MATTERHORN Findings May Offer Additional Therapy Option in Gastric Cancers

In a conversation with CancerNetwork®, Ronan J. Kelly, MD, MBA, spoke about advice he would give regarding the integration of nivolumab (Opdivo) following chemoradiation in patients with esophageal/gastroesophageal junction (GEJ) cancers following a presentation of a 5-year analysis of the phase 3 CheckMate 577 study (NCT02743494) he gave at the 2025 American Society of Clinical Oncology Annual Meeting.1

Kelly is the director of oncology at the Charles A. Sammons Cancer Center and W.W. Caruth, Jr. Endowed Chair of Immunology at Baylor University Medical Center in Dallas, Texas.

He began by suggesting that findings from the phase 3 MATTERHORN trial (NCT04592913) evaluating the addition of durvalumab (Imfinzi) to fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) in the same patient population may offer a second immune checkpoint inhibitor for this patient group if approved, thereby expanding treatment options for patients.2 He further explained that a decreasing use of neoadjuvant chemoradiation in gastric and GEJ cancers may give way to perioperative treatment with the MATTERHORN regimen, which he claimed has shown to be “the better option.”

In patients with esophageal squamous cell carcinoma, he suggested that radiation may have a role to play, expressing that patients treated with chemoradiation and surgery followed by nivolumab elicited a 19-month improvement in overall survival. Furthermore, he remarked that for those with esophageal adenocarcinoma, the regimen evaluated in the phase 3 ESOPEC trial (NCT02509286), including perioperative chemotherapy, showed benefit in younger, fitter patients. He concluded by suggesting that clinicians may consider chemoradiation/nivolumab in more frail populations given their intolerance to surgery.

Transcript:

Up to now, we’ve had only 1 immune checkpoint inhibitor approved in [patients with esophageal/GEJ cancers], which was from adjuvant nivolumab. We looked at the data from the phase 3 MATTERHORN trial in the plenary session. It’s not FDA approved yet, but I think we all expect that will be the case. I think now we have options for our patients. If you look at where perioperative chemotherapy is going, and we’ve seen a decrease in the use of radiation in this setting, gastric and GEJ cancers shouldn’t be treated with neoadjuvant chemoradiation. The data are strong there; perioperative treatment is the better option there. With durvalumab now in the phase 3 MATTERHORN study showing those benefits over FLOT alone, I expect that will become the standard of care for GEJ and gastric [cancers].

In terms of esophageal squamous cell carcinoma, I think radiation still does have a big role to play. The CheckMate 577 study design with chemoradiation and surgery followed by a year of nivolumab is a standard of care in that disease setting. If you look at the squamous group, we had shown benefits there. There was a 19-month improvement in overall survival if you just looked at esophageal squamous [histology], so clearly this is still a standard of care.

Then, in that middle group, which [is] the esophageal adenocarcinomas, MATTERHORN did not look at that group, but we had previously seen a trial from Germany called the phase 3 ESOPEC trial, which showed a benefit of perioperative chemotherapy vs chemoradiation, although they did not compare it with chemoradiation followed by adjuvant nivolumab, which was the standard there. My take-home [message] there is we need to be a little careful.

In younger, fitter patients who can tolerate FLOT, I think that will become the new normal in esophageal adenocarcinoma. But there’s an older population who may be a bit frailer–– [those in] the community setting are struggling to give FLOT in a safe manner. There is clearly a learned behavior here in terms of cancer centers that are giving this, so I think for that [older] group, I would advise doctors to make a decision about tolerance of treatment.

Each individual oncologist will be in the best position to make that decision. What we don’t want is to give people treatment that then they get too frail or sick to tolerate a subsequent surgery. That’s not in the best interest of patients. Doctors will have a choice: In an older, frailer group, they may decide to do the CheckMate 577 [regimen], given the benefits we’ve shown with adjuvant nivolumab. In a younger, fitter patient population, they may decide to go with perioperative FLOT.

References

1. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): first results of overall survival (OS) from CheckMate 577. J Clin Oncol. 2025;43(suppl 16):4000. doi:10.1200/JCO.2025.43.16_suppl.4000
2. Janjigian Y, Al-Batran SE, Wainberg Z, et al. Event-free survival (EFS) in MATTERHORN: a randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 2025;43(suppl 17):LBA5. doi:10.1200/JCO.2025.43.17_suppl.LBA5