Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study

Abstract

Purpose: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker.

Patients and methods: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported.

Results: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts.

Conclusion: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

FIG 1.

Antitumor activity of datopotamab deruxtecan (Dato-DXd). Waterfall plot of best percent change in SOD in target lesions in patients with (A) HR+/HER2– BC and (B) TNBC as assessed by BICR per RECIST version 1.1 (full analysis set). Dashed lines represent partial response (≥30% decrease) and progressive disease (≥20% increase) per RECIST version 1.1. Kinetics of tumor burden over time in patients with (C) HR+/HER2– BC and (D) TNBC. Spider plot shows percentage change in SOD in target lesions as assessed by BICR per RECIST 1.1. (E) Computed tomography scan depicting a right liver lesion (red circles) in a 53-year-old woman with HR+/HER2– BC at (i) study baseline and (ii) partial response after 16 cycles of treatment with Dato-DXd 6 mg/kg once every 3 weeks over 48 weeks, resulting in a 66% reduction in tumor lesion diameter per RECIST version 1.1. (F) Computed tomography scan of a liver lesion in a 53-year-old woman diagnosed with TNBC at (i) study baseline and (ii) showing a significant decrease in hepatic lesion (from 4.1 × 3.0 cm to 0.9 × 0.5 cm), after 42 cycles of treatment with Dato-DXd over 30 months, resulting in overall 90% reduction in tumor lesion diameter per RECIST version 1.1. ^aPostbaseline tumor assessments were not available for one patient in each cohort at data cutoff. ^bn = 39. ^cIn locally advanced or metastatic setting. ^dCDK4/6 inhibitors were not counted as CT in this study. ^en = 40. ^fEleven patients received sacituzumab govitecan, two received trastuzumab deruxtecan, and one received patritumab deruxtecan. ADC, antibody-drug conjugate; BC, breast cancer; BICR, blinded independent central review; CT, chemotherapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IO, immuno-oncology therapy; SD, stable disease; SOD, sum of the diameters; TNBC, triple-negative BC.

FIG 2.

Progression-free survival. Kaplan-Meier plots of progression-free survival by blinded independent central review per RECIST v1.1 in (A) the HR+/HER2– BC and (B) TNBC cohorts. BC, breast cancer; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; Topo I, topoisomerase I; TNBC, triple-negative BC.