First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01

Abstract

Purpose: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC).

Patients and methods: Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.

Results: Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n = 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression-free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression.

Conclusion: Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.

Trial registration: ClinicalTrials.gov NCT03401385.

FIG 1.

Antitumor activity of Dato-DXd in the NSCLC cohort. (A) Maximum percentage change from baseline in the sum of target lesion diameters according to RECIST 1.1, with the 4, 6, or 8 mg/kg dose of Dato-DXd indicated by bar color. (B) Change in size of target lesions over time with Dato-DXd 6 mg/kg with responders and nonresponders indicated by line color. (C) Computed tomography scans depicting a right middle lobe lung mass target lesion (top) for a 51-year-old woman with a scan depicting PR after six cycles of treatment with Dato-DXd 4 mg/kg and right lower-lobe lung masses (bottom) for a 54-year-old woman with a scan depicting PR after eight cycles of treatment with Dato-DXd 4 mg/kg. Dato-DXd, datopotamab deruxtecan; NSCLC, non–small-cell lung cancer; PR, partial response.

FIG 2.

Kaplan-Meier estimates of survival outcomes in patients who received Dato-DXd 6 mg/kg in the NSCLC cohort. (A) PFS assessed by blinded independent central review. (B) OS. Dato-DXd, datopotamab deruxtecan; NSCLC, non–small-cell lung cancer; OS, overall survival; PFS, progression-free survival.