Abstract OT2-01-08: SEQUence of Endocrine therapy in advanced Luminal Breast cancer (SEQUEL-Breast): A phase 2 study on fulvestrant beyond progression in combination with alpelisib for PIK3CA-mutated, HR+ HER2- advanced breast cancer
Authors: Almekinders Cornelia AM , Konings Inge RHM , van der Noort Vincent , van den Berg Susan M , Bos Monique EMM , Dezentjé Vincent O 
Published: March 2023

Goal To investigate the efficacy of alpelisib added to fulvestrant beyond progression in patients with HR+ HER2- advanced breast cancer (ABC). Background The SOLAR-1 study (Andre et al, 2019) has shown that the addition of alpelisib, an alpha-specific PI3K-inhibitor to fulvestrant led to a PFS-benefit of 5.3 months in patients with PIK3CA-mutated HR+ HER2- ABC. In this study, patients were fulvestrant-naive, and only 6% of this population was previously treated with a CDK4/6 inhibitor (CDK4/6i). Nowadays, most patients have been treated with a CDK4/6i, either combined with an aromatase-inhibitor (AI) in 1st line, or with fulvestrant in the 1st or 2nd line setting. Results of the ongoing Dutch SONIA-trial (NCT03425838) will show whether the addition of CDK4/6i to an AI in 1st line is superior to the addition of CDK4/6i to fulvestrant in 2nd line. Patients who have progressed on a CDK4/6i in either line and fulvestrant may be treated with fulvestrant and alpelisib. However, the efficacy of fulvestrant beyond progression combined with alpelisib is unknown. Aim of this study The aim is to determine if treatment with fulvestrant beyond progression and alpelisib results in a clinically meaningful median PFS of ≥6 months. Primary endpoint: Progression-free survival (PFS). Secondary endpoints: ‘On treatment’ PFS Overall survival Objective Response Rate Clinical Benefit Rate Duration of response Safety Risk factors for alpelisib-induced hyperglycemia Quality of life Pharmacokinetics Prognostic value of ctDNA Mechanisms of resistance Trial design The SEQUEL-Breast trial is a nationwide Dutch investigator-initiated phase 2 trial. 25 centers are expected to participate in the SEQUEL-Breast. Clinicaltrials.gov identifier: NCT05392608 Intervention: fulvestrant beyond progression combined with alpelisib. Population Patients must be adults with HR+ HER2- ABC with an activating PIK3CA-mutation. Prior treatment with an AI and fulvestrant is mandatory, as well as prior treatment with a CDK4/6i in either line. Patients must have progressed on fulvestrant (+/- CDK4/6i), and fulvestrant must be the most recent line of therapy. Patients with ECOG performance score 0,1 or 2 are eligible, as well as those with controlled (HbA1C &lt; 8.4%) diabetes mellitus type 2. Patients with uncontrolled diabetes, visceral crisis, symptomatic CNS metastases or clinically relevant heart disease are ineligible. Patients with diseases or previous surgery that might affect the bioavailability of alpelisib, those in need to use CYP3A4 inhibitors or BRCP inhibitors, as well as patients with any other conditions that would put them at particular risk when partaking in the study, are also ineligible. Accrual Start: June 2022 Accrual, June 27: 3 patients Target: 105 patients (minimum) to 130 patients (maximum) Estimated accrual time: 2-3 years Statistical considerations For sample size calculation, H1 (median PFS≥6 months) is weighed against H0 (median PFS≤4 months) in a one sample log rank test. α=0.05 β=0.1. 71 events are needed. We estimated that inclusion of 79 patients is required to reach 71 events, given an accrual time of 36 months and a minimum follow-up time of 6 months. To ensure that also PFS ‘on treatment’ has the desired accuracy, we accounted for 25% non-persistance due to toxicity, hence 105 patients. On top of these 105 patients, another 25 patients may be included, if they harbor rare PIK3CA mutations. Further information Corresponding author: sequel@nki.nl BOOG Study Center acts as sponsor for this trial. This trial is funded by Novartis.

Citation Format: Cornelia AM Almekinders, Inge RHM Konings, Vincent van der Noort, Susan M van den Berg, Monique EMM Bos, Vincent O Dezentjé. SEQUence of Endocrine therapy in advanced Luminal Breast cancer (SEQUEL-Breast): A phase 2 study on fulvestrant beyond progression in combination with alpelisib for PIK3CA-mutated, HR+ HER2- advanced breast cancer. [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 OT2-01-08.