Neoadjuvant concurrent or sequential anthracycline-containing chemotherapy and HER2-targeted agents for HER2-positive breast cancer: a randomized phase 2 study (METIS).

The integration of anthracyclines with HER2-targeted agents in neoadjuvant therapy for HER2-positive breast cancer has been limited by cardiotoxicity concerns. This randomized phase II METIS trial (NCT04172259) assessed whether concurrent pegylated liposomal doxorubicin (PLD)-containing chemotherapy plus dual HER2 blockade (trastuzumab/pertuzumab) could improve efficacy without increasing cardiac risk. A total of 156 patients with stage II-III HER2-positive breast cancer were randomized to a PLD-based concurrent regimen or an epirubicin and cyclophosphamide (EC)-based sequential regimen. The PLD-based concurrent group achieved a higher pathological complete response (pCR) rate (67.5% vs. 48.7%; difference, 18.8%; 95% confidence interval [CI], 3.6-34.0; P = 0.033) compared with the EC-based sequential group, with greater benefit in hormone receptor-positive disease (58.7% vs. 36.7%) and stage II tumors (82.1% vs. 48.0%). After a median follow-up of 37.5 months, fewer event-free survival (EFS) events occurred in the PLD-based concurrent group (3 vs. 8), yielding a hazard ratio (HR) of 0.35 (95% CI, 0.09-1.32; P = 0.105). The estimated 3-year EFS rates were 96.0% (95% CI, 88.1-98.7) versus 90.7% (95% CI, 81.5-95.6). Achieving pCR was significantly associated with improved EFS (HR = 0.15; 95% CI, 0.03-0.71; P = 0.006). Cardiac safety was comparable, with no symptomatic cardiac dysfunction and only one grade ≥3 cardiotoxicity in the EC-based sequential group. These findings support PLD-based concurrent therapy with trastuzumab and pertuzumab as an effective and safe neoadjuvant option for high-risk HER2-positive breast cancer, warranting further evaluation in phase III trials.