141 DESTINY-Breast06 Post Hoc Analysis by Physician’s Choice of Chemotherapy: Efficacy and Safety of Trastuzumab Deruxtecan Versus Physician’s Choice of Chemotherapy in Hormone Receptor–Positive, HER2-Low or -Ultralow Metastatic Breast Cancer

Background

DESTINY-Breast06 is a randomized, open-label phase 3 trial in patients with hormone receptor–positive (HR+), HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+ / in situ hybridization–negative) or -ultralow (IHC 0 with membrane staining) metastatic breast cancer following 1 or more lines of endocrine therapy. At primary data cutoff (March 18, 2024), trastuzumab deruxtecan (T-DXd) showed a statistically significant and clinically meaningful progression-free survival (PFS) benefit versus physician’s choice of chemotherapy (TPC). DESTINY-Breast06 led to the US FDA and European Medicines Agency approval of T-DXd for HER2-low or HER2-ultralow unresectable or metastatic breast cancer that has progressed on 1 or more endocrine therapy in the metastatic setting. We report a post hoc analysis of efficacy and safety outcomes for T-DXd vs TPC type (capecitabine or taxane) in patients with HR+, HER2-low or -ultralow metastatic breast cancer from DESTINY-Breast06.

Methods

Patients were randomly assigned (1:1) to T-DXd 5.4 mg/kg every 3 weeks or TPC (capecitabine [CAPE], nab-paclitaxel, or paclitaxel). Outcomes included PFS, confirmed objective response rate (ORR), time from randomization to second progression or death (PFS2), and safety by choice of TPC before randomization in the intent-to-treat (ITT; HER2-low and -ultralow) population.

Results

This analysis included 866 patients (T-DXd, n=436; TPC, n = 430 [59.8% CAPE; 24.4% nab-paclitaxel; 15.8% paclitaxel]). T-DXd showed increased median PFS (PFS; 13.3 vs 8.5 months; HR 0.66 [95% CI, 0.53-0.82]), confirmed ORR (57.9%; 95% CI, 51.7-63.9 vs 30.7% 95% CI, 25.2-36.8), and median PFS2 (22.6 vs 16.4 months; HR, 0.62; 95% CI, 0.49-0.78]) versus CAPE. When evaluating nab-paclitaxel and paclitaxel, T-DXd was also consistently favored (Table). The most common adverse events (AEs) per drug were nausea (69.8%, T-DXd), palmar-plantar erythrodysesthesia syndrome (57.4%, CAPE), and alopecia (45.5%, nab-paclitaxel; 50.7%, paclitaxel). Grade 3 or higher drug-related AEs were reported in 40.6% (T-DXd), 29.3% (CAPE), 27.7% (nab-paclitaxel), and 44.8% (paclitaxel).

Conclusions

In this analysis, T-DXd showed benefit over all TPC subgroups (including CAPE) with improved PFS, ORR, and PFS2. These findings support T-DXd as an effective treatment option in HR+, HER2-low/ultralow metastatic breast cancer with prior endocrine therapy but no chemotherapy, as previously reported in the ITT population. T-DXd safety outcomes were consistent with those previously reported.