Abstract OT3-26-01: CCTG MA40: DOUBLE-BLIND PLACEBO CONTROLLED PHASE III TRIAL OF FULVESTRANT AND IPATASERTIB FOR ADVANCED HER-2 NEGATIVE AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER POST FIRST LINE CDK 4/6 AND AROMATASE INHIBITOR THERAPY (FINER)
Authors: Chia Stephen K. , Cescon David W. , Redfern Andrew D. , Rodin Danielle , Simmons Christine , Ayoub Jean-Pierre , Chalchal Haji Ibrahim , Rayson Daniel , Rushton-Marovac Moira , Hay Tracey , Gallinaro Lisa , Chen Bingshu , Parulekar Wendy 
Published: March 2023

Background: The PI3K/AKT/mTOR pathway is a rational target in the metastatic disease setting for hormone receptor positive breast cancer based on preclinical and clinical data demonstrating that pathway inhibition improves outcome (Baselga 2012, Andre 2019, Jones 2019). Combining fulvestrant and AKT inhibition demonstrated efficacy in pts with HR+aBC (Howell 2022). Ipatasertib is a potent, highly selective, small-molecule inhibitor of three isoforms of serine/threonine kinase AKT. We hypothesize that Ipatasertib plus fulvestrant will improve PFS compared to fulvestrant in the second line setting post disease progression on aromatase inhibitor (AI) + CDK 4/6 inhibitor therapy. Methods: MA40 is a double blind, placebo-controlled trial in patients with hormone receptor positive, HER2-negative breast cancer with prior progression on AI plus CDK4/6 inhibitor therapy. Patients are randomized to fulvestrant/ipatasertib 400 mg po days 1-21 every 28 day or fulvestrant/placebo. The primary objective is to compare Progression Free Survival (PFS) between arms (RECIST 1.1, investigator assessed). Secondary objectives include comparisons between arms: PIK3CA/AKT1/PTEN altered cohort and non-altered cohorts; PFS by Blinded Central Radiology Review (all enrolled patients, PIK3CA/AKT1/PTEN altered and non-altered cohorts), Response rate; Duration of Response; Clinical Benefit Rate; Overall Survival; Time to Commencement of Subsequent Line of Systemic Therapy or Death; Safety and Tolerability (CTCAE version 5.0); QOL (EORTC QLQ-C30, NCI PRO-CTCAE); Economic Evaluation, (healthcare utilization and health utilities(EQ-5D-5L)). Statistical Design: Allocation 1:1 balanced for: PIK3CA/PTEN/AKT1 mutation status (ctDNA analysis using FoundationOne®Liquid Platform) (altered vs wildtype/unknown); prior treatment duration with CDK4/6 inhibitor (&lt; 6 months vs &gt; 6 months) and centre. Sample size is 250 to detect a benefit in PFS with the addition of ipatasertib. Eligibility Criteria: Histologically and/or cytologically confirmed ER positive and HER-2 negative breast cancer by local assessment that is advanced; postmenopausal status; clinical and/or radiographic progression during treatment with or within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an AI; only one prior line of chemotherapy in the advanced setting. Conduct to Date: Enrollment is ongoing. Supported by Hoffmann-La Roche Limited, CCS

Citation Format: Stephen K. Chia, David W. Cescon, Andrew D. Redfern, Danielle Rodin, Christine Simmons, Jean-Pierre Ayoub, Haji Ibrahim Chalchal, Daniel Rayson, Moira Rushton-Marovac, Tracey Hay, Lisa Gallinaro, Bingshu Chen, Wendy Parulekar. CCTG MA40: DOUBLE-BLIND PLACEBO CONTROLLED PHASE III TRIAL OF FULVESTRANT AND IPATASERTIB FOR ADVANCED HER-2 NEGATIVE AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER POST FIRST LINE CDK 4/6 AND AROMATASE INHIBITOR THERAPY (FINER) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-26-01.