Perioperative Advances in Biomarker-Defined Gastric/GEJ Cancer

Geoffrey Y. Ku, MD, of Memorial Sloan Kettering Cancer Center, discusses 2 of the most active areas of investigation in the perioperative management of gastric and gastroesophageal junction (GEJ) cancers targeting HER2-positive disease and identifying mismatch repair–-deficient (dMMR) and microsatellite instability-high (MSI-high) tumors.

Ku begins with data presented at the 2025 European Society for Medical Oncology Congress from the phase 2 PHERFLOT trial (NCT05504720), a German study that added pembrolizumab (Keytruda) and trastuzumab (Herceptin) to the FLOT chemotherapy backbone (fluorouracil, leucovorin, oxaliplatin, and docetaxel) in the perioperative setting for patients with HER2-positive esophagogastric adenocarcinoma.¹ 

Although the data remain immature, the regimen produced a pathologic complete response (pCR) rate of approximately 50%, 19% for durvalumab (Imfinzi)/FLOT in all-comers in the phase 3 MATTERHORN trial (NCT04592913).² Ku notes that pCR has historically correlated with progression-free and overall survival, making it a meaningful early signal even before mature survival data are available. He notes that phase 3 trials are now being developed to determine whether HER2-directed therapy can move from an early, promising signal to a new standard of care.

Ku next focuses on the dMMR/MSI-high subgroup, a smaller but highly immunotherapy-responsive population that makes up approximately 7% to 8% of operable esophagogastric cancers. Ku discusses data showing that combination preoperative immunotherapy (a CTLA-4 inhibitor plus a PD-1 or PD-L1 inhibitor) produces pCR rates of approximately 50% to 60% in this population. These findings have established a strong rationale for incorporating immunotherapy into the perioperative treatment of selected patients with dMMR/MSI-H disease, according to Ku.

Ku closes by explaining that the high pCR rates observed with perioperative management in these targeted populations are prompting studies into the feasibility of safely avoiding surgery altogether through nonoperative treatment for patients who achieve a pCR.

REFERENCES

1. Goekkurt E, Stein A, Al-Batran SE, et al. Pembrolizumab and trastuzumab in combination with FLOT in the perioperative treatment of HER2-positive localized esophagogastric adenocarcinoma: interim analysis of the phase II PHERFLOT/IKF-053 trial of the AIO study group (AIO STO 0321). Ann Oncol. 2025;36(suppl 2):S1102. doi:10.1016/j.annonc.2025.08.2717

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