Results of the phase Ib dose escalation study of MEN1611, a PI3K inhibitor, combined with trastuzumab (T) +/- fulvestrant (F) for HER2+/PIK3CA mutant (mut) advanced or metastatic (a/m) breast cancer (BC)

Abstract

Background: MEN1611 (MEN) is an oral PI3K inhibitor active on the p110a mut and WT, b and g isoforms, while sparing the d. Antitumor activity of MEN combined with other agents in patient-derived xenografts and BC cell lines with different PIK3CA mutations, provides a strong rationale for clinical testing. Methods: B-PRECISE-01 is an ongoing phase Ib study in patients (pts) with HER2+/ PIK3CAmut a/m BC treated with at least 2 anti-HER2 therapies. A 3+3 design combined 3 dose levels of MEN BID and T weekly IV. HR+ postmenopausal pts also received F. Primary objectives are to determine safety and recommended phase II dose (RP2D). Dose-limiting toxicities (DLTs) were assessed during cycle 1. Secondary objectives included assessment of preliminary clinical activity, pharmacokinetics and pharmacodynamics. Here we present mature data from dose escalation cohorts. Results: As of Oct. 2019, 12 female pts were treated: 9 MEN+T+F and 3 MEN+T. Median age: 59 years (range 39-77). Median prior metastatic regimens: 5.5 (4-12). No DLTs were observed at any dose cohort. 48 mg was selected as RP2D. Most common grade (G)1/2 treatment-related adverse events (TRAEs) were diarrhoea (n¼9), anemia (n¼6), nausea (n¼4), asthenia (n¼4), decreased appetite (n¼4), hyperglycemia (n¼4), and mucosal inflammation (n¼3). G3/4 TRAEs were not dose-dependent and occurred in 4 pts such as hyperglycemia (n¼3), pneumonitis (n¼1), decreased appetite (n¼1), mucosal inflammation (n¼1), and AST/ALT increase (n¼1). Dose was reduced in one pt at 48 mg. No deaths from toxicity occurred. There were no overt differences in the safety profile of MEN+T+F vs. MEN+T. 5 pts (42%) had partial response, 5 stable disease, 4 disease control >8 months (mo) and 2 were on treatment >11 mo. MEN exposure tends to increase with increasing doses. Tmax was reached after 0.5-8 h following administration and the terminal half-life was w3.5 h. Conclusions: Tolerability of MEN+T F is acceptable; most TRAEs were reversible and manageable by supportive care. Promising antitumor activity in heavily pretreated pts, together with prolonged disease control, provide the rationale for cohort expansion at RP2D in pts with HER2+/PIK3CA mut a/m BC.