What is your preferred approach to third-line treatment of metastatic HER2 positive esophageal adenocarcinoma after progression on FOLFOX/CAPOX + trastuzumab, then T-DXd?

If the patient's disease is still HER2+, I would strongly consider a clinical trial. Outside of a trial, my preferred 3L therapy would be ramucirumab/paclitaxel. The phase 3 RAINBOW trial (Wilke et al., PMID 25240821) showed a survival benefit of ram/paclitaxel over paclitaxel alone. In this trial, ...

I lean toward FOLFIRI rather than taxane-based regimens as it appears to be quite active. There are numerous phase 2 studies, just no large phase 3 due to lack in sponsor interest. Also, trifluridine/tiperacil (TAS-102) is an option here.