Results from an exploratory analysis of the TROPION-Lung01 phase 3 trial showed TROP2 as measured by quantitative continuous scoring (QCS), AstraZeneca’s proprietary computational pathology platform, was predictive of clinical outcomes in patients with advanced or metastatic non-small cell lung cancer (NSCLC) who were treated with datopotamab deruxtecan (Dato-DXd). In patients with TROP2-QCS biomarker positive tumors, datopotamab deruxtecan demonstrated a meaningfully greater magnitude of efficacy versus docetaxel than in the overall trial population. Results will be presented today during a Presidential Symposium (PL02.11) at the IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (#WCLC24).

Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

TROP2 is a protein broadly expressed in NSCLC on the surface of and inside tumor cells.^1,2 When assessed using conventional immunohistochemistry (IHC)-based pathology, TROP2 expression has not been predictive of patient responses to TROP2 directed ADCs.^3,4 QCS is a fully supervised computational pathology platform developed by AstraZeneca that analyzes digitized images of patient tissue samples and precisely quantifies targets like TROP2 on and inside a tumor cell.

In this analysis, QCS was used to analyze tissue samples collected from patients in TROPION-Lung01. This produced a normalized membrane ratio for each tumor cell in each sample. Patient tumors were considered TROP2-QCS biomarker positive if the majority (≥75%) of tumor cells exhibited a ratio below a predetermined value (≤0.56), indicating a greater proportion of TROP2 in the cytoplasm.

The analysis showed a greater proportion of patients with nonsquamous NSCLC were considered TROP2-QCS biomarker positive than those with squamous NSCLC (66% versus 44%, respectively). The threshold for biomarker positivity was optimized for progression-free survival (PFS) in the subgroup of patients with nonsquamous NSCLC without actionable genomic alterations because it represents a population with significant unmet medical need.

In patients with TROP2-QCS biomarker positive tumors (60% of the biomarker evaluable population including patients with nonsquamous and squamous NSCLC), datopotamab deruxtecan reduced the risk of disease progression or death by 43% versus docetaxel (median PFS of 6.9 months versus 4.1 months; hazard ratio [HR]=0.57; 95% confidence interval [CI]: 0.41-0.79). By comparison, in the primary analysis of the overall trial population, datopotamab deruxtecan reduced the risk of disease progression or death by 25% versus docetaxel (median PFS of 4.4 months versus 3.7 months; HR=0.75; 95% CI: 0.62-0.91; p=0.004) as presented at the European Society for Medical Oncology (#ESMO23) 2023 Congress.

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

“TROP2 is broadly expressed on solid tumor cells including non-small cell lung cancer, but it has yet to be established as a predictive biomarker for any TROP2 directed antibody drug conjugate,” said Marina Garassino, MD, Professor of Medicine, The University of Chicago and investigator in the trial. “We have shown with this analysis that the more precise quantitative measurement of TROP2 on and inside tumor cells, enabled by AstraZeneca’s computational pathology platform, can identify which patients with non-small cell lung cancer are most likely to benefit from treatment with datopotamab deruxtecan.”

“The results from the QCS analysis support the potential of TROP2, as measured by quantitative continuous scoring, as a predictive biomarker for datopotamab deruxtecan and begin to answer the question of why certain patients with non-small cell lung cancer respond better to treatment,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “These insights are critical to advancing our understanding of how we can more precisely identify patients with non-small cell lung cancer who may benefit from treatment with our TROP2 directed antibody drug conjugate.”

“This analysis demonstrates the power of our computational pathology platform to discover new predictive biomarkers and substantially improve patient selection for datopotamab deruxtecan. It also has great potential to help more precisely select patients across our broader antibody drug conjugate portfolio,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “We are excited to extend our collaboration with Roche Tissue Diagnostics with the aim of validating this exploratory approach for TROP2, developing the companion diagnostic and bringing it to the clinic as quickly as possible.”

In the biomarker evaluable population, no new safety concerns were identified and rates of grade 3 or higher treatment-related adverse events (TRAE) were similar regardless of TROP2 status. In patients with TROP2-QCS biomarker positive tumors, grade 3 or higher TRAEs occurred in 30% and 46% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common grade 3 or higher TRAEs were stomatitis (7% vs. 3%) and ocular surface events (3% vs. 0%). Grade 3 or higher adjudicated drug-related interstitial lung disease events occurred in 3% and 1% of patients in the datopotamab deruxtecan and docetaxel arms, respectively.

Summary of TROPION-Lung01 QCS Analysis Results