DESTINY-Breast03 reports longest OS in previously treated HER2-positive mBC

Long-term follow-up of the DESTINY-Breast03 trial has reported a median overall survival (OS) of 52.6 months with trastuzumab deruxtecan (T-DXd), representing the longest reported OS in previously treated HER2-positive metastatic breast cancer (mBC) to date.

Following prior success in demonstrating the longest reported progression-free survival (PFS; median, 28.8 months with T-DXd) in previously treated HER2-positive mBC in the second interim analysis (data cut-off, 21 May 2021), the DESTINY-Breast03 investigators recently reported results from a longer-term analysis (data cut-off, 20 November 2023) with updated PFS, OS and safety data. [Lancet 2023;401:105-117; Nat Med 2024;doi:10.1038/s41591-024-03021-7]

Patients with HER2-positive mBC previously treated with taxane and trastuzumab were randomized 1:1 to receive T-DXd 6.5 mg/kg (n=261; median follow-up, 43.0 months) or trastuzumab emtansine 3.6 mg/kg (T-DM1; n=263; median follow-up, 35.4 months).

Median PFS by investigator assessment was approximately four times longer with T-DXd vs T-DM1 (29.0 vs 7.2 months; hazard ratio [HR], 0.30; 95 percent confidence interval [CI], 0.24–0.38). Almost half (45.7 percent) and 41.5 percent of patients in the T-DXd group were progression-free at year 3 and year 4, respectively.

Subgroup analyses of DESTINY-Breast03 consistently showed significantly longer median PFS with T-DXd vs T-DM1 in patients with or without baseline brain metastases (BMs: median, 15.0 vs 3.0 months; HR, 0.25; 95 percent CI, 0.13–0.45) (no BMs: median, not reached vs 7.1 months; HR, 0.30; 95 percent CI, 0.22–0.40), indicating consistent benefit from T-DXd treatment in patients with HER2-positive mBC with or without BMs. [ESMO Open 2024;doi:10.1016/j.esmoop.2024.102924]

Longer-term OS results also favoured T-DXd, with an improvement of about 10 months over T-DM1 (median, 52.6 vs 42.7 months; HR, 0.73; 95 percent CI, 0.56–0.94). The 3-year OS rate was 67.6 vs 55.7 percent. [Nat Med 2024;doi:10.1038/s41591-024-03021-7]

“To our knowledge, the median OS with T-DXd in DESTINY-Breast03 is the longest reported OS in this disease setting, and more than two-thirds of patients remained alive at 3 years,” highlighted the investigators. “[The median OS of 53.6 months with T-DXd] is in the range of the CLEOPATRA trial in the first-line setting, which demonstrated a median OS of 57.1 months at the end-of-study analysis in patients with HER2-positive mBC treated with pertuzumab, trastuzumab and docetaxel combination therapy.”  

Incidence rates of any grade (99.6 vs 95.4 percent), grade ≥3 (58.0 vs 52.1 percent), and serious (27.6 vs 22.6 percent) treatment-emergent adverse events (TEAEs) were slightly higher with T-DXd vs T-DM1. Four new interstitial lung disease or pneumonitis events occurred in the T-DXd group (all grade 2). The longer-term analysis continued to show no new safety signals, supporting the favourable benefit-risk profile of T-DXd vs T-DM1 in previously treated HER2-positive mBC.

“Consistent with reports from previous analyses, the safety profile of T-DXd continued to be manageable, with no cumulative toxicities observed with longer follow-up,” pointed out the investigators.

Moving forward, the DESTINY-Breast09 trial will explore the efficacy of T-DXd in the first-line mBC setting. [NCT04784715]