Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer, followed by T-DM1 after progression

Older patients are at higher risk of chemotherapy-induced toxicity, raising interest in less toxic anti-HER2 regimens for older persons with HER2-positive (HER2+) metastatic breast cancer (MBC). This phase II study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide (M) + Trastuzumab (T) and Pertuzumab (P) or TP alone. T-DM1 was offered in case of progression. In total, 39 and 41 patients were randomized to TP and TPM arm respectively. Median follow-up is 54.0 months. 24-month PFS was 18.7% (95% CI 8.2–32.4) and 28.7% (95% CI 15.8–43.0), respectively. A total of 49 (61.3%) patients died of whom 37 (75.5%) from disease progression; number of deaths per arm was 27 (69.2%) for TP and 22 (53.7%) for TPM. There was no significant difference in OS between the two arms (median OS TP vs TPM: 32.1 vs 37.5 months, p 0.25). Among the 40 patients who have started T-DM1 after disease progression on TP/TPM, PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7–58.5) and grade 3 or higher AE occurred in 18 pts (45%). Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and relatively well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years. Nevertheless, the majority of this older/frail population died from breast cancer, highlighting the need for well tolerated and efficacious treatments in these patients. •HER2+ metastatic breast cancer in older persons represents an important challenge.•Dual anti-HER2 therapy with metronomic chemotherapy is effective and safe.•Efficacy of second line T-DM1 is similar to the general breast cancer population.•Despite comorbidities, most older/frail patients die from breast cancer. ClinicalTrials.gov Identifier: NCT01597414.