Neil M. Iyengar, MD: There are some patients in the second-line setting for whom I may consider an agent other than trastuzumab deruxtecan. These are patients for example, who may have brain metastasis. We do see emerging data supporting the activity of trastuzumab deruxtecan in patients with brain metastasis, but particularly for my patients with active CNS disease or high burden CNS disease, or predominantly CNS disease, I'm using the tucatinib-based regimen in that setting even if it's in the second-line because we certainly have the most robust data prospectively from HER2CLIMB for that patient population. Now, if I have a patient who has a heavy burden of systemic disease and who may have a single asymptomatic brain metastasis that's been stable or treated, that patient is a patient I would probably use trastuzumab deruxtecan for given their burden of heavy systemic disease in the second-line setting. There are some patients in the second-line setting who may also have contraindications due to pulmonary status. For example, if I have a patient who has pulmonary disease that makes it difficult to diagnose or monitor for interstitial lung disease, that might be a patient for whom I'm using something different than trastuzumab deruxtecan. In addition to that, I do wanna make the comment that interstitial lung disease is a very, very serious potential adverse effect of trastuzumab deruxtecan and so asking our patients to be vigilant about symptoms and for ourselves to be vigilant about radiographic findings on staging scans, follow up scans, or imaging that's done to diagnose or to evaluate new symptoms like call for shortness of breath. I'm quick to hold or pause trastuzumab deruxtecan if we're undergoing a workup for interstitial lung disease. That being said, the activity of trastuzumab deruxtecan is so impressive that if a patient has visceral disease and specifically pulmonary disease, these are patients for whom I wouldn't necessarily withhold trastuzumab deruxtecan because if we do see a favorable response in the lung, which we're likely to see that can significantly alleviate the patient's pulmonary symptoms. There are a lot of nuances in terms of deciding when or when not to use trastuzumab deruxtecan, but overall, the activity is quite favorable in the second-line setting or beyond. The risk of ILD is there, and we need to watch for it, but it is fairly low.

The management of interstitial lung disease, I would say really relies on monitoring for it, and we don't yet have great monitoring guidelines. We should have more specific guidelines with some of the newer trials as they report. I think we've overall as a community become more vigilant about monitoring for ILD from a symptomatic standpoint as well as looking more specifically at the lungs for ground glass opacities and other radiographic signs of interstitial lung disease on scans that we would typically use to evaluate for disease response. If we do have a suspicion of interstitial lung disease, particularly grade 1 pulmonary symptoms like coughing or dyspnea, that's a situation where I would hold trastuzumab deruxtecan, evaluate with chest imaging. The best type of chest imaging is a high-resolution CT scan but at the very least a chest x-ray for evaluation as well as oxygenation status. If we do see evidence or a suspicion radiographic suspicion of interstitial lung disease, this can be treated with systemic steroids. I typically start with oral steroids and monitor for response. For more severe interstitial lung disease, IV steroids or even immunosuppressants can be used. If we're in a situation where we're using IV steroids or immunosuppressants, those patients are typically hospitalized, and I would discontinue trastuzumab deruxtecan in that setting. The majority of patients who do develop grade 1 ILD, that resolves typically and can be reconsidered for reinitiating trastuzumab deruxtecan.