When Trastuzumab Deruxtecan Stops Working: — Resistance and What Comes Next

T-DXd is not the only antibody-drug conjugate that targets HER2. Different ADCs carry different payloads and different linker chemistry, so the way cancer cells develop resistance to one does not automatically make them resistant to another. Depending on your cancer type and treatment history, your oncologist may consider a different ADC as a next option. Availability and guideline support vary by diagnosis, so this is a specific question worth putting to your team.

For HER2-positive breast cancer, small-molecule drugs called tyrosine kinase inhibitors — including tucatinib, lapatinib, and neratinib — target HER2 from inside the cell rather than binding from the outside. NCCN and ASCO guidance includes these as options in later lines of treatment for HER2-positive breast cancer. They are usually taken as tablets and are often combined with chemotherapy or another HER2-targeted antibody. Your oncologist will explain which combination fits your treatment history and current health.

Certain chemotherapy regimens remain active after T-DXd, and for some cancer types they are a core part of the treatment landscape at this point. Which one your team recommends depends on your cancer type, what you have already received, and your current health and priorities. For gastric or lung cancers treated with T-DXd, the chemotherapy options differ from those used in breast cancer, so the conversation is always specific to your diagnosis.

If your breast cancer is both HER2-positive and hormone receptor-positive, hormone-directed treatment remains part of the picture at every line of therapy, including after T-DXd. CDK4/6 inhibitors — drugs that block specific proteins involved in cell division — are established in this setting alongside hormone-blocking therapy. Your oncologist will clarify whether the hormone-positive component of your cancer means these options are relevant to your next treatment plan.

Resistance to T-DXd is one of the most actively studied areas in HER2-targeted cancer treatment. At this point, clinical trials may offer access to agents not yet available in standard care — including drugs targeting HER3, newer ADC formats, and combination strategies designed specifically for the post-T-DXd setting. Your oncologist can tell you whether a relevant trial is open at your centre or through referral. Asking about trials is reasonable and does not mean standard options have been exhausted.

In some situations, oncologists discuss whether stopping T-DXd for a period and then restarting it is worth considering. The evidence on this is still developing, and NCCN and ASCO do not yet have a definitive recommendation on when re-challenge is appropriate. It is more likely to be a conversation when resistance appeared late after a long, sustained response, and less likely when the disease progressed early. This is an individual decision your oncologist will weigh against other available options.