Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): First interim BYLieve study results.

Abstract

1040 Background: In the phase 3 SOLAR-1 study, ALP + fulvestrant (FUL) improved PFS in pts with HR+, HER2– ABC with a PIK3CA mutation overall and in the small group of pts with prior cyclin-dependent kinase 4/6 inhibitor (CDKi) use. We report interim data from the BYLieve study in pts with PIK3CA-mutated ABC and prior CDKi exposure. Methods: BYLieve is an ongoing, phase 2, open-label, non-comparative study of ALP 300 mg QD + ET in men and women with PIK3CA-mutated HR+, HER2– ABC whose disease progressed on/after CDKi + ET. Pts are permitted ≤2 prior anticancer therapies and ≤1 prior chemotherapy regimen for ABC. Pts with prior CDKi and AI ( FUL cohort) receive ALP and FUL 500 mg Q28d + C1d15 IM. Pts with prior CDKi and FUL ( LET cohort) receive ALP and letrozole (LET) 2.5 mg PO QD. In this preplanned interim analysis, conducted after ≥20 pts in FUL had ≥6 mo of follow-up, descriptive data are reported for preliminary safety and efficacy in the FUL and LET cohorts. Results: At data cutoff, 64 and 36 pts were enrolled in the FUL and LET cohorts, respectively; 39 pts ( FUL, n = 21; LET, n = 18) have safety and efficacy data with ≥6 mo follow-up and are reported here. Data on 100 pts enrolled at the time of data cutoff will be presented. In the 39 pts with ≥6 mo follow-up, median ALP duration was 5.3 and 5.5 mo in FUL and LET, respectively; median duration of FUL and LET was 5.6 mo. Median relative ALP dose intensity was 93% ( FUL) and 87% ( LET). Most common grade ≥3 adverse events were hyperglycemia (38.1% ( FUL) and 27.8% ( LET)) and rash (4.8% ( FUL) and 27.8% ( LET)). Only 2 pts (5%; 1 pt per cohort) discontinued due to an AE. In pts with centrally confirmed PIK3CA mutation (n = 20 ( FUL); n = 17 ( LET)), ORR was 20% ( FUL) and 18% ( LET), CBR was 40% ( FUL) and 35% ( LET). Efficacy and safety data for the 100 enrolled pts will be presented at the meeting. Conclusions: Pending further readout of the ongoing BYLieve trial, safety and tolerability of ALP and hormonal therapy in pts with prior CDKi are consistent with those of SOLAR-1; discontinuation due to toxicity was rare. NCT03056755. Clinical trial information: NCT02437318.

Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications

“…As for Alp, small prospective trials published before the SOLAR-1 study evaluated the Let/Alp or Fulv/Alp combinations in patients with HR+ HER2− mBC progressing after previous ET. Consistent with SOLAR-1 results, these studies reported an incidence of G3/G4 hyperglycemia and rash in the 10-38.1% and 8-27.8% ranges, respectively, with longer mPFS in patients with PIK3CA-mutated neoplasms (Table 5) [30,35,51].…”

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2–, PIK3CA-Mutated Breast Cancer

“…The safety profile in this cohort was consistent with the known safety profile of alpelisib [1,18]; the most commonly experienced all-grade adverse events (AEs) were diarrhea (59.8%), hyperglycemia (58.3%), nausea (45.7%), fatigue (29.1%), decreased appetite (28.3%), rash (28.3%), and stomatitis (26.8%), with no new safety signals observed. Overall AE-related discontinuations in this cohort were 20.5% [16,17].…”

“…The Phase II, open-label, multicenter, noncomparative, 3-cohort BYLieve trial (NCT03056755) is the first study designed to assess the safety and efficacy of alpelisib combined with ET in patients with PIK3CA-mutated HR+, HER2-ABC and who progressed on/after prior CDK4/6i-based therapy. BYLieve confirmed efficacy and safety of alpelisib combined with fulvestrant in patients with confirmed PIK3CAmutated disease who received a CDK4/6i with AI as immediate prior therapy (Cohort A) [16,17]. The primary endpoint of the trial was met, as 50.4% (95% CI, 41.2%-59.6%) of patients in Cohort A were alive without disease progression at 6 months, with the lower bound of the CI being greater than the prespecified threshold of 30%.…”

CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

“…ByLieve, a phase 2 multicenter, open-label, two-cohort, noncomparative study of alpelisib + fulvestrant or letrozole, including patients who progressed on or after CDKi + AI or fulvestrant (metastatic setting) or with ≤1 line of previous chemotherapy (adjuvant or advanced setting) with the primary endpoint of patients alive and without disease progression at 6 months, will be determinant to this question. Although at the first interim analysis, the fulvestrant cohort seems to be better than the letrozolo cohort, the data are still immature [ 63 ].…”