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Dato-DXd Significantly Improves PFS in Select Subsets of Advanced/Metastatic NSCLC

*October 2023*

Take home message: Comparison Dato-DXd, a novel TROP2-directed antibody-drug conjugate, to docetaxel in pretreated advanced/metastatic non-small cell lung cancer (NSCLC) patients, revealing significantly improved progression-free survival with Dato-DXd, especially in non-squamous histology patients, while demonstrating a manageable safety profile and ongoing evaluation of overall survival. (From OncoAlert)

The Trop-2 directed antibody drug conjugate datopotamab deruxtecan (Dato-DXd; DS-1062a) demonstrated a statistically significant improvement in progression-free survival (PFS) vs docetaxel in patients with advanced or metastatic non–small cell lung cancer (NSCLC); however those with squamous histology did not experience a benefit, according to data from the phase 3 TROPION-Lung01 study (NCT04656652) presented by Aaron Lisberg, MD, at the 2023 ESMO Congress.

Patients in the intention-to-treat (ITT) population who received Dato-DXd (n = 299) achieved a median PFS of 4.4 months (95% CI, 4.2-5.6) vs 3.7 months in the docetaxel arm (n = 305), demonstrating a statistically significant improvement in PFS (HR, 0.75; 95% CI, 0.62-0.91; P = .004). The objective response rate (ORR) was 26.4% (95% CI, 21.5%-31.8%) in the Dato-DXd arm vs 12.8% in the docetaxel arm (95% CI, 9.3%-17.1%), with median durations of response (DORs) of 7.1 months (95% CI, 5.6-10.9) vs 5.6 months (95% CI, 5.4-8.1), respectively.

Data from a forest plot revealed that among key subgroups a PFS benefit with Dato-DXd vs docetaxel was experienced by almost all patients except for those with squamous histology. The most pronounced benefits were among patients who had actionable genomic alterations (HR, 0.38), non-squamous histology (HR, 0.63), and brain metastases at baseline (HR, 0.64).

Patients with non-squamous histology experienced a median PFS of 5.6 months (95% CI, 4.4-7.0) in the Dato-DXd arm (n = 229) vs 3.7 months (95% CI, 2.9-4.2) in the docetaxel arm (n = 232; HR, 0.63; 95% CI, 0.51-0.78); the ORR was 31.2% vs 12.8% and the DOR was 7.7 months vs 5.6 months, respectively. However, those with squamous histology did not experience a benefit when treated with Dato-DXd vs docetaxel; patients experienced a median PFS of 2.8 months (95% CI, 1.9-4.0) in the Dato-DXd arm (n = 70) vs 3.9 months (95% CI, 2.8-4.5) in the docetaxel arm (n = 73; HR, 1.38; 95% CI, 0.94-2.02). The ORR was 9.2% vs 12.7%, respectively, and the DOR was 5.9 months in the Dato-DXd arm vs 8.1 months in the docetaxel arm.

“The question that arises is: is [this] non-squamous benefit we’re seeing entirely driven by those patients with actual genomic alterations,” Lisberg, a thoracic medical oncologist at the University of California, Los Angeles (UCLA), said during the presentation. “All but 3 of those patients had non-squamous histology and a HR for PFS in favor of Dato-DXd of 0.38. The answer to that question is definitively no. Patients with non-squamous histology, both with and without actionable genomic alterations, are deriving a PFS benefit from Dato-DXd as the PFS HR for non-squamous patients without actionable genomic alterations is 0.71 [95% CI, 0.56-0.91].”

The interim overall survival (OS) analysis in the ITT population demonstrated that patients in the Dato-DXd arm experienced a median OS of 12.4 months (95% CI, 10.8-14.8) compared with 11.0 months (95% CI, 9.8-12.5) for patients in the docetaxel arm (HR, 0.90; 95% CI, 0.72-1.13). The HR for patients with non-squamous histology was 0.77 (95% CI, 0.59-1.01) and the HR for those with squamous histology was 1.32 (95% CI, 0.87-2.00). The information fraction at the interim analysis was 74% and the trial is continuing to the final OS analysis which Lisberg noted will be presented at a future meeting. Read more.