Abstract 351TiP
Background
The combination of trastuzumab, pertuzumab (HP) and a taxane increases progression-free survival (PFS) and overall survival (OS) in patients with HER2-positive (HER2+) advanced breast cancer (BC). PIK3CA mutations can occur in 30-35% of HER2+ tumors, independently of hormone receptor (HR) status. In an exploratory analysis from CLEOPATRA, patients with a tumor harboring a PIK3CA mutation (mut) had a shorter PFS. The AKT inhibitor ipatasertib (IPAT) blocks the PI3K/AKT pathway and has activity in PI3K/AKT-altered tumors. We hypothesize that ipatasertib + HP is safe and can be beneficial in patients with PIK3CAmut HER2+ BC.
Trial design
This is an open label, single arm, phase Ib study to evaluate the safety and preliminary efficacy of IPAT plus HP (+/- endocrine therapy [ET]) in up to 25 patients with unresectable locally advanced or metastatic HER2+ BC with a PIK3CA mut (tissue or plasma ctDNA) candidates to receive maintenance HP (+/- ET) after taxane discontinuation for a reason different to progressive disease. The primary endpoint is to define the maximum tolerated dose (MTD) and the recommended phase II dose of the combination. MTD is defined as the highest dose level at which ≤1 of 6 subjects experience a dose limiting toxicity (DLT) during the first 28 days of treatment. Grade ≥3 diarrhea for more than 72 hours or Grade ≥2 diarrhea for more than 5 days is considered a DLT. Secondary endpoints include objective response rate, duration of response, clinical benefit rate and PFS. Exploratory objectives include identification of molecular biomarkers of response to treatment both in ctDNA (Amplicon-seq) and tumor tissue (Breast Cancer 360 panel), as well as to characterize the pharmacokinetics of study drugs. Given the low risk for overlapping toxicities, full doses of IPAT (400mg orally once daily D1-21 q28d) and standard dose HP will be used in the first cohort. Dose reductions of IPAT (300mg and 200mg) are allowed if full dose exceeds MTD. Loperamide is given as prophylaxis for diarrhea. In HR-positive tumors, ET may be started after the DLT period.
Clinical trial identification
EudraCT: 2019-001526-94; NCT04253561.
Editorial acknowledgement
Legal entity responsible for the study
SOLTI Breast Cancer Research Group.
Funding
Hoffmann-La Roche.
Disclosure
M. Oliveira: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Puma Biotechnology; Research grant/Funding (institution): Philips Healthcare; Travel/Accommodation/Expenses: Grünenthal Group; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Pierre Fabre; Travel/Accommodation/Expenses: GP Pharm. P. Villagrasa: Honoraria (self), Speaker: Nanostring. E.M. Ciruelos: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer. J. Gavilá: Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Roche. A. Cortegoso: Travel/Accommodation/Expenses: Roche; Honoraria (self): SOLTI. V. Quiroga: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: Eisai; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Kern. X. Gonzalez: Honoraria (self): SOLTI; Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): Eisai. C. Saura: Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Genomic Health; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Sharp and Dhome España S.A.; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Odonate Therapeutics; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Philips Healthwork; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Travel/Accommodation/Expenses: priME Oncology; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Puma; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Synthon ; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Honoraria (institution): Lilly; Honoraria (institution): Genentech; Honoraria (institution): Immunomedics; Honoraria (institution): Macrogenics; Honoraria (institution): Piqur Therapeutics; Honoraria (institution): Zenith Pharma. All other authors have declared no conflicts of interest.