Datopotamab Deruxtecan Combinations Show Durable Activity in Advanced NSCLC

Key Clinical Summary

• Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab demonstrated durable antitumor activity in treatment-naive patients with advanced or metastatic non–small cell lung cancer (NSCLC) without actionable genomic alterations.
• Confirmed objective response rates exceeded 54% with both doublet and triplet regimens, regardless of programmed death-ligand 1 expression level.
• Exploratory biomarker analyses suggested improved outcomes among patients with higher TROP2 expression.

Dato-DXd combined with pembrolizumab, with or without platinum-based chemotherapy, demonstrated encouraging efficacy and manageable safety in patients with advanced or metastatic NSCLC, according to updated results from the phase Ib TROPION-Lung02 study.

The trial evaluated Dato-DXd, a TROP2-directed antibody-drug conjugate, in combination with pembrolizumab either as a doublet regimen or with platinum chemotherapy as a triplet regimen in patients without actionable genomic alterations.

Trial Design and Patient Population

TROPION-Lung02 enrolled 142 patients across 6 cohorts. Seventy patients received Dato-DXd plus pembrolizumab, while 72 received Dato-DXd, pembrolizumab, and platinum-based chemotherapy.

Most patients enrolled in the expansion phase were treatment-naive. The treatment-naive population included 42 patients in the doublet arm and 54 patients in the triplet arm.

The majority of patients had nonsquamous NSCLC and low programmed death-ligand 1 (PD-L1) expression. A higher proportion of patients in the triplet group had baseline brain metastases, while more patients in the doublet group were Asian.

Durable Responses Observed Across PD-L1 Subgroups

Among treatment-naive patients receiving Dato-DXd plus pembrolizumab, the confirmed objective response rate was 54.8%.

Median duration of response reached 20.1 months, while median progression-free survival was 11.2 months.

In the triplet group, the confirmed objective response rate was 55.6%, with a median duration of response of 13.7 months and median progression-free survival of 6.8 months.

Importantly, investigators observed tumor responses across all PD-L1 expression levels in both treatment groups, suggesting activity independent of baseline PD-L1 status.

Safety Profile Remained Manageable

Grade 3 or higher treatment-related adverse events occurred in 37.1% of patients receiving the doublet regimen and 59.7% of those receiving triplet therapy.

No treatment-related deaths were reported.

The higher rate of severe treatment-related adverse events in the triplet arm was consistent with the addition of platinum chemotherapy. Despite this, investigators reported that the overall safety profile remained manageable and aligned with previous experience with the individual treatment components.

Biomarker Findings May Guide Future Development

Exploratory analyses evaluated TROP2 normalized membrane ratio as a potential predictive biomarker.

Patients classified as biomarker-positive demonstrated trends toward improved survival outcomes compared with biomarker-negative patients, suggesting TROP2 expression may help identify individuals most likely to benefit from Dato-DXd–based treatment strategies.

Although these findings remain exploratory, they may inform future patient selection efforts as development of TROP2-targeted therapies continues.

Implications for Managed Care

The results are particularly relevant because many patients with advanced NSCLC lack actionable genomic alterations and continue to rely on immunotherapy-based treatment approaches.

The durable responses observed with Dato-DXd plus pembrolizumab, including activity across PD-L1 expression levels, suggest the regimen may eventually expand treatment options beyond currently available immunotherapy combinations.

For managed care decision-makers, future considerations will include balancing the potential clinical benefit of antibody-drug conjugate combinations against treatment costs, toxicity management requirements, and biomarker-guided patient selection strategies.

Conclusion

Results from TROPION-Lung02 indicate that Dato-DXd combined with pembrolizumab, with or without platinum chemotherapy, produces durable responses and manageable toxicity in advanced NSCLC. Ongoing development will help clarify the role of these regimens and the potential value of TROP2 biomarker selection in optimizing treatment outcomes.

References

Levy B, Paz-Ares L, Lin C-C, et al. Datopotamab Deruxtecan Plus Pembrolizumab With or Without Platinum-Based Chemotherapy for Advanced or Metastatic NSCLC: The Phase Ib TROPION-Lung02 Trial. J Thorac Oncol. 2026. doi: 10.1016/j.jtho.2026.103688