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TROP2 ADCs in NSCLC
Implementing TROP-2–Directed ADC Therapy in EGFR-Mutated NSCLC: From Clinical Trial Evidence to Clinical Decision-making

Released: March 11, 2026

Matthew Gubens
Matthew Gubens, MD, MS, FASCO
Helena Yu
Helena Yu, MD
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Key Takeaways
  • Datopotamab deruxtecan (Dato-DXd) has FDA accelerated approval (June 23, 2025) for locally advanced or metastatic EGFR-mutated NSCLC after prior EGFR-directed therapy and platinum-based chemotherapy.
  • With deruxtecan-class ADCs, suspected interstitial lung disease or pneumonitis should prompt holding therapy and reassessment, including for grade 1 findings.
  • Dato-DXd can be considered across EGFR mutation subtypes, including exon 20 insertions and uncommon EGFR mutations, when selecting and sequencing therapy after EGFR-directed treatment and chemotherapy.

In this commentary, adapted from a live expert webinar titled “Setting New Standards With TROP-2 Directed Therapy in NSCLC: Leveraging ADC Innovation to Meet Unmet Patient Needs”, we summarize how Matthew Gubens, MD, and Helena Yu, MD, approached real-world treatment decisions in EGFR-mutated disease and highlight practice-ready safety workflows.

Although much of the early development of TROP2-directed antibody–drug conjugates (ADCs) focused on unselected non-small-cell lung cancer (NSCLC) populations, interest has accelerated as these agents have demonstrated meaningful activity in molecularly defined settings. In EGFR-mutated metastatic NSCLC in particular, treatment options become more limited after progression on an EGFR-directed tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy. This later-line setting is where datopotamab deruxtecan (Dato-DXd) has become especially relevant in clinical practice, and where sequencing and adverse event (AE) management questions are most urgent.

After EGFR TKI and platinum chemotherapy, what is the appropriate approved next systemic option in EGFR-mutated metastatic NSCLC?

Helena Yu, MD:
In EGFR-mutated metastatic NSCLC, we now have multiple effective earlier-line options, including EGFR-directed TKIs and platinum-based chemotherapy combinations. However, once a patient has progressed after both an EGFR-directed TKI and platinum-based chemotherapy, treatment selection becomes more nuanced and evidence driven.

Based on currently available evidence, Dato-DXd is an option and the only FDA-approved TROP2-directed ADC for patients with EGFR-mutated metastatic NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy. This accelerated approval was based on TROPION-Lung05 and supported by data from TROPION-Lung01. The FDA accelerated approval was based on objective response rate and duration of response.

Other TROP2 ADCs remain investigational in NSCLC. Sacituzumab govitecan was evaluated in the phase III EVOKE-01 study in an unselected population of previously treated metastatic NSCLC and did not meet its primary endpoint of overall survival. Sacituzumab tirumotecan has also been evaluated in EGFR-mutated NSCLC after EGFR TKI resistance. In the phase III OptiTROP-Lung04 study, sacituzumab tirumotecan demonstrated improved outcomes vs chemotherapy in this setting, but it is not approved for NSCLC at this time.

It is also important to distinguish this later-line setting from earlier-line EGFR-directed strategies. For example, amivantamab plus lazertinib is approved in the first-line setting for NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, and amivantamab combined with chemotherapy is an option as first-line treatment for EGFR exon 20 insertion mutations. In addition, amivantamab is an option after progression on or after treatment with an EGFR TKI for EGFR exon 19 deletions or exon 21 L858R substitution mutations.

If grade 1 (asymptomatic) interstitial lung disease (ILD) or pneumonitis is detected on Dato-DXd, what is the best next step?
ILD or pneumonitis is a key safety consideration with deruxtecan-class ADCs because it can be serious if not treated promptly, and early detection can prevent escalation. Grade 1 ILD or pneumonitis, with asymptomatic radiographic findings, is most often picked up on restaging scans rather than because of patient-reported symptoms. Although other AEs can also affect patients on TROP2 ADCs, including stomatitis, nausea, and ocular toxicities, ILD requires particular vigilance because management decisions change even at grade 1.

Helena Yu, MD:
If I see grade 1 asymptomatic ILD or pneumonitis, I do not continue treatment. The prescribing information instructions are to hold Dato-DXd until ILD or pneumonitis is completely resolved, then resume dosing based on the time to resolution. If it resolves in less than 28 days, maintain the current dose. If it resolves in more than 28 days, reduce by 1 dose level. I also consider corticosteroids as soon as ILD or pneumonitis is suspected.

Matthew Gubens, MD:
I agree. Even when the differential for grade 1 ILD is not perfectly clear, which is often the case for patients with lung cancer, I still hold therapy and use short-interval reassessment to determine when I can restart Dato-DXd if the finding resolves. Once a patient becomes symptomatic, such as an oxygen drop, cough, or functional limitation, my threshold changes, and I am more conservative about stopping therapy and escalating management.

For symptomatic ILD or pneumonitis (grade 2 or higher), the prescribing instructions are to permanently discontinue Dato-DXd and administer corticosteroids as soon as ILD or pneumonitis is suspected. This is 1 of the areas where having a consistent team workflow helps, including early symptom checks, timely imaging follow-up, and a clear plan for when to hold treatment and when to escalate care.

How are you using Dato-DXd in EGFR exon 20 insertions and uncommon EGFR, and would you extrapolate the “Actionable Genomic Alteration (AGA)” signal outside EGFR?

Helena Yu, MD:
I was surprised the EGFR-mutant label was broad, particularly because uncommon EGFR mutation subsets are often represented by relatively small numbers in clinical trials. That said, I am inclined to use that breadth thoughtfully in practice. Conceptually, we are not targeting EGFR with Dato-DXd. We are leveraging a broadly expressed tumor antigen, TROP2, to deliver a topoisomerase I payload. For that reason, I do not see a biologic rationale for activity to be limited only to exon 19 deletion and L858R substitutions, and I am comfortable considering it across EGFR subsets, including exon 20 insertions and uncommon EGFR mutations, especially because those patients often have fewer good options.

For sequencing in patients with exon 20 or uncommon EGFR, I am considering Dato-DXd after other targeted approaches, such as amivantamab or an exon 20-directed TKI, like sunvozertinib, and after chemotherapy. This approach is consistent with how we are already using Dato-DXd in EGFR-mutated disease more broadly, after patients have received appropriate EGFR-directed options for their subtype and after platinum chemotherapy.

When I think about patients with “AGA” as a complete subgroup, I try not to assume all driver-positive subsets behave the same way. There is real heterogeneity when these groups get bundled together. At the same time, I think the AGA signal may reflect greater chemotherapy sensitivity in oncogene-driven disease, which could translate into increased sensitivity to cytotoxic ADC payloads, and I would not be surprised if benefit could be recapitulated in other driver-positive subsets such as ALK-positive or RET-positive NSCLC. However, we also must recognize that dedicated trials may be difficult in very small genomic subgroups. I view that as hypothesis-generating and practice-informing, rather than definitive evidence in those non-EGFR subsets.

Your Thoughts
How might the evolving data on TROP2-targeted ADCs in NSCLC influence your approach to treatment sequencing, supportive care planning, and toxicity monitoring over the next few years? Get involved in the discussion by posting a comment below.

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