ASCO 2026 | The emerging role of T-DXd in earlier settings for upper gastrointestinal cancers

The shaping of TDXd in first-line setting is complex as the HER2 space is going to become more and more complex with the Horizon data and Xanidadamab, Trastuzumab combination, and of course the standard of care is still Pembrolizumab, Trastuzumab combination. So in Destiny Gastric 05, we’re comparing TDXd-based regimen with Pembrolizumab and capecitabine to KENOD811, which is the pembrolizumab CAPOX regimen. Ultimately, what we need to see is the durability of the response, the toxicity profile, and the overall survival data. Because, of course, TDXd is also available in later line settings. So the sequence will depend on various degrees of efficacy, but also toxicity. And of course, what brings TDXd to the clinic is the off-target effect and bystander effect that it may impart on the HER2 low heterogeneous tumors that we see in first line. But also the side effect profile, because as you know, it’s an oxaliplatin-sparing regimen. So increasingly, as we’re bringing immunotherapy in early-stage, perioperative setting, patients who are recurring and may have HER2-positive disease, so non-platinum-containing regimen may be very appealing to them because it’s an irinotecan-type regimen. So I’m excited about all the options for patients. And what we’re hoping to see is the future where the field is crowded and it allows many options because if all of those options are approved and first-line setting, the clinician and the physician can choose how to sequence them in the best way. And then we just need to do additional studies to see if the, for example, next-generation antibodies such as Xanidadamab or even newer ADCs have other activities in later lines.

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