Dato-DXd Plus Pembrolizumab Elicits Responses Even With Low PD-L1

Adding the immune checkpoint inhibitor pembrolizumab (Keytruda) to the antibody-drug conjugate datopotamab deruxtecan (Dato-DXd; Datroway), produced responses in more than half of previously untreated patients with advanced or metastatic non–small cell lung cancer (NSCLC) lacking targetable genomic alterations, including those with low tumor PD-L1 expression, according to results from the phase Ib TROPION-Lung02 trial (NCT04526691) published in the Journal of Thoracic Oncology.¹

TROPION-Lung02 enrolled 142 patients across 6 dose-escalation and dose-expansion cohorts. Seventy received Dato-DXd (4 or 6 mg/kg) plus pembrolizumab 200 mg without chemotherapy (doublet therapy), and 72 received the same combination plus carboplatin or cisplatin (triplet therapy), all administered every 3 weeks. Ninety-six patients, just over two-thirds of the total, received one of the regimens as first-line treatment; this treatment-naive subset was the focus of the efficacy analysis.

Among treatment-naive patients, the confirmed objective response rate (ORR) was 54.8% with doublet therapy and 55.6% with triplet therapy. Responses were durable, with a median duration of response of 20.1 months for doublet and 13.7 months for triplet therapy. Median progression-free survival (PFS) was 11.2 months with doublet therapy and 6.8 months with triplet therapy; median overall survival was not yet reached with doublet therapy and was 17.4 months with triplet therapy. Notably, patients with low PD-L1 expression responded at rates similar to the overall treatment-naive population—a confirmed ORR of 50.0% with doublet therapy and 52.5% with triplet therapy—suggesting the combination may help address the shortfall seen with checkpoint inhibitors alone in this harder-to-treat group.

Safety findings were consistent with the known profiles of the individual drugs. Grade 3 or higher treatment-related adverse events (AEs) occurred in 37.1% of patients receiving doublet therapy and 59.7% of those receiving triplet therapy, with no treatment-related deaths in either group. The most common AEs with doublet therapy were stomatitis, nausea, and alopecia; with triplet therapy, nausea, anemia, and decreased platelet count were most frequent, reflecting the added hematologic burden of chemotherapy. Interstitial lung disease or pneumonitis, a recognized risk with both checkpoint inhibitors and Dato-DXd, occurred in 26.2% of treatment-naive patients receiving doublet therapy and 25.9% receiving triplet therapy, a higher rate than reported in Dato-DXd monotherapy trials (8.8% in TROPION-Lung01 and 3.6% in TROPION-Lung05), though the authors noted most cases were low-grade and none were fatal. Oral mucositis or stomatitis, thought to reflect TROP2 expression on healthy tissue, was the most frequently reported adverse event of special interest with either regimen.

An exploratory biomarker analysis using a computational pathology method called TROP2 normalized membrane ratio, previously validated in TROPION-Lung01 (NCT04656652), showed a trend toward longer PFS and overall survival in biomarker-positive patients compared with biomarker-negative patients, though confidence intervals were wide given the small numbers involved. The authors described the finding as hypothesis-generating rather than confirmatory.

Clinical Context

The findings address a persistent gap in first-line NSCLC treatment: patients with low PD-L1 expression tend to derive less benefit from standard immunotherapy-chemotherapy combinations than those with high expression. In the phase 3 KEYNOTE-189 trial (NCT02578680), for example, 5-year overall survival with pembrolizumab plus chemotherapy was 29.6% in patients with PD-L1 tumor proportion scores of 50% or higher, compared with 19.8% and 9.6% in those with intermediate or low expression, respectively.² Dato-DXd, an antibody-drug conjugate targeting TROP2 with a topoisomerase I inhibitor payload, already holds accelerated approval from the FDA for previously treated, EGFR-mutated NSCLC, based on pooled data from the single-arm phase 2 TROPION-Lung05 trial (NCT04484142) and the phase 3 TROPION-Lung01 trial which compared Dato-DXd with docetaxel.^3,4 Preclinical work suggesting that DNA-damaging topoisomerase I inhibitors can prime antitumor immune responses provided the rationale for combining Dato-DXd with checkpoint blockade.

REFERENCES

1. 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;21:103688. doi:10.1016/j.jtho.2026.103688

2. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023;41:1992-1998.

3. Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab deruxtecan versus docetaxel for previously treated advanced or metastatic non-small cell lung cancer: the randomized, open-label phase III TROPION-Lung01 study. J Clin Oncol. 2025;43:260-272.

4. Sands J, Ahn MJ, Lisberg A, et al. Datopotamab deruxtecan in advanced or metastatic non-small cell lung cancer with actionable genomic alterations: results from the phase II TROPION-Lung05 study. J Clin Oncol. 2025;43:1254-1265.