Tucatinib + trastuzumab/pertuzumab extends HER2+ mBC maintenance PFS, but adds liver AEs

Tucatinib is an oral HER2-selective TKI added to trastuzumab + pertuzumab maintenance after taxane + HP induction in HER2-positive metastatic breast cancer, testing whether HER2 blockade can be intensified after initial disease control rather than changing induction therapy. In the randomized, double-blind Phase III HER2CLIMB-05 trial (NCT05132582; n=654), tucatinib + HP improved investigator-assessed median PFS to 24.9 months vs 16.3 months with placebo + HP after a median of 6 induction cycles; that compares with the CLEOPATRA-era first-line standard of taxane + trastuzumab/pertuzumab followed by HP maintenance, where median PFS was 18.7 months from treatment start and long-term median OS reached ~56.5–57.1 months. The safety update shows the cost of intensification: grade ≥3 TEAEs were 42.3% vs 24.4%, grade ≥3 hepatic events 18.1% vs 1.2%, any-grade diarrhea 72.7% vs 51.2%, dose holds 49.4% vs 25.3%, dose reductions 29.1% vs 11.1%, and tucatinib discontinuation due to TEAEs 13.5%, while cardiac TEAEs remained similar at 4.3% vs 6.2%.