While Trastuzumab deruxtecan (TDXD) is effective in HER2-low breast cancer, there is no evidence that it benefits patients with HER2-low or HER2-intermediate (IHC 2+/FISH negative) gastric cancer. Its use should be strictly limited to truly HER2-positive cases in this disease.

For HER2+ metastatic colorectal cancer, experts choose HER2-targeted therapies like TDXD or tucatinib/trastuzumab over standard second-line chemotherapy (FOLFIRI/BEV), despite label constraints. The rationale is the significantly higher response rate from targeting the oncogenic driver directly.

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.

Unlike the US, where Phase 2 trial data can support flexible use of drug combinations, European practice varies significantly. The UK strictly adheres to drug labels, while countries like Germany allow for more flexibility based on updated national guidelines and specific clinical contexts.

Despite a study showing a minor hazard ratio benefit for a FLOT-like regimen over FOLFOX in the metastatic setting, experts advise against it. The significant increase in toxicity outweighs the small efficacy advantage, especially in symptomatic metastatic patients who are often nutritionally deficient and less able to tolerate aggressive chemotherapy.

For HER2-positive gastric cancer, treatment choice depends on patient fitness. For young, fit patients, the more potent but toxic HORIZON-GA regimen (zanidatamab-based) is preferred. For elderly or less fit patients, the better-tolerated KEYNOTE-811 regimen (pembrolizumab/trastuzumab) remains the standard of care.

Experts recommend using the most effective first-line therapy, like zanidatumab combinations, for HER2-positive gastric cancer, despite the risk of the tumor losing HER2 expression upon progression. The substantial upfront survival benefit outweighs the concern of losing a second-line target like T-DXd.

Clinicians advise against continuing targeted agents like zolbituximab or trastuzumab after disease progression in gastroesophageal cancer. The biological heterogeneity of this cancer type means that if a targeted therapy isn't working, it's unlikely to provide benefit with a different chemotherapy backbone.

In the DESTINY-CRC02 trial, the lower 5.4 mg/kg dose of trastuzumab deruxtecan (TDXD) resulted in a higher response rate in colorectal cancer compared to the 6.4 mg/kg dose used in gastric cancer. This counter-intuitive finding suggests better tolerability led to longer treatment duration and superior outcomes.