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.

If gastroesophageal cancer does not respond to first-line zolbetuximab, experts advise against continuing it with a new chemo backbone. This is based on tumor heterogeneity and parallels with a negative trial of continuing trastuzumab past progression in HER2+ disease.

Oncologists distinguish between HER2 amplification (the target for ADCs like TDXD) and activating mutations. A patient whose tumor loses amplification but retains a mutation is considered "HER2 mutated," not "HER2 positive," and is generally not a candidate for ADC therapy.

Before starting a second-line HER2-targeted therapy like trastuzumab deruxtecan, it is critical to re-biopsy the tumor if feasible. HER2 status can change after first-line treatment, and confirming persistent HER2 positivity is essential to ensure the subsequent therapy will be effective.

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.

Nearly half of HER2-positive gastric cancer patients lose HER2 expression after initial chemotherapy and trastuzumab. This dynamic biomarker status requires re-testing at progression to confirm eligibility for subsequent HER2-targeted therapies like trastuzumab deruxtecan, ensuring the right patients receive the treatment.

Due to selective pressure from first-line treatment, 30-40% of HER2-positive gastroesophageal cancers lose HER2 expression by the time of progression. It is crucial to re-test these patients, either via tissue biopsy or ctDNA, to confirm continued HER2 positivity before initiating second-line HER2-targeted therapy like TDXD.

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.