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Clinical Integration of ADCs Into Treatment Plans for Patients With NSCLC: Answers to Your Questions

Released: September 23, 2025

Matthew Gubens
Matthew Gubens, MD, MS, FASCO
Rebecca S. Heist
Rebecca S. Heist, MD, MPH
Ticiana Leal
Ticiana Leal, MD
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Key Takeaways
  • Early interstitial lung disease (ILD) detection while on treatment with antibody–drug conjugates (ADCs) requires close monitoring of respiratory symptoms and regular imaging (eg, every 6-9 weeks at the beginning of treatment).
  • Rechallenging with ADCs after ILD depends on adverse event severity and must be done with caution especially if following grade 2 ILD.

In this commentary, a panel of experts addressed key clinical questions raised by participants during a Grand Rounds–style meeting series titled, “A Practical Framework for Clinical Integration of ADCs Into Individualized Treatment Plans for Patients With NSCLC.” These programs were held at sites across the US and brought together oncologists, nurses, pharmacists, and other healthcare professionals (HCPs) engaged in the care of patients with advanced non-small-cell lung cancer (NSCLC). The program was focused on integrating antibody–drug conjugates (ADCs) into clinical practice and applying multidisciplinary approaches to effectively manage treatment-related adverse events (TRAEs) in patients with advanced NSCLC.

How do you identify and manage ILD early with T-DXd or Dato-DXd? 

Ticiana Leal, MD:
Interstitial lung disease (ILD) is observed mainly with trastuzumab deruxtecan (T-DXd) but also with datopotamab deruxtecan (Dato-DXd). Typically, symptoms in patients with lung cancer are taken seriously and investigated early, even when they appear mild. The most notable symptoms are cough, shortness of breath, and changes in oxygen level. All are very important to investigate if identified to ensure they are not the early start of ILD. Frequent scanning is also essential to addressing and mitigating this issue. In the lung cancer field, HCPs probably perform more scans than HCPs in other oncology fields. I frequently do scans every 6-9 weeks at the beginning of treatment with ADCs to ensure patients are doing well, experiencing a response, and monitoring for ILD.  

Proper clinical judgment can be tricky—especially with grade I pneumonitis—in a patient who has already received radiation. For these patients, I keep a very close eye on their status and the symptoms they develop. I also investigate the symptoms fully and not simply call it pneumonitis if a patient is benefiting from treatment. If questionable, I consult with a multidisciplinary team. Perhaps the patient is a candidate for bronchoscopy to fully determine whether there is an infection vs true ILD. If deemed to be ILD, it is important to treat as soon as possible. Hold T-DXd, initiate steroids, and exhaust all the supportive care options throughout the prolonged steroid course. The key decision will be determining whether it is safe to rechallenge. With grade 1, I feel very comfortable. With grade 2, a lot of thought and consideration should go into determining whether rechallenge with T-DXd is worthwhile. With grade 3, I would not rechallenge. In summary, ILD management requires extreme caution in real-time clinical practice.

What can infusion center staff do to catch early signs of ADC-related ILD before they appear on scans?

Rebecca Heist, MD, MPH:
This is a really important question. I think everyone—infusion staff, nurses, physicians, nurse practitioners, and physician associates—can ask patients, “How is your breathing feeling?” and pay close attention to what may seem like relatively minor changes. If patients respond with something like, “I used to walk a mile, and now I am getting a little huffy and puffy after a short distance,” attention is needed. I often check O2 saturation in clinic and walk patients around to ensure it does not drop. Symptoms related to dyspnea should be taken seriously.  

What are your thoughts on sequencing T-DXd and Dato-DXd in HER2-overexpressing vs TROP-2–positive tumors?  

Matthew Guebens, MD, MS, FASCO:
At present, we do not assess TROP-2 positivity. Some interesting evidence suggests that immunohistochemistry (IHC) assays do not distinguish benefit or not, perhaps because a large majority of lung cancers express it anyway. Researchers are actively investigating this issue. Some quantitative assessments of TROP-2 using artificial intelligence may be helpful, but there are no such tools at present. I believe this decision is mostly relevant in the setting of EGFR-mutated advanced NSCLC based on the approved indications for Dato-DXd and T-DXd. In this setting, it is fair to look for HER2 overexpression; however, I often do not see it. If a patient with EGFR-mutated advanced NSCLC was HER2 IHC 3+ at a point of resistance, I would likely choose T-DXd before Dato-DXd, but any sequence is reasonable. If and when TROP-2–directed ADCs get approved outside the EGFR-mutated setting, HCPs could strategically think about treatment sequence. Certain complications come with additional options, but it is exciting to see that patients may have more therapeutic possibilities.

Your Thoughts
What are your biggest barriers to incorporating approved ADCs into your practice for your patients with advanced NSCLC and what questions do you have about using ADCs for these patients? Join the discussion by posting a comment below.

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Which approved ADCs have you incorporated into your practice for patients with previously treated advanced NSCLC?

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