Trastuzumab deruxtecan (TDXD) and datopotamab deruxtecan (Dato-DXd) share the same cytotoxic payload, yet Dato-DXd has a much lower rate of interstitial lung disease (ILD). This indicates the toxicity is driven by the antibody-antigen interaction, not the payload itself.

While caution is necessary, a patient's prior history of pneumonitis does not automatically disqualify them from receiving an ADC with a known risk of this side effect. Clinical judgment is key; if the prior event was from a specific, known drug combination and has fully resolved, proceeding with careful monitoring can be a viable option.

For urothelial cancer patients treated with trastuzumab deruxtecan (TDXD), developing symptomatic (Grade 2) interstitial lung disease or pneumonitis is a critical event. Following protocols from other cancers, this requires permanent discontinuation of the therapy. Re-challenging the patient with TDXD after a Grade 2 event is not recommended without more disease-specific safety data.

The discovery of low-grade, asymptomatic interstitial lung disease (ILD) on scans for patients on certain ADCs does not mandate permanent discontinuation. By holding the drug, initiating steroids, and involving pulmonology, the inflammation can resolve, often allowing the patient to safely resume a highly effective therapy.

With ADCs carrying a risk of interstitial lung disease (ILD), a critical safety measure is to act on radiological findings alone. Even if a patient is completely asymptomatic, new ground-glass opacities on a CT scan require an immediate treatment hold to prevent potentially rapid and severe pneumonitis.

The management of treatment-induced pneumonitis differs significantly between drug classes. While clinicians may treat through low-grade pneumonitis from immune checkpoint inhibitors, the safest approach for antibody-drug conjugates (ADCs) like TDXD is to stop the drug immediately upon any radiographic evidence, even if the patient is asymptomatic.

Unlike some immunotherapy guidelines, experts recommend immediate steroid treatment for even Grade 1 (asymptomatic) ADC-induced pneumonitis or interstitial lung disease (ILD) found on scans. This aggressive, proactive approach is considered necessary due to the risk of rapid clinical deterioration, prioritizing safety and the ability to resume cancer therapy.

Despite label warnings against rechallenging trastuzumab deruxtecan (TDXD) after any symptomatic (Grade 2+) interstitial lung disease (ILD), some experts differentiate. For 'soft call' cases with minimal symptoms, they may consider restarting after a transparent patient discussion, believing not all Grade 2 ILDs carry the same risk.

Interstitial lung disease (ILD) is a serious risk with trastuzumab deruxtecan (TDXD). Oncologists must take it extremely seriously, engaging a pulmonologist immediately at the first sign of symptoms or CT scan findings. A collaborative, multidisciplinary approach is essential for safely managing this potentially fatal toxicity.