Sequencing Trastuzumab Deruxtecan After Zanidatamab: Biopsy and ctDNA Considerations

In this episode, Dr. Wainberg, Dr. Shameem, Dr. Elimova, and Dr. Shah discuss second-line sequencing after zanidatamab-based first-line therapy. Dr. Wainberg notes that trastuzumab deruxtecan (T-DXd) is supported by two studies confirming single-agent efficacy in the Western world, plus a randomized phase 3 trial (DESTINY-Gastric04) conducted outside the US because the drug was already approved there. He asks how T-DXd might fit after a zanidatamab-based first line.

Dr. Shameem would confirm HER2 positivity before offering T-DXd, ideally by biopsy. He considers that the different mechanisms of action, biparatopic antibody versus antibody-drug conjugate, support a reasonable expectation of response, particularly in patients who are IHC 3+, whom he views as having the best magnitude of benefit. He highlights pneumonitis as the most feared toxicity, noting deaths in clinical trials and post-marketing, and states that patients with prior interstitial lung disease or prior immunotherapy-related pneumonitis are not appropriate candidates. He also counsels patients on chemotherapy-like adverse events from the ADC payload, including myelosuppression and GI toxicity.

Dr. Elimova raises whether HER2 retesting is actually happening in routine practice and reports variability in Canada. Dr. Wainberg estimates about half his patients get tissue re-biopsy and half get circulating tumor DNA (ctDNA) testing, citing roughly 90% concordance for HER2-positive gastric cancer. Dr. Shameem reports community cases where T-DXd was given without HER2 reconfirmation and views this as an education gap.

Dr. Shah cautions that ctDNA sensitivity for HER2 declines when tumor shedding is low, which can produce false negatives in responding patients. The panel agrees to prefer tissue biopsy when feasible, with ctDNA as an alternative and appropriate counseling about its limitations.

In the next episode, “Upcoming First-Line HER2-Positive Trials: ARTEMIDE-Gastric01, DESTINY-Gastric05, and HLX22,” Dr. Wainberg and Dr. Shah preview several phase 3 trials that may inform future first-line decision-making.