KEY TAKEAWAYS
- This TROPION-Lung 01 phase 3 trial aimed to determine if TROP2 NMR determined by QCS could be a predictive biomarker for Dato-DXd treatment.
- Researchers concluded Dato-DXd showed strong efficacy in TROP2-positive NSQ/non-AGA advanced NSCLC, warranting further investigation.
Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody-drug conjugate (ADC). Unlike other TROP2 ADCs, it has a plasma-stable linker that requires active internalization to release the cytotoxic payload. Previous studies have shown that visual scoring of immunohistochemical (IHC) assays by pathologists to assess target expression is not predictive of therapeutic response to TROP2-directed ADCs in patients with non-small cell lung cancer (NSCLC).
M.C. Garassino and the team aimed to investigate whether a more precise and quantitative assessment of TROP2 expression on the cell membrane and cytoplasm would be predictive of therapeutic response to Dato-DXd.
Researchers utilized digitized TROP2 IHC-stained whole-slide images (WSI) of tissue samples from patients with NSCLC to develop the Quantitative Continuous Scoring (QCS) model. QCS uses a fully supervised deep learning algorithm trained on pathologist annotations. It identifies tumor areas and cellular compartments (membrane and cytoplasm) of individual tumor cells across the WSI. The QCS model measured TROP2 expression in the membrane relative to the cytoplasm of tumor cells, termed the normalized membrane ratio (NMR).
Tumors with a majority of cells displaying a TROP2 NMR below a specific value determined in biomarker development were defined as TROP2 QCS-NMR+. They optimized QCS-NMR for PFS in the biomarker-evaluable patient subgroup with non-squamous (NSQ) NSCLC without actionable genomic alterations (non-AGA) in the phase 3 TROPION-Lung01 trial (Dato-DXd vs docetaxel in 2L+ advanced/metastatic NSCLC). They then assessed the association of TROP2 QCS-NMR status with clinical outcomes in all biomarker-evaluable patients.
Of the 604 patients randomized in TROPION-Lung01, 352 were biomarker evaluable. This included 221 patients in the NSQ/non-AGA subgroup. There were no significant differences in baseline characteristics between the randomized and biomarker-evaluable populations, with similar overall PFS outcomes. Sixty-three percent of evaluable patients were TROP2 QCS-NMR+, which was most common in NSQ/AGA (75%), followed by NSQ/non-AGA (63%) and SQ (43%) subgroups.
Dato-DXd showed higher ORR and longer median PFS vs docetaxel in TROP2 QCS-NMR+ subgroups. Overall/grade 3+ adverse event rates were similar regardless of TROP2 QCS-NMR status.
In an exploratory biomarker-defined population, Dato-DXd demonstrated strong efficacy in patients with TROP2 QCS-NMR+ NSQ/non-AGA advanced/metastatic NSCLC. TROP2 NMR determined by QCS demonstrated potential as a predictive biomarker for Dato-DXd.
The trial was sponsored by Daiichi Sankyo.
Source: https://cattendee.abstractsonline.com/meeting/20598/presentation/3197
Clinical Trial: https://clinicaltrials.gov/study/NCT04656652
Garassino MC, Sands J, Paz-Ares L, et al. (2024). “Normalized membrane ratio of TROP2 by quantitative continuous scoring is predictive of clinical outcomes in TROPION-Lung 01.” Presented at: World Conference on Lung Cancer (WCLC); September 8, 2024; Singapore.
