TROP2 Biomarker Predicts Outcomes in NSCLC Patients in TROPION-Lung01 Trial

Wilmington, Del. -- Results from an exploratory analysis of the TROPION-Lung01 Phase III trial revealed that TROP2, quantified using AstraZeneca’s proprietary computational pathology platform known as Quantitative Continuous Scoring (QCS), could predict clinical outcomes in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with datopotamab deruxtecan (Dato-DXd). The findings indicated that patients with TROP2-QCS biomarker-positive tumors showed significantly greater efficacy with datopotamab deruxtecan compared to those treated with docetaxel, outperforming the overall trial population.

These results are set to be presented at the Presidential Symposium (PL02.11) during the IASLC 2024 World Conference on Lung Cancer, organized by the International Association for the Study of Lung Cancer.

TROP2 is a protein commonly found in NSCLC cells, both on the surface and inside. Traditional immunohistochemistry (IHC)-based pathology has not been effective in predicting patient responses to TROP2-directed antibody drug conjugates (ADC). QCS, a computational pathology platform created by AstraZeneca, analyzes digitized patient tissue images and accurately measures targets like TROP2 in tumor cells.

Datopotamab deruxtecan is a TROP2-directed DXd ADC, developed jointly by AstraZeneca and Daiichi Sankyo. In the TROPION-Lung01 trial, QCS was employed to assess tissue samples from patients, producing a normalized membrane ratio for each tumor cell. Tumors were classified as TROP2-QCS biomarker-positive if the majority (≥75%) of tumor cells had a ratio below a specific threshold (≤0.56).

The analysis indicated that a higher proportion of patients with nonsquamous NSCLC were TROP2-QCS biomarker-positive compared to those with squamous NSCLC (66% vs. 44%). The biomarker positivity threshold was optimized for progression-free survival (PFS) in patients with nonsquamous NSCLC without actionable genomic alterations—a group with significant unmet medical needs.

In patients with TROP2-QCS biomarker-positive tumors, datopotamab deruxtecan reduced the risk of disease progression or death by 43% compared to docetaxel (median PFS of 6.9 vs. 4.1 months; HR 0.57; 95% CI 0.41-0.79). In the overall trial population, datopotamab deruxtecan reduced this risk by 25% (PFS of 4.4 vs. 3.7 months; HR 0.75; 95% CI 0.62-0.91).

For nonsquamous NSCLC patients without actionable genomic alterations and with TROP2-QCS biomarker-positive tumors, datopotamab deruxtecan reduced the risk of disease progression or death by 48% (PFS of 7.2 vs. 4.1 months; HR 0.52; 95% CI 0.35-0.78).

Dr. Marina Garassino from The University of Chicago commented on the analysis, highlighting that precise quantitative measurement of TROP2 could help identify NSCLC patients who might benefit from datopotamab deruxtecan treatment. Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, emphasized the potential of their computational pathology platform in discovering new predictive biomarkers and improving patient selection for datopotamab deruxtecan. Ken Takeshita, Global Head of R&D at Daiichi Sankyo, noted that the analysis provides critical insights into more precisely identifying NSCLC patients who could benefit from their TROP2-directed ADC.

No new safety concerns were reported in the biomarker evaluable population. Grade 3 or higher treatment-related adverse events (TRAE) were similar in frequency regardless of TROP2 status. In TROP2-QCS biomarker-positive patients, 30% on datopotamab deruxtecan and 46% on docetaxel experienced Grade 3 or higher TRAEs. The most common TRAEs were stomatitis and ocular surface events. Grade 3 or higher drug-related interstitial lung disease events occurred in 3% of datopotamab deruxtecan and 1% of docetaxel patients.

The TROPION-Lung01 trial is a global, randomized Phase III study evaluating the efficacy and safety of datopotamab deruxtecan versus docetaxel in patients with locally advanced or metastatic NSCLC. The primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include objective response rate, duration of response, and safety, among others. Approximately 600 patients were enrolled across various regions, including Asia, Europe, North America, Oceania, and South America.

Datopotamab deruxtecan (Dato-DXd) is an investigational ADC targeting TROP2, designed using Daiichi Sankyo’s DXd ADC Technology. The drug is part of a broad clinical development program assessing its efficacy and safety across multiple cancers, including NSCLC and various breast cancers.

AstraZeneca and Daiichi Sankyo have a collaboration to develop and commercialize datopotamab deruxtecan. AstraZeneca continues to innovate in lung cancer treatment, aiming to improve patient outcomes through new therapeutic targets and innovative treatment approaches. The company strives to revolutionize oncology by discovering, developing, and delivering life-changing medicines.