidine or platinum + taxane; dose-reduced oxaliplatin + capecitabine in frail patients | — |
| Second line | Nivolumab or tislelizumab (if no prior immunotherapy) | Irrespective of PD-L1 |
| Second–third line | Irinotecan or a taxane | According to prior treatments |
Gastric and oesophageal adenocarcinoma: first line
| Biomarker | Recommended treatment | Evidence / approval |
|---|---|---|
| HER2-positive (IHC 3+ or 2+ and ISH+) | Zanidatamab + tislelizumab + chemotherapy (where available) | HERIZON-GEA-01: overall survival HR 0.72; FDA-approved, not EMA-approved |
| If IHC 3+, zanidatamab + chemotherapy (without tislelizumab) | Benefit mainly in the IHC 3+ subgroup | |
| If zanidatamab is unavailable, trastuzumab + chemotherapy; add pembrolizumab if PD-L1 CPS ≥1 | Remains a standard option | |
| HER2-negative, PD-L1-positive | Nivolumab + chemotherapy | CPS ≥5 |
| Pembrolizumab + chemotherapy | CPS ≥1 | |
| Tislelizumab + chemotherapy | TAP ≥5% | |
| CLDN18.2-positive | Zolbetuximab + chemotherapy | 2+/3+ in ≥75% of cells; ESMO-MCBS 2; nausea and vomiting common with the first infusions |
| MSI-H / dMMR | Nivolumab, pembrolizumab or tislelizumab + chemotherapy | No specific approval in this subgroup; evidence from subgroup analyses |
| Biomarker-negative | Platinum + fluoropyrimidine; docetaxel-containing triplet (TFOX) in selected young, fit patients | Oxaliplatin preferred, especially in older patients |
| Progression during or shortly after (D)-FLOT | FOLFIRI | Limited benefit from re-treatment with platinum |
The guideline stresses that adding immunotherapy to chemotherapy offers little or no benefit in patients with low or absent PD-L1 expression. Immunotherapy decisions should therefore be based on the PD-L1 method and cut-off used in each drug's own trial.
Figure 2 · First-line treatment selection in advanced adenocarcinoma
Simplified; a patient may be positive for more than one biomarker.
Second and later lines
- Standard second line: Ramucirumab + paclitaxel. If ramucirumab is unavailable, irinotecan or a taxane alone; FOLFIRI is also an option.
- HER2-positive: Trastuzumab deruxtecan is recommended in the second or third line after trastuzumab. This recommendation is based on the phase 3 trial in which trastuzumab deruxtecan prolonged overall survival compared with ramucirumab + paclitaxel. Among patients screened for that trial, HER2 positivity had been lost after first-line treatment in about 30%; re-biopsy is therefore encouraged.
- MSI-H / dMMR: Pembrolizumab is preferred in patients who did not receive immunotherapy in the first line; it should also be considered in the third line.
- Third line: Trifluridine/tipiracil if oral treatment is feasible (TAGS trial); alternatively, irinotecan or a taxane if not previously used.
- Surgery in metastatic disease: In the REGATTA and RENAISSANCE trials, adding surgical removal of the primary tumour or metastases to chemotherapy did not prolong survival. Radiotherapy is an option for dysphagia, bleeding, pain and oligometastatic disease.
- Supportive care: Early palliative care and nutritional support should be part of treatment.
Follow-up
- Structured follow-up for at least 5 years after surgery: clinical review, blood tests, endoscopy and cross-sectional imaging every 3 months for the first 2 years, then every 6 months.
- In squamous cell carcinoma with a complete response to definitive chemoradiotherapy, endoscopy, biopsy and CT every 3 months for at least 2 years; a recurrence detected early can be treated with salvage surgery.
- Vitamin D, iron, zinc, folate and B12 deficiencies are common after surgery; they should be monitored and replaced when needed. Screening for osteoporosis is important after gastric surgery.
- In patients receiving treatment for advanced disease, CT or MRI every 6–12 weeks.
Access in Turkey to many of the new treatments recommended by the guideline is limited. Under the SUT reimbursement rules, SGK covers the following in gastric, junctional and oesophageal cancer: first-line trastuzumab + platinum-based chemotherapy in HER2-positive metastatic adenocarcinoma (IHC 2+ or 3+ together with ISH positivity is required; unlike the guideline, IHC 3+ alone is not sufficient), nivolumab + chemotherapy in HER2-negative adenocarcinoma with PD-L1 CPS of 5 or more (for a maximum of 24 months), and nivolumab in oesophageal squamous cell carcinoma after chemotherapy.
The following are not reimbursed: perioperative durvalumab (D-FLOT), postoperative nivolumab, trastuzumab deruxtecan, ramucirumab, and pembrolizumab in gastric and oesophageal cancer. These drugs are licensed in Turkey, but these uses fall into the licensed but not reimbursed group. Zolbetuximab, trifluridine/tipiracil and tislelizumab are not licensed in Turkey; they can be obtained through importation from abroad. Zanidatamab is not yet approved in Europe either. Assessment of CLDN18.2 and of PD-L1 by different methods (CPS, TPS, TAP) may not be available in every pathology laboratory; planning the tests at diagnosis is important.
Practical advice for patients and their families
- When you are diagnosed, ask whether your biopsy report includes HER2, MSI/MMR, PD-L1 and CLDN18.2 results; these tests determine your treatment options.
- If chemotherapy is planned, ask whether a DPD test has been done before 5-FU or capecitabine.
- Having surgery at an experienced, high-volume centre affects outcomes. If needed, seek a second opinion.
- Nutritional support and physical preparation before and after treatment are important; always tell your team about any weight loss.
- Reimbursement and licensing status may determine access to new immunotherapies; clinical trials may also be an option.
Frequently asked questions
- When was the new ESMO gastric and oesophageal cancer guideline published?
- The guideline was published online in Annals of Oncology on 15 October 2026 and was approved by the ESMO Guidelines Committee in September 2026. It covers gastric and oesophageal cancers in a single guideline for the first time.
- Is preoperative immunotherapy now standard in gastric cancer?
- In resectable gastric and oesophageal adenocarcinoma, adding durvalumab to FLOT chemotherapy (D-FLOT) is recommended as the preferred treatment where the drug is available. In the MATTERHORN trial, it prolonged event-free and overall survival. In Turkey, this use is not reimbursed by SGK.
- Which tests should be done in gastric cancer?
- In adenocarcinoma, HER2, MSI/dMMR, PD-L1 and CLDN18.2 testing should be performed at diagnosis. In oesophageal squamous cell carcinoma, PD-L1 should be assessed. DPD deficiency testing before 5-FU or capecitabine is also routinely recommended.
- What is the second-line treatment for HER2-positive gastric cancer?
- Trastuzumab deruxtecan is recommended in the second or third line after trastuzumab. Because HER2 positivity can be lost over time in about 30% of patients, re-biopsy before treatment is encouraged.
Glossary
- GOAC
- Umbrella term for gastric, oesophagogastric junction and oesophageal adenocarcinomas.
- OSCC
- Oesophageal squamous cell carcinoma.
- FLOT
- A chemotherapy regimen of docetaxel, oxaliplatin, 5-FU and folinic acid.
- CROSS
- Preoperative weekly carboplatin–paclitaxel with concurrent radiotherapy.
- CPS, TPS, TAP
- Different methods for scoring PD-L1 staining; each immunotherapy drug was approved with its own method and cut-off.
- CLDN18.2
- A protein on the membrane of gastric cells, targeted by zolbetuximab.
- DPD deficiency
- Deficiency of the enzyme that breaks down 5-FU and capecitabine; it can cause severe drug toxicity.
- ESMO-MCBS
- ESMO's scale for grading the magnitude of clinical benefit of treatments; A–C in the curative (perioperative) setting, 1–5 in advanced disease.
DROZDOGAN Academy Commentary
The new ESMO guideline formalises the shift in gastric and oesophageal cancer from asking "which organ?" to asking "which histology and which biomarker?" when planning treatment.
⚡ Why it matters
For the first time, immunotherapy has become part of the preferred treatment in resectable adenocarcinoma. Trastuzumab's 15-year sole dominance in HER2-positive disease is ending, and four biomarker tests are becoming mandatory at diagnosis.
✅ Strengths
The recommendations rest on large phase 3 trials (MATTERHORN, ESOPEC, HERIZON-GEA-01, CheckMate 577) and ESMO-MCBS scores; approval status (FDA, EMA) is clearly stated for each recommendation. Areas where evidence is limited are explicitly flagged as expert opinion.
⚠️ Limitations
Postoperative nivolumab continues to receive a strong recommendation even though no overall survival benefit has been shown. Zanidatamab is not approved in Europe. Non-operative management in MSI-H tumours still rests on phase 2 data. The use of three different scoring methods for PD-L1 may cause confusion in practice.
🩺 In practice
For every new diagnosis, request HER2, MSI/dMMR, PD-L1 and CLDN18.2 testing on the initial biopsy, and add DPD testing before treatment. FLOT is standard in resectable adenocarcinoma; in Turkey, access to durvalumab may require an off-label application. In HER2-positive patients, consider re-biopsy before second-line treatment.
❓ Open questions
Which patients benefit most from D-FLOT, and is PD-L1 or MSI status decisive? Is it safe to avoid surgery altogether in MSI-H gastric cancer? How should zanidatamab and trastuzumab deruxtecan be sequenced in HER2-positive disease? And when will these treatments reach patients in Turkey?
Bottom line: The new ESMO guideline shows that biomarker-driven treatment has matured in gastric and oesophageal cancer. Yet the first step towards the right treatment is performing the right tests at diagnosis; in Turkey, access to these treatments remains the greatest barrier.
- This article was prepared in October 2026.
- It is based on the journal pre-proof version of the guideline published in Annals of Oncology; the final version may contain minor changes. Trial data are taken from the guideline text.
- Turkish licensing and reimbursement information is based on SUT and TİTCK records as of October 2026; whether the Turkish prescribing information for durvalumab includes a perioperative gastric cancer indication should be verified separately.
- The comparisons in the charts are between the randomised arms of each individual trial. The diagrams are derived from the text and contain no new data. The Academy commentary is our own.
References
- Al-Batran SE, Bencivenga M, Crosby T, et al.; ESMO Guidelines Committee. Gastric and oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2026 (online 15 October 2026). doi.org · annalsofoncology.org
- ESMO. ESMO Clinical Practice Guideline: Gastric and Oesophageal Cancer. esmo.org
- ESMO. Oesophageal cancer: ESMO Clinical Practice Guideline (2022). annalsofoncology.org
- ESMO. Gastric cancer: ESMO Clinical Practice Guideline (2022). annalsofoncology.org
- Janjigian YY, et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer (MATTERHORN). N Engl J Med 2025. PubMed
- Hoeppner J, et al. Perioperative chemotherapy or preoperative chemoradiotherapy in esophageal cancer (ESOPEC). N Engl J Med 2025. PubMed
- Kelly RJ, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (CheckMate 577). N Engl J Med 2021;384:1191-1203. PubMed
- HERIZON-GEA-01: zanidatamab ± tislelizumab + chemotherapy in HER2-positive gastric and oesophageal adenocarcinoma (guideline reference 86). PubMed
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