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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)
Piccart, M. Borrego, M. R. Duhoux, F. Arkenau, H. T. de Speville, B. D. Wildiers, H. Campone, M. Tosi, D. Garcia-Corbacho, J. Jimenez, B.
Piccart, M.
Borrego, M. R.
Duhoux, F.
Arkenau, H. T.
de Speville, B. D.
Wildiers, H.
Campone, M.
Tosi, D.
Garcia-Corbacho, J.
Jimenez, B.
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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.
Description
Date
2020
Publisher
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Keywords
Type
Meetings and Proceedings
Citation
Piccart M, Borrego MR, Duhoux F, Arkenau HT, Doger de Spéville B, Wildiers H, et al. 347P 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). Annals of Oncology. 2020;31:S386-S.