Abstract PD15-01: Impact of ESR1 mutations on endocrine therapy (ET) plus alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC) who progressed on or after prior cyclin-dependent kinase inhibitor (CDK4/6i) therapy in the BYLieve trial
Authors: Turner Nick , Rugo Hope S , Ciruelos Eva M , Ruiz-Borrego Manuel , Drullinsky Pamela , Lerebours Florence , Prat Aleix , Bachelot Thomas , Chia Stephen , Balbin Alejandro , Joshi Mukta , Roux Estelle , Arce Christina H , Akdere Murat , Juric Dejan 
Published: March 2022

Abstract
Introduction: Endocrine-based therapy is the standard of care for patients (pts) with HR+ ABC. Acquired ESR1 mutations (mut) have been reported in up to 56% of pts with HR+ ABC progressing after prior treatment with ET, and aromatase inhibitors (AIs) in particular. Alpelisib (ALP) is an α-selective PI3K inhibitor and degrader approved in combination with fulvestrant (FUL) for the treatment of HR+, HER2-, PIK3CA-mut ABC. The primary analysis of Cohorts A and B of the Phase II BYLieve trial demonstrated the safety and efficacy of ALP + ET in the post-CDK4/6i setting. We assessed the association between progression-free survival (PFS) and baseline ESR1 mut among pts in Cohorts A and B of the BYLieve trial. Methods: Cohorts A and B of the BYLieve trial included pre-/postmenopausal women with HR+, HER2-, PIK3CA-mut ABC who received CDK4/6i + AI (Cohort A) or CDK4/6i + FUL (Cohort B) as immediate prior therapy. Pts in Cohort B may have also received prior AI therapy. Pts received ALP 300 mg PO QD + FUL 500 mg IM Q28D and C1D15 (Cohort A) or ALP 300 mg PO QD + LET 2.5 mg PO QD (Cohort B). ESR1 mut was analyzed as an exploratory endpoint, using an error-corrected sequencing ctDNA assay (Novartis PanCancer gene-panel), in baseline plasma samples from pts with centrally confirmed PIK3CA mut in tumor tissue from Cohorts A and B. PFS by mut status was estimated using the Kaplan-Meier method. P values provided are nominal. No multiplicity adjustments were made, therefore, statistical interpretation should be made with caution. Results: 127 pts with ≥6 mo follow-up (median follow-up: 11.7 mo) were enrolled in Cohort A as of the 17 December 2019 data cut-off and 126 pts with ≥6 mo follow-up (median follow-up: 15.0 mo) were enrolled in Cohort B as of the 14 August 2020 data cut-off. 103 (81.7%) pts in Cohort B progressed on prior AI therapy (adjuvant/metastatic setting). 102 pts from Cohort A and 97 pts from Cohort B had available plasma samples and were included in this analysis. Similar outcomes were observed in this analysis and in the overall population (Table 1). At baseline, 26% (27/102) of pts in Cohort A and 26% (25/97) of pts in Cohort B had ESR1 mut detected. In Cohort A (ALP + FUL), a numerically lower PFS was observed in pts with ESR1-mut disease, but the wide confidence interval (CI) suggests no difference in risk of progression between those with and without ESR1 mut. In Cohort B (ALP + LET), pts with ESR1-mut disease had a shorter PFS compared with those without ESR1-mut disease. A possible limitation is that baseline characteristics of these subgroups may not be balanced.
Conclusion: Similar proportion of pts had ESR1-mut disease at baseline in both cohorts. All pts in Cohort A progressed on prior CDK4/6i + AI and most pts enrolled in Cohort B also progressed on prior AI therapy. This analysis suggests that pts with ESR1 mut tend to have lower PFS than those without a mut, and that ALP + LET might be less effective in pts with ESR1 mut. This adds to prior data that ESR1 mut reduce the efficacy of AI-based combination therapy. In pts with ESR1 mut detected after prior CDK4/6i therapy, ALP + FUL (the approved combination for PIK3CA-mut ABC) warrants consideration as an alternative treatment option. Studies of ALP in combination with new oral, selective estrogen-receptor degraders are also ongoing.
Table 1.Median PFS in BYLieve Cohorts A and B.Cohort A (ALP + FUL)Cohort B (ALP + LET)Overall (mFASa), N1,2121115mPFS, months (95% CI)7.3 (5.6-8.3)5.7 (4.5, 7.2)Patients with available plasma samples for ESR1-mutation testing,b N10297mPFS, months (95% CI)7.37 (5.60-8.67)5.70 (3.77-7.33)With ESR1 mutation (n=27)With ESR1 mutation (n=25) Without ESR1 mutation (n=72)mPFS, months (95% CI)5.55 (3.75-8.54)8.28 (5.45-9.46)4.57 (3.06-5.65)7.03 (4.50-8.31)Hazard ratio (95% CI)0.76 (0.44-1.33)0.55 (0.32-0.92)P value (nominal)0.30.02ALP, alpelisib; FUL, fulvestrant; LET, letrozole; mFAS, modified full analysis set; mPFS, median progression-free survival. . aPatients who received at least 1 dose of study treatment and had centrally confirmed PIK3CA mutation by a Novartis-designated laboratory were included in the mFAS. bOnly includes patients with centrally confirmed PIK3CA mutation in tumor tissue.1. Rugo HS, et al. Lancet Oncol. 2021;22(4):489-498; 2. Rugo HS, et al. SABCS 2020. Poster PD2-07.
Citation Format: Nick Turner, Hope S Rugo, Eva M Ciruelos, Manuel Ruiz-Borrego, Pamela Drullinsky, Florence Lerebours, Aleix Prat, Thomas Bachelot, Stephen Chia, Alejandro Balbin, Mukta Joshi, Estelle Roux, Christina H Arce, Murat Akdere, Dejan Juric. Impact of ESR1 mutations on endocrine therapy (ET) plus alpelisib benefit in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced breast cancer (ABC) who progressed on or after prior cyclin-dependent kinase inhibitor (CDK4/6i) therapy in the BYLieve trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-01.