Datopotamab Deruxtecan Trial Shows Negative OS in TROPION-Lung 01 – Panot Sainamthip

“Recent data updates from the International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer show negative overall survival (OS) results for a new antibody-drug conjugate (ADC) in the lung cancer paradigm, but some patients may still benefit.

Introduction
Datopotamab deruxtecan (Dato-DXd) is a specifically engineered TROP2-directed DXd antibody-drug conjugate currently under investigation in the TROPION-Lung01 trial, which compares its efficacy with docetaxel-based regimens, the current standard of care in second-line and beyond settings.

Design

TROPION-Lung01 is a randomized, open-label, global phase III study comparing the safety and efficacy of Dato-DXd versus docetaxel in patients with advanced/metastatic non-small cell lung cancer (NSCLC).

The dual primary endpoints were progression-free survival (PFS), assessed by blinded independent central review per RECIST version 1.1, and overall survival (OS). The trial was considered positive if either endpoint hypothesis was met. Objective response rate (ORR), duration of response (DOR), and safety were secondary endpoints.

Results

Dato-DXd demonstrated a statistically significant improvement in progression-free survival (PFS) (median, 4.4 vs. 3.7 months; hazard ratio [HR], 0.75; P = .004) and a numerical improvement in overall survival (OS) (median, 12.9 vs. 11.8 months; HR, 0.94; P = .530) over docetaxel.

What We Learned.

1. Antibody-drug conjugates (ADCs) are being extensively investigated across various cancers. In lung cancer, only T-DXd has been approved. Datopotamab deruxtecan (Dato-DXd) could potentially become the next approved ADC for this indication.
2. Lung cancer encompasses numerous actionable targets, and this trial includes biomarker-unselected populations in second-line settings after exposure to contemporary first-line agents.
3. EVOKE-01, which evaluated sacituzumab govitecan (a TROP2-directed ADC with a plasma-labile linker) in a similar NSCLC population, failed to meet its primary endpoint of improved OS, with no improvement in PFS or ORR compared to docetaxel.
4. The trial pre-stratified lung cancer patients into two distinct subgroups—squamous and non-squamous—though it was not powered to define efficacy within these individual subgroups.
5. Dato-DXd demonstrated improved outcomes over docetaxel in the non-squamous NSCLC group, including higher response rates (31.2% vs. 12.8%), longer median PFS (5.5 vs. 3.6 months), and a trend toward improved OS (14.6 vs. 12.3 months).
6. ADCs targeting the same molecule, like TROP-2 in sacituzumab govitecan and Dato-DXd, may yield different results in similar populations, likely due to differences in the efficacy of their payloads.
7. Subgroup analysis is crucial in selecting treatments. For instance, pemetrexed is ineffective in squamous cell lung cancer due to high levels of thymidylate synthase (TS), highlighting the importance of tailored approaches.

Conclusion

As healthcare providers, we are encouraged to see more treatment options emerging from this trial. ADCs may represent a promising new approach, potentially replacing conventional chemotherapy. However, their side effect profile, particularly concerns like interstitial lung disease (ILD), requires careful attention. From a research perspective, we must focus on refining patient selection to maximize therapeutic benefit and ensure the best outcomes for our patients.”

written by Panot Sainamthip

Panot Sainamthip is a lecturer in the Department of Pharmacology and a researcher at the CU-Stem Cell and Cell Therapy Research Center at Chulalongkorn University, Thailand. His research focuses on cancer biology, particularly the clinical applications of established and novel therapies in cancer organoid models, as well as integrated biomarkers for gastrointestinal cancer patients. Currently, he is investigating mechanisms of resistance in pancreatic cancer and seeks to enhance international research collaboration to drive scientific innovation in Thailand.