Abstract 347P
Background
MEN1611 (MEN) is an oral PI3K inhibitor active on the p110α mut and WT, β and γ isoforms, while sparing the δ. 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 (n=9), anemia (n=6), nausea (n=4), asthenia (n=4), decreased appetite (n=4), hyperglycemia (n=4), and mucosal inflammation (n=3). G3/4 TRAEs were not dose-dependent and occurred in 4 pts such as hyperglycemia (n=3), pneumonitis (n=1), decreased appetite (n=1), mucosal inflammation (n=1), and AST/ALT increase (n=1). 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 ∼3.5 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.
Clinical trial identification
NCT03767335.
Editorial acknowledgement
Legal entity responsible for the study
Menarini Ricerche S.p.A.
Funding
Menarini Ricerche S.p.A.
Disclosure
M. Piccart: Speaker Bureau/Expert testimony, Board Member (Scientific Board): Oncolytics; Honoraria (self), Research grant/Funding (institution), Consultant: AstraZeneca; Honoraria (self), Consultant: Camel-IDS; Honoraria (self), Consultant: Crescendo Biologics; Honoraria (self), Consultant: Debiopharm; Honoraria (self), Consultant: G1 Therapeutics; Honoraria (self), Research grant/Funding (institution), Consultant: Genentech; Honoraria (self), Consultant: Huya; Honoraria (self), Consultant: Immunomedics; Honoraria (self), Research grant/Funding (institution), Consultant: Lilly; Honoraria (self), Consultant: Menarini; Honoraria (self), Research grant/Funding (institution), Consultant: MSD; Honoraria (self), Research grant/Funding (institution), Consultant: Novartis; Honoraria (self), Consultant: Odonate; Honoraria (self), Consultant: Periphagen; Honoraria (self), Research grant/Funding (institution), Consultant: Pfizer; Honoraria (self), Research grant/Funding (institution), Consultant: Roche; Honoraria (self), Consultant: Seattle Genetics; Research grant/Funding (institution): Radius; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Synthon. F. Duhoux: Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Lilly; Travel/Accommodation/Expenses: Teva. H-T. Arkenau: Full/Part-time employment: HCAInternational; Full/Part-time employment: Sarah Cannon; Advisory/Consultancy: Lonctura; Advisory/Consultancy: Roche; Advisory/Consultancy: Bicycle; Advisory/Consultancy: Biontech; Advisory/Consultancy: Guardant; Advisory/Consultancy: Bayer; Advisory/Consultancy: Servier; Advisory/Consultancy: Taiho; Advisory/Consultancy: Boehringer Ingelheim. H. Wildiers: Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Biocartis; Honoraria (institution), Advisory/Consultancy: Lilly; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (institution), Advisory/Consultancy: PUMA Biotechnology; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (institution), Advisory/Consultancy: Sirtex. M. Campone: Honoraria (self), Advisory/Consultancy: GT1; Honoraria (institution), Advisory/Consultancy: Sanofi; Honoraria (institution), Advisory/Consultancy: Pierre Fabre; Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Servier; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (institution), Advisory/Consultancy: AbbVie; Honoraria (institution), Advisory/Consultancy: Accord; Honoraria (institution), Advisory/Consultancy: Pfizer; Speaker Bureau/Expert testimony: Lilly. D. Tosi: Travel/Accommodation/Expenses, Spouse/Financial dependant, An immediate family member: Biomarin; Spouse/Financial dependant, An immediate family member: Actelion; Research grant/Funding (self), Travel/Accommodation/Expenses: Astellas Pharma; Research grant/Funding (self): Jansen; Research grant/Funding (self): Ipsen; Licensing/Royalties, Pending patent on a new drug combination for prostate cancer treatment: Pending patent; Travel/Accommodation/Expenses, An immediate family member: Nutricia; Travel/Accommodation/Expenses, An immediate family member: Amicus Therapeutics; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: AstraZeneca. S. Escrivá-de Romaní: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre Fabre; Speaker Bureau/Expert testimony: Eisai; Research grant/Funding (institution): Synthon; Travel/Accommodation/Expenses: Daiichi Sankyo. A.M. Wardley: Honoraria (self), Honoraria (institution), Contract research: Roche; Honoraria (self), Honoraria (institution), Joint working agreement, contract research: Novartis; Honoraria (self), Joint working agreement, contract research: Pfizer; Honoraria (self), Honoraria (institution), Contract research: Daiichi Sankyo; Honoraria (institution), Contract research: Seattle Genetics; Honoraria (self), Honoraria (institution), Contract research: Eli Lilly; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses, Travel assistance: MSD; Honoraria (self): Athenex; Honoraria (self), Honoraria (institution), Contract research: AstraZeneca; Honoraria (self): Andrew Wardley Limited; Leadership role, Director: Manchester Cancer Academy; Leadership role, Director: Outreach Research & Innovation Group Limited; Honoraria (self): Gerson Lehman Group; Honoraria (self): Guidepoint Global; Honoraria (self): Coleman Expert Network; Honoraria (self): Helios; Honoraria (self): Health Care America; Honoraria (self): 1G1 Therapeutics, Inc.; Honoraria (self): Research Triangle Park, NC, USA. P.G. Aftimos: Honoraria (self): Boehringer Ingleheim; Honoraria (self): Macrogenics; Honoraria (self): Amcure; Honoraria (self): Synthon; Honoraria (self): G1 Therapeutics; Honoraria (self), Travel/Accommodation/Expenses, Travel grant: Roche; Honoraria (self): Novartis; Honoraria (self), Travel/Accommodation/Expenses, Travel grant: Amgen; Travel/Accommodation/Expenses, Travel grant: MSD; Travel/Accommodation/Expenses, Travel grant: Pfizer; Honoraria (self): Radius; Honoraria (self): Servier. F. Amair-Pinedo: Full/Part-time employment: Menarini Ricerche S.p.A./Laboratorios Menarini. A.U.E. Pellacani: Full/Part-time employment: Menarini Ricerche S.p.A.; Leadership role: VaxYnethic; Shareholder/Stockholder/Stock options: Amgen. D.O. Laurent: Leadership role, Full/Part-time employment: Menarini. All other authors have declared no conflicts of interest.