Impact of duration of prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy on alpelisib (ALP) benefit in patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–), PIK3CA-mutated advanced breast cancer (ABC) from BYLieve.
Authors: Chia Stephen K. L. , Ruiz-Borrego Manuel , Drullinsky Pamela , Juric Dejan , Bachelot Thomas , Rugo Hope S. , Ciruelos Eva M. , Lerebours Florence , Prat Aleix , Akdere Murat , Arce Christina , Gu Ennan , Turner Nicholas C. 
Published: June 2021

1060 Background: Mutations in PIK3CA (encoding PI3Kα) are present in ̃40% of HR+, HER2– ABC tumors and are associated with relative endocrine resistance and poor prognosis. ALP inhibits and degrades PI3Kα. Primary analyses of Cohorts A and B from the phase 2 BYLieve study demonstrated that ALP + endocrine therapy (ET; fulvestrant [FUL] or letrozole [LET]) is effective and safe in pts with HR+, HER2– PIK3CA-mutated ABC with prior CDK4/6i therapy. Here, we evaluate if duration of prior CDK4/6i-based therapy impacts benefit of ALP + ET in these 2 cohorts. Methods: Cohorts A and B of BYLieve included pre/postmenopausal women who received CDK4/6i + AI or FUL, respectively, as immediate prior therapy. Cohort A received ALP 300 mg PO QD + FUL 500 mg IM Q28D + C1D15; Cohort B received ALP 300 mg PO QD + LET 2.5 mg PO QD. Within each cohort, pts were divided into 2 subgroups per duration of prior CDK4/6i therapy (“high”/”low,” above/below median duration of therapy) and the association of progression-free survival (PFS) with this covariate was analyzed using stratified log-rank test and Cox PH model. This analysis included pts for whom duration of prior CDK4/6i therapy was known, and efficacy was assessed in pts with centrally confirmed PIK3CA mutation in tumor tissue. Results: Of the 126 pts in Cohort A with duration of prior CDK4/6i available, 120 had centrally confirmed PIK3CA-mutated disease; 60 were exposed to CDK4/6i for > 380 days (high) and 60 for < 380 days (low), with similar demographics/disease characteristics between subgroups. There was no significant difference in PFS between the high vs low subgroups (HR 1.03; 95% CI, 0.64-1.64; P= 0.927; median 8.0 vs 7.0 mo). Grade ≥3 adverse events (AEs) were experienced by 66.9% (n = 85) of all pts in Cohort A and 66.7% (n = 42)/68.3% (n = 43) in the high/low subgroups, respectively. Of the 123 pts in Cohort B with duration of prior CDK4/6i available, 113 had centrally confirmed PIK3CA-mutated disease; 57 were exposed to CDK4/6i for > 305 days (high) and 56 for < 305 days (low), with similar demographics/disease characteristics between subgroups. There was no significant difference in PFS between high vs low subgroups (HR 1.20; 95% CI, 0.78-1.84; P= 0.400; median 5.4 vs 5.9 mo). Grade ≥3 AEs were experienced by 69.8% (n = 88) of all pts in Cohort B and 71.0% (n = 44)/68.9% (n = 42) in the high/low subgroups, respectively. Conclusions: This analysis demonstrates that the benefit and safety profiles of ALP + ET are similar in pts with HR+, HER2– PIK3CA-mutated ABC who achieved relatively shorter duration of disease control with prior CDK4/6i vs those with longer duration of disease control, and suggests that ALP overcomes acquired resistance to CDK4/6i in these pts. Clinical trial information: NCT03056755 .