Durvalumab Plus FLOT Receives Upgrade in New NCCN Guidelines

The National Comprehensive Cancer Network (NCCN) has upgraded 2 durvalumab (Imfinzi; AstraZeneca) recommendations and added 4 zanidatamab-hrii regimens in version 4.2026 of its Esophageal and Esophagogastric Junction Cancers guidelines released September 16, 2026.¹ This update also replaces the guidelines’ genetic risk section with a link to the NCCN’s Genetic/Familial High-Risk Assessment guideline, which encompasses further risk evaluation criteria for squamous cell carcinoma (SCC) and adenocarcinoma, plus screening recommendations for esophageal SCC.

Durvalumab Recommendations Now Category 2A

Perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) plus durvalumab remains a preferred treatment regimen, and 2 subgroup recommendations now carry stronger NCCN consensus. Now, for patients with a PD-L1 combined positive score (CPS) below 1 or tumor area positivity (TAP) below 1%, the regimen have moved from category 2B to category 2A. The same upgrade now also applies to diffuse-type esophagogastric junction (EGJ) adenocarcinoma.

The core recommendation is unchanged. FLOT plus durvalumab still is preferred for a PD-L1 CPS of 1 or higher or a TAP of 1% or higher: category 1 for EGJ adenocarcinoma and category 2A for esophageal adenocarcinoma. Version 2.2026 had added clinical node-negative tumors, PD-L1–negative disease, and diffuse-type EGJ adenocarcinoma as subgroups, the latter 2 at category 2B.

However, a footnote in the new guidelines still cautions that diffuse-type gastric or EGJ adenocarcinoma showed no overall survival (OS) advantage when durvalumab was added to FLOT in the phase 3 MATTERHORN trial (NCT04592913).² Version 2.2026 changed that wording from “event-free survival” (EFS) to “overall survival.”

What Did the MATTERHORN Data Show?

The randomized, double-blind, placebo-controlled phase 3 MATTERHORN trial randomized 948 patients with resectable gastric or gastroesophageal junction adenocarcinoma to perioperative FLOT plus durvalumab (n = 474) or FLOT plus placebo (n = 474); the safety analysis comprised 475 patients and 469 patients, respectively.^3,4 Primary data showed 2-year EFS of 67.4% vs 58.5% (HR, 0.71; 95% CI, 0.58-0.86; P < .0001) and a pathological complete response rate of 19.2% vs 7.2% (relative risk, 2.69; 95% CI, 1.86-3.90).³

Final OS results were presented at the 2025 European Society for Medical Oncology Congress (ESMO).⁵ Durvalumab improved OS, with an HR of 0.78 (95% CI, 0.63-0.96; P = .021). The benefit was similar by PD-L1 status, although the CI was wide for TAP that was below 1% (HR, 0.79; 95% CI, 0.41-1.50). Josep Tabernero, MD, PhD, Vall d’Hebron Institute of Oncology, Barcelona, who presented the data at ESMO, explained that female patients, patients with node-negative disease, and patients with diffuse-type disease might benefit less, but these numbers were small.

Durvalumab plus FLOT was approved by the FDA on November 25, 2025.⁶

Zanidatamab-hrii Joins First-Line HER2-Positive Options

Four zanidatamab-hrii combinations were added for first-line therapy of HER2-positive adenocarcinoma:

• Fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and zanidatamab-hrii
• Fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, zanidatamab-hrii, and tislelizumab-jsgr
• Fluoropyrimidine, cisplatin, and zanidatamab-hrii (category 2B)
• Fluoropyrimidine, cisplatin, zanidatamab-hrii, and tislelizumab-jsgr

HER2 testing language now applies to patients being considered for zanidatamab-hrii or trastuzumab, with a recommendation now for antidiarrheal prophylaxis when zanidatamab-hrii is administered with chrmotherapy. With FOLFOX (fluorouracil, leucovorin, and oxaliplatin), fluorouracil should not be given as a bolus because of a potentially higher risk of diarrhea.

Reference

1. NCCN Clinical Practical Guidelines in Oncology (NCCN Guidelines): Esophageal and esophagogastric junction cancers: version 4.2026—September 16, 2026. NCCN. September 16, 2026. Accessed October 22, 2026. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
2. Assessing durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer. ClinicalTrials.gov. Updated December 12, 2024. Accessed October 22, 2026. https://clinicaltrials.gov/study/NCT04592913
3. Janjigian YY, Al-Batran SE, Wainberg ZA, et al; MATTERHORN investigators. Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med. 2025;393(3):217-230. doi:10.1056/NEJMoa2503701
4. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative durvalumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable gastric and gastro-oesophageal junction adenocarcinoma (MATTERHORN): final results of overall survival and event-free survival by pathological response in a global, randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet. 2026;408(10560):1114-1128. doi:10.1016/S0140-6736(26)01254-7
5. Cipriano J. Final overall survival confirms benefit of durvalumab plus FLOT in resectable gastric and gastroesophageal junction adenocarcinomas. The ASCO Post. December 10, 2025. Accessed October 22, 2026. https://ascopost.com/issues/december-10-2025-supplement-conference-highlights-esmo-2025/final-overall-survival-confirms-benefit-of-durvalumab-plus-flot-in-resectable-gastric-and-gastroesophageal-junction-adenocarcinomas/
6. McCormick B. FDA Approves Durvalumab With FLOT Chemotherapy for Resectable Gastric and Gastroesophageal Junction Cancer. AJMC^®. November 25, 2025. Accessed October 22, 2026. https://www.ajmc.com/view/fda-approves-durvalumab-with-flot-chemotherapy-for-resectable-gastric-and-gastroesophageal-junction-cancer