Final overall survival data from TROPION-Lung01
The most recent results of the TROPION-Lung01 study demonstrate that datopotamab deruxtecan did not meet its secondary dual primary endpoint of overall survival (OS) for patients with advanced non-small cell lung cancer (NSCLC). Nonetheless, the regimen did show a trend of improved OS compared with docetaxel in the non-squamous subgroup.
Patients with advanced non-small cell lung cancer (NSCLC) have limited treatment options after lung cancer progresses on first-line therapies. Datopotamab deruxtecan (Dato-DXd) is a novel trophoblast cell surface antigen 2-directed antibody-drug conjugate under clinical evaluation in multiple solid tumour types. The pivotal TROPION-Lung01 trial in patients with previously treated advanced NSCLC met its dual primary endpoint of improved progression-free survival (PFS) versus docetaxel (p= 0.004), with superior efficacy outcomes observed with Dato-DXd in patients with non-squamous histology. At WCLC 2024, the final analysis of the second dual primary endpoint of overall survival (OS) and updated safety findings were presented.
Study design
TROPION-Lung01 is a global, phase III, open-label study in which patients were randomised 1:1 to receive Dato-DXd 6 mg/kg (N= 299) or docetaxel 75 mg/m2 (N= 305) Q3W. All patients were required to have an ECOG performance status of 0 or 1 and were not allowed to have received prior docetaxel. PFS by blinded independent central review and OS were dual primary endpoints. PFS and OS by histology were prespecified subgroup analyses. Safety, including treatment-related adverse events (TRAEs), was a secondary endpoint.
Results
Baseline characteristics were well-balanced between study arms. After a median follow-up of 23.1 months in both arms, median OS was 12.9 months with Dato-DXd, versus 11.8 months with docetaxel (HR[95%CI]: 0.94[0.78-1.14], p= 0.530). However, median OS was numerically longer in the prespecified non-squamous subgroup, with 14.6 months with Dato-DXd vs. 12.3 months with docetaxel, resulting in a 16% reduction in the risk of death in this subgroup (HR[95%CI]: 0.84[0.68-1.05]). Moreover, OS improvements in the non-squamous subset were seen regardless of actionable genomic alteration status (Present: 15.6 vs. 9.8 months (HR[95% CI]: 0.65[0.40–1.08]); Absent: 13.6 vs. 12.3 months (HR[95% CI]: 0.89[0.70–1.13]). Sensitivity analyses in the non-squamous patient population found no meaningful impact on OS by removing the effect of subsequent use of docetaxel in the Dato-DXd arm after failure of therapy, neither by removing the effect of all post-treatment anti-cancer therapies in both arms.
Compared with the prior PFS data cutoff, the overall safety profile was consistent and no late-onset toxicities were reported. The median treatment durations for Dato-DXd and docetaxel were 4.2 and 2.8 months, respectively. Overall, there were fewer grade ≥3 treatment-related adverse events (TRAEs, 42% vs. 26%) and fewer TRAEs leading to dose reductions or discontinuations (12% vs. 8%) seen with Dato-DXd compared with docetaxel. The most frequent TRAEs with Dato-DXd were stomatitis (47% vs. 16% with docetaxel) and nausea (34% vs. 17%), while the most frequent TRAEs with docetaxel were alopecia (35% vs. 32% with Dato-DXd) and neutropenia (26% vs. 5% with Dato-DXd). No new adjudicated drug-related interstitial lung disease events or deaths occurred since the PFS database lock.
Conclusion
The dual primary endpoint of OS showed a numerical improvement but was not statistically significant. However, there was a consistent benefit seen with Dato-DXd across all efficacy endpoints in patients with non-squamous histology. The tolerability of Dato-DXd remains manageable and no new safety signals were identified.
Reference
Sands J, et al. Datopotamab Deruxtecan vs Docetaxel in Patients with Non-Small Cell Lung Cancer: Final Overall Survival from TROPION-Lung01. Presented at WCLC 2024; Abstract 2640.