FDA Approves Durvalumab Plus FLOT in Resectable Gastric/GEJ Cancers

The Approval

The FDA has approved durvalumab (Imfinzi) plus 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) neoadjuvant and adjuvant treatment, followed by single agent durvalumab as a treatment for patients with resectable gastric and gastroesophageal junction (GEJ) cancers, according to a release from the FDA.¹

The recommended durvalumab dose for patients who weigh 30 kg or more is 1500 mg every 4 weeks with chemotherapy for up to 4 cycles, followed by 1500 mg as a single agent every 4 weeks for up to 10 cycles. For patients with a body weight less than 30 kg, the recommended durvalumab dose is 20 mg/kg with chemotherapy every 4 weeks for up to 4 cycles and 20 mg/kg as a single agent every 4 weeks for up to 10 cycles.

Warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity were included in the prescribing information.

Previously, in July 2025, the FDA granted priority review and breakthrough therapy designation to durvalumab in this indication based on results from the phase 3 MATTERHORN trial (NCT04592913).²

Most recently, results from MATTERHORNthat were shared at the 2025 European Society of Medical Oncology (ESMO) Congress showed that adding durvalumab to FLOT chemotherapy significantly improved overall survival (OS) compared with FLOT plus placebo.³

“This [data], I believe, will seal durvalumab and FLOT as the standard of care for resectable gastric and GEJ cancers. The interesting thing about this is that it looks like the benefit is largely driven by the PD-L1–positive group,” said Timothy Brown, MD, an assistant professor in the department of Internal Medicine at UT Southwestern Medical Center, during an X Space hosted by CancerNetwork®. “But the study was not adequately powered to say, definitively, that there’s no benefit in the PD-L1–negative group. It’s going to be standard across the board, regardless of PD-L1 expression.”

MATTERHORN Results

The median OS with durvalumab plus FLOT was not reached (NR; 95% CI, NR-NR) compared with NR (95% CI, NR-NR) with placebo plus FLOT (HR, 0.78; 95% CI, 0.63-0.96; P = .021). The 18-month OS rates were 81.1% vs 77.1%, respectively; the 24-month OS rates were 75.5% vs 70.4%, and the 36-month OS rates were 68.6% vs 61.9%.

The OS benefit with durvalumab plus FLOT was consistent across most key subgroups, including male patients (HR, 0.74; 95% CI, 0.58-0.95), those with positive clinical lymph node status (HR, 0.73; 95% CI, 0.57-0.94), and those with intestinal histology (HR, 0.76; 95% CI, 0.56-1.05).

In patients with a PD-L1 tumor area positivity (TAP) of 1% or more, the median OS was NR (95% CI, NR-NR) in the durvalumab group vs NR (95% CI, NR-NR) in the placebo group (HR, 0.79; 95% CI, 0.63-0.99). In patients with a PD-L1 TAP less than 1%, the median OS was NR (95% CI, 43.66-NR) vs NR (95% CI, 21.72-NR), respectively (HR, 0.79; 95% CI, 0.41-1.50).

It was also revealed that patients who experienced a pathological complete response (pCR) had a 24-month EFS rate of 92.7% with durvalumab vs 79.4% with placebo (HR, 0.29; 95% CI, 0.08-0.96); in patients with a major pathological response, the 24-month EFS rate was 92.7% vs 79.4%, respectively (HR, 0.32; 95% CI, 0.15-0.68); and in patients with any pathological response, the 24-month EFS rate was 78.3% vs 68.0% , respectively (HR, 0.60; 95% CI, 0.46-0.79).

Patients with pathological node status–negativity had a median EFS of NR (95% CI, NR-NR) with durvalumab compared with NR (95% CI, NR-NR) with placebo (HR, 0.74; 95% CI, 0.46-1.18); those with pathological node status–positivity had a median EFS of 33.84 months (95% CI, 23.33-NR) vs 25.56 months (95% CI, 18.83-29.14), respectively (HR, 0.77; 95% CI, 0.58-1.02).

These results built upon previously published results in the New England Journal of Medicine that demonstrated a benefit with durvalumab plus FLOT for EFS, with a median value of NR (95% CI, 40.7 months-NR) vs 32.8 months (95% CI, 27.9-NR) with placebo plus FLOT (HR, 0.71; 95% CI, 0.58-0.86; P <.001).⁴

Trial Breakdown

A total of 948 patients with histologically documented gastric or GEJ adenocarcinoma who had not received prior anticancer therapy were included in the full analysis population, of whom 474 each were randomly assigned to receive either durvalumab or placebo plus FLOT.

Treatment consisted of 1500 mg durvalumab or placebo, administered intravenously every 4 weeks on day 1 of every cycle, plus FLOT chemotherapy, administered intravenously every 2 weeks on day 1 and day 15 of each cycle for 4 cycles, with 2 each being neoadjuvant therapy or adjuvant therapy. Patients then received 1500 mg durvalumab or placebo, intravenously every 4 weeks on day 1 of each cycle for 10 cycles.

Eligible patients were 18 years or older, had an ECOG performance status of 0 or 1, adequate organ and bone marrow function, and availability of a tumor sample for assessment of PD-L1 expression.

The primary end point of the trial was EFS. Key secondary end points were OS and pCR; additional secondary end points were disease-free survival, surgery, and R0 resection.

Safety

Regarding safety, any-grade adverse events (AEs) occurred in 99.2% of the durvalumab group vs 98.7% of the placebo group; 59.6% vs 59.1%, respectively, experienced AEs possibly related to any component of the trial regimens. The most common AE was diarrhea, occurring in 62.3% of the durvalumab group and 57.6% of the placebo group. AEs led to death in 5.1% of the durvalumab group compared with 4.3% of the placebo group.

References

1. FDA approves durvalumab for resectable gastric or gastroesophageal junction adenocarcinoma. News release. FDA. November 25, 2025. https://tinyurl.com/mrsfxta8
2. IMFINZI (durvalumab) granted priority review and breakthrough therapy designation in the US for patients with resectable early-stage gastric and gastroesophageal junction cancers. News release. AstraZeneca. July 28, 2025. Accessed November 18, 2025. https://tinyurl.com/bdvtxze3
3. Tabernero J. Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: a randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Presented at: ESMO 2025 Congress; October 17–20, 2025; Berlin, Germany. Abstract LBA81.
4. Janjigian YY, Al-Batran SE, Wainberg Z, et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med. 2025;393(3):217-230. doi:10.1056/NEJMoa2503701