Dato-DXd Confers Clinical Benefit Regardless of TROP2 NMR Status in EGFR-Mutant NSCLC

March 27, 2026 | Courtney Flaherty

This lack of association suggests that TROP2 NMR is not a value marker for further patient selection for Dato-DXd in NSCLC.

TROP2 normalized membrane ratio (NMR) status was not associated with improved response rates or survival outcomes in patients with EGFR-mutant, nonsquamous (NSQ) NSCLC receiving datopotamab deruxtecan-dlnk (Datroway; Dato-DXd) monotherapy in the phase 2 TROPION-Lung05 (NCT04484142) and phase 3 TROPION-Lung01 (NCT04656652) studies or in combination with osimertinib (Tagrisso) in the phase 2 ORCHARD study (NCT03944772).¹

According to data presented during the 2026 European Lung Cancer Congress, in TROPION-Lung01 and TROPION-Lung05, overall response rates (ORRs) were numerically lower in evaluable patients with samples that were TROP2 NMR-positive (n = 45) vs -negative (n = 23). These respective ORRs were 40% (95% CI, 25.7%-55.7%) vs 56.5% (95% CI, 34.5%-76.8%). However, the median progression-free survival (PFS) was comparable between these respective subgroups, at 5.8 months (95% CI, 5.4-9.7) vs 5.7 months (95% CI, 4.2-15.4). This translated to a HR of 0.95 (95% CI, 0.53-1.72; P = .88). Of note, in the unselected, biomarker-evaluable population per quantitative continuous scoring (QCS BEP), the ORR was 45.6% (95% CI, 33.5%-58.1%) and the median PFS was 5.8 months (95% CI, 5.4-8.3).

The same trend was observed with Dato-DXd plus osimertinib in ORCHARD. In the TROP2 NMR–positive group (n = 20), the median ORR was 35% (95% CI, 15.0%-59.0%) and the median PFS was 11.1 months (95% CI, 6.2-18.0). In the TROP2 NMR–negative group, respective values were 80% (95% CI, 28.0%-99.0%) and 9.5 months (95% CI, 6.2-not applicable [NA]). However, interpretation is limited due to a smaller number of patients with TROP2 NMR–negative samples. The ORR for patients in the QCS BEP group was 44% (95% CI, 24.0%-65.0%) and the median PFS was 9.9 months (95% CI, 7.2-11.7).

“Data indicate that Dato-DXd provides clinical benefit for patients with EFGR-mutant NSCLC regardless of TROP2 NMR status, suggesting no value in patient selection beyond EGFR mutations for Dato-DXd in this setting,” lead study author Jacob Sands, MD, and colleagues wrote in a poster presentation of the data. “This finding is not unexpected; EGFR-mutant and NSCLC [without actionable genomic alterations (AGAs)] are distinct biological subtypes, and TROP2 NMR was optimized in NSQ non-AGA NSCLC only.”

Sands is the associate chief of the Lowe Center for Thoracic Oncology and oncology medical director of the International Patient Center at Dana-Farber Cancer Institute, as well as an assistant professor at Harvard Medical School in Boston, Massachusetts.

What prior data provided the impetus for evaluating TROP2 NMR as a potential marker for outcomes with Dato-DXd?

Data from a prior analysis of TROPION-Lung01 presented at the International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer showed that ORRs were higher and median PFS was longer with Dato-DXd vs docetaxel in patients with non-AGA NSQ NSCLC (n = 221) who were TROP2 NMR–positive per QCS.² The rates of overall and grade 3 or higher toxicities were similar regardless of TROP2 NMR positivity.

These data suggested that TROP2 NMR as measured by QCS could potentially serve as a predictive biomarker for responses with Dato-DXd.

How was TROP2 NMR status determined in this analysis?

The current analysis was conducted to determine whether patients with EGFR-mutant NSCLC achieved better ORR and PFS with Dato-DXd with/without osimertinib if they were positive for the TROP2 marker.

Investigators identified a total of 115 patients with EGFR-mutant NSQ NSCLC from TROPION-Lung01 and TROPION-Lung05 who received Dato-DXd monotherapy; and 68 patients with EGFR-mutant NSQ NSCLC from ORCHARD who received Dato-DXd plus osimertinib. Digital TROP2 immunohistochemistry-stained, whole-slide images of tumor samples from these patients were analyzed for the TROP2 NMR biomarker using QCS.

TROP2 NMR was defined as a measure of TROP2 expression in the membrane relative to TROP2 expression across the membrane and cytoplasm. Patient samples were considered TROP2 NMR–positive if at least 75% of tumor cells had a TROP2 NMR of 0.56 or less. Those with less than 75% of tumor cells displaying a TROP2 NMR of no more than 0.56 were deemed TROP2 NMR–negative.

What should be known about the patient population included in the study?

Of the patients originally identified for analysis from TROPION-Lung01/TROPION-Lung05 and ORCHARD, 68 and 25, respectively, had evaluable samples for QCS. In total, 66% and 80% of patients with evaluable samples from TROPION-Lung01/TROPION-Lung05 and ORCHARD, respectively, were TROP2 NMR–positive.

Baseline characteristics in the biomarker-unselected populations for TROPION- Lung01/ TROPION-Lung05 and ORCHARD, respectively, were as follows:

• Median age: 62 years (range, 36-75); 65 years (range, 46-78)
• Male: 36.8%; 40.0%
• ECOG performance status of 1: 66.2%; 44.0%
• Current or former smoker: 44.1%; 40.0%
• Brain metastasis at study entry: 25.0%; 44.0%
• Prior receipt of 3 or more regimens: 2.9%; N/A

Did safety outcomes with Dato-DXd differ according to TROP2 NMR status?

The safety profile for Dato-DXd was generally comparable across TROP2 NMR subgroups in both TROPION-Lung01/TROPION-Lung05 and ORCHARD, with the caveat of small patient numbers for some events in TROPION-Lung01/TROPION-Lung05 and all events in ORCHARD.

In TROPION-Lung01/TROPION-Lung05, any-grade treatment-related adverse effects (TRAEs) were presented in 93.3% of patients with TROP2 NMR–positive samples vs 100% of those with TROP2 NMR–negative samples. Of these, 26.7% and 26.1%, respectively, were grade 3 or higher.

Any-grade TRAEs of special interest in the TROP2 NMR–positive vs –negative subgroups, respectively, were as follows:

• Stomatitis/oral mucosal inflammation: 73.3%; 69.6%
• Ocular surface events: 22.2%; 43.5%
• Adjudicated interstitial lung disease (ILD): 4.4%; 0.0%

In ORCHARD, any-grade TRAEs were presented in 90.0% of patients with TROP2 NMR–positive samples vs 100% of those with TROP2 NMR–negative samples. Of these, 45.0% and 40.0%, respectively, were grade 3 or higher.

Any-grade TRAEs of special interest in the TROP2 NMR–positive vs –negative subgroups, respectively, were as follows:

• Stomatitis/oral mucosal inflammation: 70.0%; 40.0%
• Ocular surface events: 15.0%; 0.0%
• Adjudicated ILD: 10.0%; 0.0%

What’s next for Dato-DXd in EGFR-mutant NSCLC?

Dato-DXd is currently being evaluated as a second-line regimen with/without osimertinib in the phase 3 TROPION-Lung15 (NCT0417814) study and as a first-line regimen in combination with osimertinib in the phase 3 TROPION-Lung14 (NCT06350097) study.

Sands and colleagues expressed that these ongoing studies will further reveal the efficacy of Dato-DXd in EGFR-mutant NSCLC.

Disclosures: Sands holds consulting roles for AbbVie, Amgen, AstraZeneca, Catalyst, Curadev, Daiichi Sankyo, Fosun, Genentech, Gilead, Jazz Pharmaceuticals, Lilly, Merck, Novartis, PharmaMar, Sanofi and Summit Therapeutics; he has also received institutional research funding from Amgen and Novartis.

References

Sands J, Lisberg A, Le X, et al. TROP2 normalised membrane ratio (NMR) assessed by quantitative continuous scoring (QCS): association with clinical outcomes with datopotamab deruxtecan (Dato-DXd) ± osimertinib (osi) in EGFR-mutated (EGFRm) NSCLC. Presented at: 2026 ELCC; March 25–28, 2026; Copenhagen, Denmark. Abstract 42P.

Normalized membrane ratio of TROP2 by quantitative continuous scoring predictive of clinical outcomes in TROPION-Lung 01. News Release. IASLC. September 8, 2024. Accessed March 27, 2026. https://www.iaslc.org/iaslc-news/press-release/normalized-membrane-ratio-trop2-quantitative-continuous-scoring-predictive