Perioperative Durvalumab: The New Standard for Gastric or GEJ Cancer
Key Points
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The MATTERHORN trial established perioperative durvalumab plus chemotherapy followed by durvalumab alone as the new standard of care for patients with resectable gastric or gastroesophageal junction (GEJ) cancer.
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The FDA approved the regimen for all patients, regardless of PD-L1 status, broadening eligibility compared with the initial National Comprehensive Cancer Network (NCCN) guidelines.
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Durvalumab is well tolerated, and toxicity can often be controlled by modifying the chemotherapy regimen and providing appropriate antiemetic and antidiarrheal medications.
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Circulating tumor DNA (ctDNA) in gastric or GEJ cancer remains a prognostic but not predictive biomarker, and does not appear sensitive enough to guide treatment modifications.
Perioperative Durvalumab for Gastric or GEJ Adenocarcinoma
In November 2025, based on data from the MATTERHORN trial, the FDA approved perioperative durvalumab plus FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) followed by durvalumab monotherapy for patients with resectable gastric or GEJ cancer.
At the 2026 ASCO Gastrointestinal Cancers Symposium, cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, discussed how to approach the new standard of care with four medical oncologists: Angela Alistar, MD, of Atlantic Health; Steven Maron, MD, MSc, of Memorial Sloan Kettering Cancer Center; Reetu Mukherji, MD, of Medstar Health; and Raji Shameem, MD, of Orlando Health.
MATTERHORN Trial Findings
The MATTERHORN trial evaluated 2 neoadjuvant and 2 adjuvant cycles of durvalumab or placebo plus FLOT, followed by single-agent durvalumab or placebo for up to 10 cycles in resectable gastric or GEJ cancers. Over a median follow-up of 31.5 months (interquartile range, 26.7-36.6), 2-year event-free survival was 67.4% with durvalumab versus 58.5% with placebo (HR, 0.71; 95% CI, 0.58-0.86; P < .001), according to the initial publication. The pathological complete response (pCR) rate was 19.2% in the durvalumab arm versus 7.2% in the placebo arm (relative risk, 2.69; 95% CI, 1.86-3.90). Compared with placebo, durvalumab did not increase the proportion of patients with delayed surgery (10.1% vs 10.8%) or adjuvant therapy initiation (2.3% vs 4.6%). In the final overall survival (OS) analysis, durvalumab significantly improved OS compared with placebo (HR, 0.78; 95% CI, 0.63-0.96; P = .021).
Although NCCN guidelines initially recommended that patients have PD-L1–positive disease to be eligible for perioperative durvalumab, the FDA approved durvalumab for all patients based on the outcomes of the intention-to-treat population in MATTERHORN. Patients with uncontrolled autoimmune bowel disease may not be suitable candidates for durvalumab because of intolerance to immunotherapy.
Managing Durvalumab Side Effects
Durvalumab is well tolerated, and much of the toxicity is driven by FLOT. Dr. Mukherji tries to start all patients at full doses of FLOT and durvalumab, although she may reduce FLOT doses for frail patients or those with cardiac comorbidities. For patients with preexisting neuropathy, she may consider dropping docetaxel and proceeding with only fluorouracil and oxaliplatin. Regardless of modifications, patients should be counseled on expected side effects like nausea and diarrhea, and oncologists should make sure patients have proper antiemetics and antidiarrheals before initiating therapy.
Treatment Modifications
The expert panel also discussed the balance between undertreating and overtreating, and the potential role of ctDNA to guide treatment decisions. In patients with either a pCR or with no response, adjuvant chemotherapy appears to be marginal, and prioritizing adjuvant durvalumab may be more effective, said Dr. Maron. For patients in between those extremes, especially those with evidence of clinical or pathological regression, Dr. Maron said he leans more on chemotherapy.
The role of ctDNA is a hot topic across all disease sites. In patients with gastric or GEJ adenocarcinoma, ctDNA positivity after surgery is associated with a poor prognosis. Dr. Maron suggested exploring novel clinical trial options in ctDNA-positive patients, as the benefit of additional adjuvant FLOT after neoadjuvant FLOT failure is unclear. Conversely, current evidence doesn’t support using ctDNA to de-escalate therapy, especially given that available assays may not be sensitive enough to fully verify ctDNA negativity, Dr. Maron said.
Approaches After Immunotherapy Progression
If patients progress during neoadjuvant durvalumab plus FLOT, they may have had metastatic disease to begin with, said Dr. Alistar. For this population, oncologists should assess whether patients are eligible for clinical trials or targeted therapies; otherwise, they may need to move on to second-line treatments approved for metastatic disease. The paradigm is similar for patients who progress during adjuvant durvalumab plus FLOT or single-agent durvalumab. “Progression at any point in my opinion would mean failure of durvalumab plus FLOT, and I would be looking into something else,” Dr. Alistar said.
Ultimately, the MATTERHORN trial brings an important update to the standard of care for patients with resectable gastric or GEJ adenocarcinomas, Dr. Shameem said. FDA approval for all patients, regardless of PD-L1 status, is a practical option for community oncologists who want to start treatment immediately without waiting for PD-L1 testing.