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.

To manage the risk of interstitial lung disease (ILD) with TDXD, experts now recommend routine screening with high-resolution chest CT scans every 6-12 weeks. This practice aims to catch asymptomatic, grade 1 ILD early, allowing for treatment holds and steroid intervention, which may preserve the option to rechallenge.

Interstitial Lung Disease (ILD) is a significant risk with TDXD. However, a history of a completely resolved grade 1 event does not automatically preclude a patient from receiving the drug again. Clinicians may consider a re-challenge, balancing the risk against the lack of other viable therapies.

While the feared side effect of severe lung inflammation (pneumonitis) did not increase, other immune-mediated adverse events did. This led to higher rates of treatment discontinuation in the experimental arm, potentially negating any benefits of the concurrent approach and contributing to the trial's failure.

Adopting T-DXd in early-stage breast cancer requires frequent chest CT scans to monitor for potentially fatal interstitial lung disease (ILD), a practice not standard for current therapies. This presents significant new logistical challenges, including securing insurance approvals, managing patient access, and increasing the overall burden of care.

Drawing from experience in breast cancer, oncologists advocate for proactive management of the ADC Dato-DXd's side effects. Specifically, they recommend prophylactic corticosteroid mouthwash and ice chips during infusion to prevent or mitigate mucositis, which can severely impact a patient's quality of life.

For patients with actionable mutations like EGFR or ALK, targeted therapy is the priority, regardless of PD-L1 score. Starting immunotherapy first in these patients can significantly increase the risk of developing severe pneumonitis (ILD) when they later switch to targeted therapy like osimertinib.

Contrary to initial fears, both clinical trial and real-world data show that patients experiencing asymptomatic, grade 1 interstitial lung disease (ILD) from TDXD can be safely retreated. This allows patients to continue benefiting from a highly effective therapy without undue risk.