Experts Say FDA Approval of Perioperative Durvalumab Plus FLOT Sets New Standard of Care for Early-Stage Gastric, GEJ Cancers

Last week, the FDA approved durvalumab (Imfinzi; AstraZeneca) in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy as a neoadjuvant and adjuvant treatment, followed by single-agent durvalumab, for adults with resectable, early-stage, or locally advanced gastric or gastroesophageal junction adenocarcinoma. This marks the first perioperative immunotherapy approved for patients with early gastric and gastroesophageal cancers.

The approval was supported by findings from the phase 3 MATTERHORN trial (NCT04592913), whose results were presented this past summer at the 2025 American Society of Clinical Oncology Annual Meeting. Investigators Yelena Y. Janjigian, MD, and Zev A. Wainberg, MD, spoke with The American Journal of Managed Care^® about the impact of this approval, as well as the regimen's safety and tolerability profile.

This transcript has been lightly edited for clarity; captions were auto-generated.

Transcript

As the first perioperative immunotherapy approved in this setting, how does durvalumab change the current standard of care for resectable gastric and gastroesophageal junction adenocarcinoma?

Janjigian: It was exciting to get FDA approval so quickly after we presented the overall survival data. This is the first type of approval of its kind for our disease, so it really opens a new chapter of how we can improve outcomes for early-stage gastroesophageal cancer.

This is the first global study to demonstrate that you can give FLOT perioperatively to patients globally, so in patients in Asia, the same as the Western population, and even in South America. It also demonstrated that durvalumab before surgery improves survival. It's important because these patients also have access to immunotherapy, potentially in a stage IV setting when the cancer occurs, and despite that, the survival benefit was still demonstrated in the perioperative setting.

What we see is that these data demonstrate what we have already known as a scientist in the lab, that doing immunotherapy while the tumor is still in place in a perioperative setting, before we remove the bulk of the cancer, actually helps potentiate that anti-tumor immune response and expand the T-cell population. That's what our hypothesis was preclinically, and that's what the MATTERHORN survival data suggests. So, even after the operation, the patient's body can continue to suppress micrometastasis using the immune system that we've now educated.

Now, of course, these are only hypotheses, and we're now doing biomarker analyses from the MATTERHORN study to demonstrate the T-cell population expansion, the ctDNA [circulating tumor DNA] dynamics, and all of the exciting biomarker work that this large phase 3 study enables.

Wainberg: In my opinion, this immediately makes the FLOT plus durvalumab the new standard of care in this scenario, such that almost every patient, unless there's a reason not to, ought to be considered for FLOT plus durvalumab in the perioperative management of gastric and gastroesophageal cancer.

What should clinicians know about the safety and tolerability of this regimen?

Janjigian: We know that 3-drug chemotherapy can cause increased side effects in patients, especially in patients who present as frail or have nutritional compromise. FLOT chemotherapy has now been shown to be effective in 2 separate phase 3 studies before we even got to MATTERHORN. TOPGEAR (NCT01924819) and many other studies have shown that FLOT is feasible.

We need to understand that these are 3 drugs, oxaliplatin, docetaxel, and 5-FU [5-fluorouracil] that can cause side effects. As the clinicians become more comfortable with managing them with dose reductions, hydration, antinausea medicines, we show that the addition of durvalumab did not show any meaningful increase in adverse events. There's some increase in immune-related adverse events, as expected, but the compromise of surgery was not there. Patients were able to get surgery and go to completion of even more cycles of FLOT than what historically was shown, which shows that even for the patients in the United States or Asia, where FLOT was historically considered to be a less commonly used regimen, the doctors know how to use it, and they're starting to accept it.

It's very feasible to give FLOT globally. Of course, there's a bit of a learning curve, but I can tell you that our patients are willing to put up with side effects if they know their survival is improved. In my elderly, more frail patients, I don't start with full-dose FLOT. We know the 3-drug combination is important, but you don't have to go with a parent compound combination; you can start with lower doses.

Wainberg: Most clinicians are quite familiar with this group of drugs. Checkpoint inhibitors have been around in oncology for over a decade, and almost every oncologist has experience and has some context.

Here, the context is a little different because you're given a disease where the patients are a little sicker, perioperative gastric cancer, so you have to keep that in mind. Also, postoperatively, when they've recovered from a gastrectomy or a partial gastrectomy, there is also a consideration of using the drug [durvalumab] in combination with chemo.