MEN1611, a PI3K inhibitor, combined with trastuzumab (T) +/- fulvestrant (F) for HER2+/PIK3CA mutant (mut) advanced or metastatic (a/m) breast cancer (BC): Safety and efficacy results from the ongoing phase Ib study (B-PRECISE-01)

Abstract

Background MEN1611 (MEN) is an oral PI3K inhibitor active on the p110? mut and WT, ? and ? isoforms, while sparing the ?. B-PRECISE-01 is an ongoing phase 1b study investigating MEN in combination with T � F. No dose-limiting toxicities (DLTs) were observed during the escalation step and MEN 48 mg BID was selected as Recommended Phase 2 Dose (R2PD) for cohort expansion (CE). Methods In this open-label, 2-arm study, eligible patients (pts) had HER2+/PIK3CAmut locally unresectable advanced or metastatic (a/m) BC and were treated with at least 2 prior anti-HER2 therapies in the metastatic setting including T. All pts received MEN+T, while F was added in hormone receptor positive (HR+) postmenopausal women. Pooled safety and efficacy data from the two subpopulations of CE are presented herein. Results As of March 2021, 42 female pts were treated: 36 of them with MEN 48 mg BID (18 MEN+T and 18 MEN+T+F). Median age 55 years (range 34-78), 25% premenopausal, ECOG PS 0-1: 95.2%. Median metastatic regimes 4; 57.1% had prior pertuzumab and 73.8% had prior T-DM1. Common treatment-emergent adverse events (TEAEs, ?20%) were diarrhea 64.3%, nausea 42.8%, asthenia 31%, decreased appetite 28.6%, anemia 28.6%, and hyperglycemia 23.8%. Most treatment-related AE (TRAEs) were reversible and manageable by supportive care. TRAEs caused treatment interruption in 14 pts (33.3%, 1 pt definitely) and dose reduction in 6 pts (16.7%, only allowed in CE) mostly hyperglycemia, diarrhea, nausea, asthenia and decreased appetite. Serious TRAEs were experienced by 8 pts (19%): hyperglycemia 3 pts, diarrhea 2 pts, general physical health deterioration, generalized edema, and pneumonitis (1 pt each). In the efficacy-evaluable population (n=29) 9 pts showed partial response (MEN+T 4/11, MEN+T+F 5/18), and 18 pts had stable disease (MEN+T 6/11, MEN+T+F 10/18) as best response. Seven pts were on treatment > 6 months (MEN+T 3, MEN+T+F 4), and 1 pt received MEN+T > 12 months. Conclusions MEN combined with T � F shows a manageable safety profile with encouraging duration of antitumoral activity in heavily pre-treated pts with HER2+/PIK3CAmut a/m BC. Recruitment for CE is open.