In advanced gastroesophageal cancer, a common clinical practice for patients achieving a complete response on immunotherapy is to stop treatment after two years. For those with residual disease confirmed by biopsy, clinicians advocate for extending therapy beyond this point, contingent on payer approval.

The Matterhorn study found that adding the immunotherapy drug Durvalumab to FLOT chemotherapy significantly improved survival in localized gastric cancer. Surprisingly, this benefit extended to patients with low or negative PD-L1 expression, challenging the biomarker's predictive value for immunotherapy efficacy in this perioperative setting.

In the increasingly common scenario of gastric cancer with multiple biomarkers (HER2, PD-L1, Claudin), experts recommend a clear hierarchy. Based on data maturity, HER2-targeted therapy is the first choice, followed by PD-L1 immunotherapy, with Claudin-targeted therapy third.

Experts indicate that Tumor Mutational Burden (TMB) is losing relevance for guiding immunotherapy in GI cancers. The TMB cutoff of 10 is not considered reliable across tumor types, and clinicians still prefer combination chemo-immunotherapy even in TMB-high patients, unless MMR deficiency is also present.

For highly symptomatic gastric cancer patients needing rapid cytoreduction, oncologists may initiate treatment with chemotherapy alone. This approach aims to quickly control the disease and avoids confounding potential drug toxicities with rapid progression before adding biomarker-driven agents.

Retrospective data suggests patients with MSI-high rectal cancer might not just respond poorly to standard neoadjuvant chemoradiation (TNT), but their disease could actually progress. This makes immunotherapy a potentially safer and more effective first-line neoadjuvant choice, not just an alternative.

Frontline treatment selection hinges on histology. Non-epithelioid mesothelioma responds poorly to chemotherapy, making dual immunotherapy (Nivo/Ipi) the clear choice. For epithelioid cases, chemo-immunotherapy is a strong option, especially for symptomatic patients, due to its higher and faster response rate.

Data shows that patients who permanently stopped ipilimumab due to immune-related side effects still had exceptionally good outcomes. This gives clinicians confidence to manage toxicity by discontinuing the CTLA-4 inhibitor portion of the regimen while continuing nivolumab, without fearing a loss of efficacy.

In the increasingly common scenario of a patient with multiple positive biomarkers, a clear hierarchy exists for treatment decisions. Based on the robustness and maturity of clinical trial data, HER2-directed therapy is the top priority, followed by PD-L1 immunotherapy, with Claudin-18.2 targeting considered third.