Abstract PD3-09: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II study

Introduction: Pertuzumab (P) is approved as first line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC) combined with trastuzumab (T) and docetaxel. However older patients are at higher risk of chemotherapy-induced toxicity raising high interest in a less toxic backbone such as metronomic chemotherapy and in chemo-free dual HER2 blockade (TP). Patients and Methods: This phase II selection study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide 50 mg/day + TP (TPM) or TP alone. Prior endocrine therapy and up to 1 line of anti-HER2 therapy (without chemotherapy) for MBC were allowed.T-DM1 was offered in case of progression. Randomization was stratified according to hormonal receptors, previous anti-HER2 treatment and geriatric assessment. Primary endpoint was progression-free survival (PFS) rate at 6 months seeking a difference of ≥ 10% between the two arms. Results: Between July 2013 and May 2016, 39 and 41 patients were randomized to TP and TPM arm respectively: median age 76.7 years, hormone receptor positivity 69%, prior adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 71% and/or to short physical performance battery ( 0 in 40%. With 20.7 months of median follow-up, 6-month and median PFS were 46.2% (95% CI 30.2-60.7) and 5.6 months (95% CI 3.6-16.8) versus 73.4% (95% CI 56.6-84.6) and 12.7 months (95% CI 6.7-24.8) for TP and TPM, respectively. Four patients in TPM and 2 in TP developed brain metastases only as progression event. OS and breast cancer specific survival were comparable between the two arms; 9/29 deaths were not breast cancer-related. Response rate was 44% in TP arm and 53% in TPM arm. In 29 patients who received T-DM1 second line, 6-month PFS, median PFS and response rate were 49.5% (95% CI 29.2-66.9), 5 months (95% CI 2.5-12.5) and 13.5%. In patients who discontinued TP(M), 37, 9 and 14 stopped because of progression, toxicity or other reasons, respectively. During TPM treatment, 1 patient died of heart failure and 1 developed grade 3 heart failure; 1 patient in each arm developed a ≥ 10% asymptomatic left ventricular ejection fraction decrease below 50%. Diarrhea any grade and grade ≥ 3 were observed in 56% and 8% versus 71% and 12% patients in TP and TPM arms, respectively. No grade 3 or febrile neutropenia was reported. There was no relevant difference in functional evolution between both groups. In the whole population, several geriatric items were of prognostic value by multivariate analysis: e.g. for OS, G8 >14 vs ≤ 14 HR=0.12 (95% CI 0.03-0.55, p 0.006). In 29 patients receiving T-DM1, grade 3 toxicity was rare: fatigue (2 patients), thrombocytopenia and epistaxis (1 patient). Conclusions: Metronomic chemotherapy-based dual blockade (TPM) seems to be superior to dual blockade alone (TP) in an elderly/frail HER2+ MBC population, with an attractive safety profile. TPM, followed by T-DM1 after progression, may delay or supersede taxane chemotherapy in this population. Citation Format: Wildiers H, Tryfonidis K, dal Lago L, Vuylsteke P, Curigliano G, Waters S, Brouwers B, Aalders K, Meulemans B, Litiere S, Touati N, Cardoso F, Brain E. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-09.