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 high risk of chemotherapy-induced toxicity ,raising interest in less toxic anti-HER2 therapy regimens.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 6months, already reported (Lancet Oncol 2018, Wildiers et al). We now present data on long term outcome (including cause of death), and on response and tolerance of T-DM1 given after progression on TP(M).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 (neo)adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 70% and/or to short physical performance battery (<10) 81%, Charlson comorbidity score > 0 in 41%. With 54.0 months of median follow-up, 6-month PFS was 43.1% (95% CI 27.1-58.1) versus 73.0% (95% CI 55.8-84.3) for TP and TPM, respectively. 12-month PFS was 33.7% and 51.9%, and 24-month PFS 18.7% and 28.7%, respectively. A total of 49 (61.3%) patients died, 27 (69.2%) in the TP arm and 22 (53.7%) in the TPM arm. There was no significant difference in OS between the two arms (TPM vs TP: HR=0.72, 95% CI 0.41-1.26) with median OS 32.1 months for TP, and 37.5 months for TPM. The causes of death were progressive disease (N=37, 75.5%), toxicity (cardiac failure, N=1, 2.0%), and other causes not due to PD/toxicity (N=9, 22.5%). Among the 40 patients who have started T-DM1 (22 in TPM arm and 18 in TP arm), median follow-up was 33.7 months from T-DM1 start. PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7-58.5). Grade 3 or higher AE occurred in 18 pts (45%). Most relevant reported grade III or higher toxicities on T-DM1 were fatigue (N=3), anorexia (N=2), anemia (N=1), febrile neutropenia (N=1), diarrhoea (N=1), hepatic failure (N=1), lung infection (N=1), increased GGT (N=1), thrombocytopenia (N=1), weight loss (N=1), hypophosphatemia (N=1), dyspnoea (N=1), epistaxis (N=1), hematoma (N=1). Two patients (5%) experienced grade 5 toxicity: one death was considered as related to cachexia and tumor progression; the other death was considered to be related to acute pneumonia and renal failure. The prognostic impact of geriatric assessment on PFS and OS, and frailty evolution during therapy will be presented at the meeting.Conclusions: Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years despite the associated frailty in the majority of the study population. T-DM1 provides a PFS rate at 6 months of 43.6% (95% CI: 27.7-58.5) with a wide range of possibly related toxicities in this generally frail population.

Citation Format: Hans Wildiers, Sandrine Marreaud, Lissandra Dal Lago, Peter Vuylsteke, Giuseppe Curigliano, Simon Waters, Barbara Brouwers, Bart Meulemans, Berta Sousa, Coralie Poncet, Etienne Brain. 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 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-06.