Unlike immunotherapy, where re-challenge after progression is dubious, there is an emerging clinical practice of re-challenging patients with the same antibody-drug conjugate (ADC), such as enfortumab vedotin (EV), after a treatment break forced by toxicity. Anecdotally, patients are showing great responses, highlighting a key area for prospective data generation.

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.

ITP caused by immune checkpoint inhibitors (ICIs) is rare (0.25% incidence) but generally has a good prognosis. Most patients respond to standard first-line ITP therapies, and approximately 70% of those re-challenged with the ICI can continue treatment without a recurrence of ITP.

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.

High rates of interstitial lung disease (ILD) in TDXD trials for brain metastases might be partly attributable to opportunistic infections like PJP, not direct drug toxicity. This occurs in patients receiving steroids for brain edema, underscoring the need for PJP prophylaxis.

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.

While oncologists focus on the low 4% rate of Interstitial Lung Disease (ILD) from neoadjuvant TDXD, surgeons worry this complication could prevent patients from reaching potentially curative surgery, drawing parallels to issues seen with neoadjuvant immunotherapy.