Phase 3 trials presented this year’s San Antonio Breast Cancer Symposium included HER2CLIMB-05 (NCT05132582), investigating the efficacy and safety of adding tucatinib, a selective HER2 tyrosine kinase inhibitor, to trastuzumab (H) and pertuzumab (P) as first-line maintenance therapy in patients with HER2+ metastatic breast cancer (MBC. Results were published in the Journal of Clinical Oncology simultaneously with presentation (DOI: 10.1200/JCO-25-02600).
Patients were randomly assigned to tucatiniib+HP (n=326) or placebo + HP (n=328); they could also receive endocrine therapy (ET). The primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival (OS), PFS per blinded independent central review (BICR), and central nervous system (CNS)-PFS.
Tucatinib+HP demonstrated a statistically significant PFS benefit. At a median follow-up of 23 months, median PFS was 24.9 vs 16.3 months for tucatinib vs placebo, a 36% improvement (P<.0001). Benefit was observed across all prespecified subgroups, and hormone receptor (HR) status. BICR-PFS was 28.9 vs 16.0 months (34.6% improvement), favoring tucatinib. Median OS and CNS-PFS are not reached.
Tucatinib+HP had a manageable safety profile, with diarrhea, nausea, and elevated liver enzymes, mostly of low grade, being the most common adverse events (AE).
Erika Hamilton, MD, said HER2CLIMB-05 demonstrated that adding tucatinib to HP is an enhanced first line maintenance therapy option in HER2+ MBC, providing longer time to disease progression with time off chemotherapy.
lidERA (NCT0496199) assigned patients with medium to high risk estrogen receptor (ER)-positive, HER2-negative early (e) BC to giredestrant, an oral next-generation ER antagonist and degrader (SERD) (n=2084) or standard of care (SOC) adjuvant ET (tamoxifen or aromatase inhibitor) (n=2086). The primary endpoint was invasive disease-free survival (IDFS). Secondary endpoints included distant recurrence-free interval (DRFI), OS, and safety.
There was a statistically significant improvement in IDFS at a median follow-up of 32.3 months (HR 0.70, P=.0014) with giredestrant vs SOC, a 30% reduced risk, which was consistent across prespecified subgroups. DRFI was improved vs SOC ET (HR 0.69), 31% reduction in risk of developing metastatic disease. OS requires further follow-up.
AE were comparable between arms. Thromboembolic events were higher with SOC; giredestrant was associated with asymptomatic bradycardia, both known issues, according to presenter Aditya Bardia, MD. Giredestrant had a lower discontinuation rate.
In a rapid-fire presentation, Guiseppe Curigliano, MD, presented safety data from DESTINY-Breast11, (NCT05113251), comparing neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+ eBC.
T-DXd-THP AE were manageable, with less toxicity than ddAC-THP, including fewer grade ≥3 events of interstitial lung disease/pneumonitis. There were fewer grade ≥3 left ventricular dysfunction events with T-DXd-THP than ddAC-THP, and no cardiac failure with T-DXd-THP.
Rates of nausea and vomiting were higher with T-DXd-THP than ddAC-THP, highlighting the importance of following guideline recommendations for antiemetics. T-DXd-THP was associated with fewer hematologic toxicities. Most peripheral neuropathy events occurred during the THP phase, cycles 5-8, and were non-serious and generally low grade.
Dr. Curigliano said the safety results support T-DXd-THP as a potential neoadjuvant treatment option in high-risk HER2+ eBC.
Dr. Lederman has no conflicts of interest to report.
Illustration by April Brust
