Datopotamab deruxtecan (Dato-DXd), a novel TROP2-directed antibody-drug conjugate, has demonstrated promising activity in previously treated patients with advanced non-small cell lung cancer (NSCLC). The phase III TROPION-Lung01 trial revealed a numerical improvement in overall survival and a statistically significant improvement in progression-free survival, particularly in the nonsquamous NSCLC cohort, supporting its potential as a new therapeutic option.
TROPION-Lung01 Trial Results
The TROPION-Lung01 trial, a global, open-label study, randomized 604 patients with previously treated advanced NSCLC to either Dato-DXd (6 mg/kg) or docetaxel (75 mg/m2) every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. While the overall survival benefit was numerical (12.9 months vs 11.8 months; HR = 0.94, 95% CI = 0.78–1.14; P = .530), the nonsquamous cohort showed a more pronounced trend toward prolonged overall survival (14.6 vs 12.3 months; HR = 0.84, 95% CI = 0.68–1.05).
Dr. Jacob M. Sands of the Dana-Farber Cancer Institute noted, "The results, when looking specifically at the nonsquamous cohort with a statistically significant improvement in the median progression-free survival, a substantial improvement in the overall response rate…support the use of Dato-DXd as a potential new therapeutic option."
Previously reported results from the trial demonstrated a statistically significant improvement in progression-free survival with Dato-DXd compared to docetaxel (median, 4.4 vs 3.7 months; HR = 0.75, 95% CI = 0.62–0.91; P = .004). The benefit was more pronounced in the nonsquamous cohort (median, 5.5 months with Dato-DXd and 3.6 months with docetaxel; HR = 0.63, 95% CI = 0.51–0.79), with overall response rates of 31.2% and 12.8%, respectively.
Safety Profile
The updated safety analysis revealed no new safety signals with longer follow-up. The median treatment duration was longer for Dato-DXd (4.2 months) compared to docetaxel (2.8 months), yet dose reductions (20% vs 30%) and treatment discontinuations (8% vs 12%) due to treatment-related adverse events were less frequent with Dato-DXd.
The most common treatment-related adverse events with Dato-DXd were stomatitis (47%) and nausea (34%), while alopecia (35%) and neutropenia (26%) were more frequent with docetaxel. Grade 3 or higher treatment-related adverse events occurred in 26% of patients treated with Dato-DXd and 42% of those who received docetaxel. Stomatitis (7%) and pneumonitis/interstitial lung disease (4%) were the most common grade 3 or higher events with Dato-DXd, while neutropenia (23%) and leukopenia (13%) were more common with docetaxel.
Novel TROP2 Biomarker
An exploratory analysis presented by Dr. Marina Chiara Garassino of the University of Chicago introduced a novel, digitally defined biomarker, TROP2 normalized membrane ratio (NMR), determined by quantitative continuous scoring (QCS). This biomarker showed predictive value for improved overall response rate and longer progression-free survival in TROPION-Lung01 patients treated with Dato-DXd.
In patients with TROP2 QCS-NMR–positive tumors, the objective response rate for Dato-DXd was 32.7% compared to 10.3% for docetaxel, and median progression-free survival was 6.9 months vs 4.1 months (HR = 0.57; 95% CI = 0.41–0.79). Dr. Garassino emphasized that this biomarker test applies only to Dato-DXd and not to other TROP2-directed agents.
Expert Commentary
Dr. Saiama N. Waqar of Washington University School of Medicine highlighted that Dato-DXd could be a possible treatment option for patients with previously treated nonsquamous NSCLC, but cautioned that patients with pre-existing interstitial lung disease or pneumonitis should be excluded due to the risk of interstitial lung disease. She also noted the ongoing phase III AVANZAR trial evaluating Dato-DXd in combination with platinum-based chemotherapy and immunotherapy in the first-line setting.
Regulatory Status
Dato-DXd is currently under review by the U.S. Food and Drug Administration.
