Gastro-esophageal cancer

While ASCO GI 2025 did not feature any read-outs from important phase III studies in gastro-esophageal cancer, the congress did provide an important platform for discussions on the contemporary treatment landscape for these malignancies. In this video, Prof Em Eric Van Cutsem, digestive oncologist at the University Hospitals Leuven shares some of the key take-aways from the meeting related to gastric, gastro-esophageal-junction (GEJ) and esophageal cancer.

In the EORTC-1203-GITC INNOVATION study, investigators evaluated the impact of integrating trastuzumab, with or without pertuzumab, into the perioperative treatment for patients with resectable, HER2-positive stomach cancer.¹ In contrast to what was observed in the metastatic setting, HER2-directed therapies did not provide a progression-free survival (PFS) benefit in this trial. As such, FLOT should remain the standard of care for patients with HER2-positive, resectable gastric cancer.

Also in HER2-positive patients, the randomized, phase II ASPEN-06 study yielded promising results with evorpacept, an agent directed against CD47.² In this trial, including 127 patients with HER2-positive gastric or GEJ cancer who progressed after prior HER2-directed therapy, adding evorpacept to trastuzumab-ramucirumab-paclitaxel (TRP) significantly boosted the objective response rate from 26.6% to 41.3%. In addition, responses to the quadruplet regimen also proved to be more durable, with a median duration of response of 15.7 months as compared to 9.1 months with TRP alone. As such, this study provides a basis for future phase III studies with this agent.²

In recent years, we have witnessed many innovations in the treatment for patients with HER2-positive gastro-esophageal cancer. In first line, the current standard of care consists of FOLXOX plus trastuzumab and the further addition of pembrolizumab in patients with PD-L1 expression. In 2^nd line, the antibody-drug-conjugate (ADC) trastuzumab-deruxctecan (T-DXd) recently received EMA approval, offering an alternative for ramucirumab-paclitaxel in that setting. A formal comparison between these two 2^nd line options is currently ongoing in the DESTINY-Gastric04 study and the results of this trial are eagerly awaited. In HER2-negative disease we are seeing that the American colleagues are now following the existing European guidelines and have also restricted the use of immune checkpoint inhibitors (ICI) to patients with PD-L1 expression. 

In recent years, 4 different therapeutic biomarkers have emerged in gastro-esophageal cancer: MSI status, HER2 overexpression, PD-L1 expression and Claudin expression. However, this multitude of biomarkers may also create certain challenges. For example, how should you treat a metastatic gastric cancer who is PD-L1 positive and also tests positive for claudin? Should you start with an ICI or go for zolbetuximab in 1^st line. From the discussions at ASCO GI it became clear that there is a large level of agreement among experts on the hierarchy of the different biomarkers. In decreasing order of therapeutic importance, these biomarkers were ranked as MSI, HER2, PD-L1 and claudin. As such, this means that the patient sketched before should receive chemotherapy plus pembrolizumab in 1^st line and receive zolbetuximab in 2^nd line.

On a final note, Prof Van Cutsem touched upon the long-term results of the pivotal CheckMate 649 study. These long-term data indicate that 15-20% of patients receiving a first line treatment with chemotherapy plus nivolumab were still alive after 5 years.³ A decade ago, this level of long-term survival was unimaginable in metastatic gastro-esophageal cancer. As such, these long-term data clearly illustrate the dramatic therapeutic revolution that we are living through in this setting, laying the ground for further improvements in the years to come.