Background

The management of HER2-positive metastatic breast cancer (HER2+ mBC) has rapidly evolved. We assessed the real-world efficacy and safety of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) and tucatinib by emulating two phase III trials.

Methods

We emulated two target trials using the French National Health Data System: T-DXd versus T-DM1 and T-DXd versus tucatinib, for second- and third-line HER2+ mBC treatment. We included patients from September 2020 to September 2023, and followed them until death or April 2024. We emulated treatment assignment randomization with inverse probability of treatment weighting. Efficacy outcomes included time to treatment discontinuation (TTD) and overall survival (OS). Safety outcomes included cause-specific hospitalizations.

Findings

In the second-line treatment emulation (n = 2931: 1633 T-DM1, 1298 T-DXd), T-DXd had longer TTD (median 14⋅1 versus 6⋅5 months; weighted hazard ratio, wHR [95% confidence interval, CI], 0⋅46 [0⋅42–0⋅51]) and OS (median not reached; wHR [95% CI], 0⋅66 [0⋅55–0⋅80]) than T-DM1. We observed more cases of interstitial lung disease in the T-DXd group. In the third-line treatment emulation (n = 2391: 566 tucatinib, 1825 T-DXd), T-DXd had longer TTD (median 11⋅8 versus 5⋅8 months; wHR [95% CI], 0⋅60 [0⋅53–0⋅68]) and OS (median 31⋅7 versus 26⋅6 months; wHR [95% CI], 0⋅79 [0⋅69–0⋅92]) than tucatinib. T-DXd tended to protect from cardiac disorders (wHR [95% CI], 0⋅44 [0⋅26–0⋅74]) while enhancing respiratory disorders occurrence (wHR [95% CI], 1⋅72 [1⋅03–2⋅89]).

Interpretation

In this real-world study, T-DXd was more effective than T-DM1 as a second-line treatment and tucatinib as a third-line treatment, in line with clinical trial results.