Interstitial lung disease (ILD) / pneumonitis
Interstitial lung disease (ILD) is lung inflammation, a serious side effect of some ADCs (especially Enhertu) and immunotherapy.
Occurs in ~10-15% of T-DXd patients (grade 5 in ~1%); also with Dato-DXd, HER3-DXd, checkpoint inhibitors, and mTOR inhibitors. Requires monitoring, prompt steroids, and permanent discontinuation for grade ≥2 with T-DXd. Mechanism with DXd is incompletely understood (alveolar macrophage uptake proposed).
Patients with hormone-receptor-positive metastatic breast cancer that has stopped responding to endocrine therapy can be offered trastuzumab deruxtecan as their first chemotherapy-type treatment if the tumour shows any HER2 staining, rather than waiting until after conventional chemotherapy. Whether to use it before or after chemotherapy is now a choice, since overall survival was not shown to differ and the drug carries a risk of lung inflammation.
For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
Patients whose breast cancer was previously called HER2-negative may now be eligible for an effective HER2-directed drug if their tumour has even low-level HER2 staining, so pathology reports must now distinguish HER2-low (1+ or 2+/ISH-negative) from HER2-zero. This applies to metastatic disease after at least one line of chemotherapy; it does not mean these patients benefit from trastuzumab or other older HER2 drugs.