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From Data to Decisions: Integrating TROP2 ADC Evidence Into NSCLC Care

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Released: November 03, 2026

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As TROP2-directed antibody–drug conjugates (ADCs) reshape the treatment landscape for advanced non-small-cell lung cancer (NSCLC), healthcare professionals face important questions about treatment sequencing, patient selection, and toxicity management. In this commentary, experts examine emerging clinical evidence for datopotamab deruxtecan and sacituzumab tirumotecan, the potential role of predictive biomarkers, and opportunities to integrate ADCs into earlier treatment settings. They also discuss practical strategies for managing adverse events and highlight the importance of balancing efficacy, tolerability, and quality of life to optimize individualized patient care.

Christine M. Bestvina
Christine M. Bestvina, MD
Joshua E. Reuss
Joshua E. Reuss, MD
TROP2 ADC NSCLC

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The treatment landscape for advanced non-small-cell lung cancer (NSCLC) continues to evolve, and TROP2-directed antibody–drug conjugates (ADCs) represent an exciting addition to our treatment tool kit. As these agents move through clinical development, our challenge is determining where they fit into existing treatment algorithms, which patients are most likely to benefit, and how we balance efficacy with tolerability and quality of life.

Although emerging data are encouraging, we believe one critical question remains: How do we translate these findings into meaningful improvements in patient care?

Where Does Dato-DXd Fit Into Current Practice?

Joshua E. Reuss, MD:
Consider a patient with metastatic EGFR-mutated NSCLC who experiences disease progression following osimertinib and platinum-based chemotherapy. Before selecting another systemic therapy, I would first consider several factors: Is this oligoprogression or widespread progression? Have we identified a resistance mechanism through repeat biopsy? What treatments has the patient already received, and what is their current organ function?

These questions are particularly important as frontline treatment evolves. With osimertinib plus chemotherapy (FLAURA2) and amivantamab plus lazertinib (MARIPOSA) available, subsequent treatment decisions increasingly depend on prior exposure, tolerability, and emergent resistance patterns.

I tend to use osimertinib plus chemotherapy upfront. For patients who subsequently progress and are unlikely to benefit from additional platinum chemotherapy, datopotamab deruxtecan (Dato-DXd) becomes an important consideration.

Dato-DXd is currently the only FDA-approved TROP2 ADC for NSCLC, indicated for patients with EGFR-mutated disease previously treated with EGFR-directed therapy and platinum-based chemotherapy. Its approval was supported by pooled data from TROPION-Lung01 and TROPION-Lung05, demonstrating an overall response rate of 45% and a median duration of response of approximately 7 months. These findings provide an encouraging alternative to historical subsequent-line options such as docetaxel.

Can Biomarkers Help Us Select the Right Patients?

Christine M. Bestvina, MD:
One of the most compelling developments in the TROP2 ADC space is the emergence of normalized membrane ratio (NMR), a computational pathology biomarker designed to estimate aspects of TROP2 internalization.

In TROPION-Lung01, patients identified as TROP2 NMR-positive experienced a median progression-free survival (PFS) of 6.9 months with Dato-DXd. What makes this particularly interesting is the possibility that NMR may be predictive rather than simply prognostic. The biomarker appeared to identify patients more likely to benefit from Dato-DXd without predicting a similar benefit from docetaxel.

I find this encouraging because it demonstrates how biomarker development can move forward alongside ADC development. Rather than relying solely on target expression, we may eventually identify patients based on how effectively an ADC can deliver its payload.

Prospective validation remains essential, but this approach could have important implications for future patient selection.

Interpreting Emerging Evidence Without Getting Ahead of the Data

Joshua E. Reuss, MD:
Sacituzumab tirumotecan (sac-TMT) has generated considerable interest, particularly following the phase III OptiTROP-Lung05 study in patients with PD-L1–positive, EGFR/ALK-negative advanced NSCLC.

The combination of sac-TMT and pembrolizumab demonstrated a PFS HR of 0.35 compared with pembrolizumab alone. The PFS benefit was broadly consistent across PD-L1 expression subgroups, including patients with PD-L1 tumor proportion scores (TPS) of 1% to 49% (HR: 0.28) and those with PD-L1 TPS of ≥50% (HR: 0.47).

These findings are encouraging, but several considerations influence their clinical applicability. The study was conducted exclusively in China, making confirmation in broader global populations important. In addition, pembrolizumab monotherapy may not represent the preferred comparator for many US patients with PD-L1 TPS of 1% to 49%, for whom chemotherapy plus immunotherapy is commonly used. For patients with PD-L1 TPS of ≥50%, the results are especially intriguing. However, I believe overall survival should remain a critical benchmark when considering treatment intensification.

If we are adding toxicity and more frequent infusions, we need to know whether that additional treatment ultimately helps patients live longer. The negative EVOKE-03 results with sacituzumab govitecan plus pembrolizumab also remind us that we cannot extrapolate findings from one TROP2 ADC to another.

Moving ADCs Into Earlier Treatment Settings

Christine M. Bestvina, MD:
As we consider incorporating TROP2 ADCs into earlier lines of treatment, one of my biggest concerns is the tolerability of combination regimens. Several ongoing studies are evaluating ADCs combined with immunotherapy with or without platinum chemotherapy. For patients with nonsquamous NSCLC, this may involve substituting an ADC for pemetrexed, which is generally well tolerated. We know that ADCs can cause clinically meaningful cytopenias, and I am particularly interested in whether triplet regimens will provide sufficient benefit to justify their additional toxicity.

I am also encouraged that some studies are evaluating ADC plus immunotherapy without additional chemotherapy. These combinations may offer an opportunity to maintain efficacy while reducing treatment burden. Studies including TROPION-Lung07 (NCT05555732), TROPION-Lung08 (NCT05215340), and AVANZAR (NCT0568726) should provide important information about the potential role of these strategies in frontline treatment.

OptiTROP-Lung06 looked at the combination of sac-TMT plus pembrolizumab, the same combination from OptiTROP-Lung05. However, Lung06 looked at patients with PD-L1 <1%, nonsquamous only and compared this regimen with platinum-pemetrexed plus pembrolizumab. Although overall survival data are immature, the median PFS was improved from 5.7 months with the sac-TMT plus pembrolizumab regimen compared with 15.0 months with chemotherapy plus pembrolizumab regimen (HR: 0.49). Patients with PD-L1 <1% represent a huge unmet need in NSCLC, as they are known to have inferior outcomes that are less durable.

Ultimately, I want to see whether treatment escalation translates into meaningful survival improvements without compromising quality of life.

Treatment Sequencing and the Importance of Clinical Trials

Joshua E. Reuss, MD:
For patients with EGFR-mutated NSCLC, another important question is whether we should continue osimertinib when introducing an ADC after progression. There are compelling biological reasons to maintain EGFR inhibition, particularly given concerns about central nervous system progression after discontinuing an EGFR-directed tyrosine kinase inhibitor.

Findings from ORCHARD (NCT03944772) suggest promising activity with osimertinib plus Dato-DXd after progression on first-line osimertinib. However, the study did not directly compare the combination with Dato-DXd alone, so randomized evidence is needed to establish the contribution of continued EGFR inhibition.

OptiTROP-Lung04 demonstrated improved PFS with sac-TMT monotherapy vs platinum plus pemetrexed after EGFR TKI progression (8.3 vs 4.3 months; HR: 0.49), with updated median overall survival of 25.9 vs 17.4 months (HR: 0.69). However, the trial did not evaluate continued EGFR inhibition.

TROPION-Lung15 (NCT06417814) is evaluating Dato-DXd alone and Dato-DXd plus osimertinib vs platinum-based chemotherapy and will help clarify these approaches. In the meantime, I encourage healthcare professionals to consider clinical trial referral when appropriate, particularly for patients whose disease has progressed after established treatment options.

Proactive Toxicity Management Is Essential

Christine M. Bestvina, MD:
As we incorporate TROP2 ADCs into clinical practice, supportive care becomes increasingly important.

Stomatitis and ocular toxicities are notable concerns with Dato-DXd. In my practice, prevention is a central component of patient counseling. We discuss dexamethasone mouth rinses 4 times daily and consider oral cryotherapy with ice chips or ice water during infusion. Lubricating eye drops are also important for preventing and managing ocular symptoms.

Interstitial lung disease is another critical consideration. We counsel patients to contact us promptly if they experience a new cough, shortness of breath, or declining oxygen saturation, including changes noticed during routine activities. Early recognition and intervention are essential to minimizing serious pulmonary complications.

Our oncology pharmacists, physician associates, and nurse practitioners have essential roles in reinforcing these recommendations and helping patients manage treatment-related adverse events. For me, these supportive care strategies are not secondary considerations. They are fundamental to helping patients receive treatment safely while preserving their quality of life.

Looking Ahead

Joshua E. Reuss, MD:
I believe TROP2 ADCs are here to stay. We will likely see these therapies evaluated in more frontline settings and across additional NSCLC populations. What I am most interested in seeing is prospective randomized evidence from global studies, along with validation of biomarkers such as QCS-NMR that may help us select patients most likely to benefit. Ultimately, the goal is not simply to introduce more treatment options, but to make better treatment decisions for the individual patient in front of us.

Your Thoughts
As evidence grows supporting a role for TROP2-directed ADCs in the care of patients with advanced NSCLC, what questions do you and your patients have about these therapies? Leave your questions and comments below.

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