Phase 3 TROPION-Lung17 Trial Initiates TROP2-Directed Therapy in NSCLC

The first patient has been dosed in the phase 3 TROPION-Lung17 clinical trial (NCT07291037), marking the initiation of the first biomarker-directed phase 3 study for datopotamab deruxtecan (Dato-DXd; Datroway) in patients with advanced nonsquamous non–small cell lung cancer (NSCLC).¹ This trial specifically targets patients whose tumors express TROP2 as identified by a novel computational pathology platform.

The multicenter, open-label trial is evaluating the efficacy and safety of Dato-DXd compared with docetaxel, the current standard of care for second-line NSCLC. Eligible participants include those with locally advanced or metastatic nonsquamous NSCLC without actionable genomic alterations who have previously experienced disease progression on or after platinum-based chemotherapy and an immune checkpoint inhibitor.^1,2

“We initiated TROPION-Lung17 to further evaluate [Dato-DXd] in this patient population, building on results from retrospective analyses of several clinical trials, including TROPION-Lung01 [NCT04656652], which showed a correlation between TROP2 [normalized membrane ratio (NMR)] positivity and outcomes for patients with lung cancer,” said Abderrahmane Laadem, MD, head, Late-Stage Oncology Clinical Development, Daiichi Sankyo, in a news release.¹ “TROPION-Lung17 is the first phase 3 trial to prospectively enroll patients using a TROP2 biomarker to determine whether [Dato-DXd] can improve survival compared to current standard-of-care chemotherapy.”

Dato-DXd has already showed to be an effective agent in other forms of lung cancer. In June 2025, the FDA granted accelerated approval to Dato-DXd for adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have previously received systemic therapies, including EGFR-targeted treatments.³ This approval was supported by data from the phase 3 TROPION-Lung01 and phase 2 TROPION-Lung05 (NCT04484142) trials.

A Precision Shift in TROP2-Targeted Therapy

Dato-DXd is a specifically engineered TROP2-directed antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker. While TROP2 is broadly expressed in NSCLC, previous all-comer trials, such as TROPION-Lung01, suggested that clinical benefit might be more pronounced in specific subgroups, particularly those with nonsquamous histology.

The TROPION-Lung17 trial represents a pivotal shift toward precision medicine for TROP2 ADCs. It utilizes AstraZeneca’s proprietary quantitative continuous scoring (QCS) platform to measure the TROP2 NMR. This AI-powered computational pathology tool identifies TROP2 NMR-positive tumors, characterized by a higher proportion of TROP2 localized within the cytoplasm vs the cell membrane, a metric that exploratory analyses suggest correlates with increased drug internalization and efficacy.

Clinical Rationale and TROPION-Lung01 Data

The initiation of TROPION-Lung17 is supported by retrospective exploratory analyses from the TROPION-Lung01 trial presented at the 2024 World Conference on Lung Cancer.⁴ In that analysis, patients identified as TROP2 QCS NMR-positive experienced a 43% reduction in the risk of disease progression or death when treated with Dato-DXd compared with docetaxel (median progression-free survival [PFS] 6.9 vs 4.1 months; HR, 0.57; 95% CI, 0.41–0.79). In contrast, biomarker-negative patients did not show a clear benefit over docetaxel.

In the primary analysis of TROPION-Lung01, the overall nonsquamous population demonstrated a statistically significant improvement in PFS (5.6 vs 3.7 months; HR, 0.63; 95% CI, 0.51–0.78), although the benefit in the intention-to-treat population was more modest due to the lack of efficacy in squamous histology. These findings underscored the necessity of histology- and biomarker-driven selection in subsequent phase 3 efforts.

Trial Design and End Points

TROPION-Lung17 will enroll approximately 400 patients across global sites. Participants are randomized 1:1 to receive either Dato-DXd (6.0 mg/kg intravenously every 3 weeks) or docetaxel (75 mg/m² intravenously every 3 weeks). The dual primary end points are PFS, as assessed by blinded independent central review, and overall survival.

Secondary end points include objective response rate, duration of response, and safety. The safety profile of Dato-DXd is well-characterized from previous studies, with the most common treatment-related adverse events including stomatitis and ocular surface events. In the biomarker-positive cohort of TROPION-Lung01, grade 3 or higher treatment-related adverse events occurred in 30% of patients receiving the ADC vs 46% for docetaxel.

This trial signifies a growing trend in oncology where digital pathology and AI-driven biomarkers are used to refine patient selection for ADCs, potentially establishing a new standard of care for a molecularly defined subset of patients with nonsquamous NSCLC.

REFERENCES

1. TROPION-Lung17 TROP2 biomarker directed phase 3 trial of DATROWAY® initiated in patients with previously treated advanced nonsquamous non-small cell lung cancer. News release. Daiichi Sankyo. January 13, 2025. Accessed January 13, 2025. https://tinyurl.com/mry3u2we

2. Phase III study of datopotamab deruxtecan versus docetaxel in previously treated TROP2-positive advanced or metastatic non-squamous NSCLC without actionable genomic alterations (TROPION-Lung17). ClinicalTrials.gov. Updated December 18, 2025. Accessed January 13, 2026. https://clinicaltrials.gov/study/NCT07291037

3. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. US FDA. June 23, 2025. Accessed January 13, 2026. https://tinyurl.com/mu5spftb

4. Novel computational pathology-based TROP2 biomarker for datopotamab deruxtecan was predictive of clinical outcomes in patients with non-small cell lung cancer in TROPION-Lung01 Phase III trial. News release. AstraZeneca. September 8, 2024. Accessed January 13, 2026. https://tinyurl.com/3dhk52mf