| Abstract: |
Background: Alpelisib, a PI3Kα-selective inhibitor and degrader, plus fulvestrant showed efficacy in hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer in SOLAR-1; limited data are available in the post-cyclin-dependent kinase 4/6 inhibitor setting. BYLieve aimed to assess alpelisib plus endocrine therapy in this setting in three cohorts defined by immediate previous treatment; here, we report results from cohort A. Methods: This ongoing, phase 2, multicentre, open-label, non-comparative study enrolled patients with hormone receptor-positive, HER2-negative, advanced breast cancer with tumour PIK3CA mutation, following progression on or after previous therapy, including CDK4/6 inhibitors, from 114 study locations (cancer centres, medical centres, university hospitals, and hospitals) in 18 countries worldwide. Participants aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 2 or less, with no more than two previous anticancer treatments and no more than one previous chemotherapy regimen, were enrolled in three cohorts. In cohort A, patients must have had progression on or after a CDK4/6 inhibitor plus an aromatase inhibitor as the immediate previous treatment. Patients received oral alpelisib 300 mg/day (continuously) plus fulvestrant 500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1. The primary endpoint was the proportion of patients alive without disease progression at 6 months per local assessment using Response Evaluation Criteria in Solid Tumors, version 1.1, in patients with a centrally confirmed PIK3CA mutation. This trial is registered with ClinicalTrials.gov, NCT03056755. Findings: Between Aug 14, 2017, and Jul 29, 2022 (data cutoff), 127 patients with at least 18 months’ follow-up were enrolled into cohort A. 119 patients had a centrally confirmed PIK3CA mutation. At data cutoff, median follow-up was 21·8 months (IQR 10·8–37·6). 64 (53·8%; 95% CI 44·4–63·0) of 119 patients were alive without disease progression at 6 months. The most frequent grade 3 or worse adverse events were hyperglycaemia (37 [29%] of 127 patients), rash (13 [10%]), and rash maculopapular (11 [9%]). Serious adverse events occurred in 37 (29%) of 127 patients. No treatment-related deaths were reported. Interpretation: BYLieve showed activity of alpelisib plus fulvestrant with manageable toxicity in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, after progression on a CDK4/6 inhibitor plus an aromatase inhibitor. Funding: Novartis Pharmaceuticals. © 2024 Elsevier Ltd |
| Keywords: |
adult; cancer chemotherapy; treatment response; aged; middle aged; unclassified drug; gene mutation; major clinical study; overall survival; genetics; mutation; clinical trial; drug tolerability; cancer growth; drug dose reduction; drug safety; drug withdrawal; cancer staging; nuclear magnetic resonance imaging; outcome assessment; follow up; antineoplastic agent; metabolism; progression free survival; computer assisted tomography; multiple cycle treatment; phase 2 clinical trial; protein kinase inhibitor; antineoplastic combined chemotherapy protocols; epidermal growth factor receptor 2; aromatase inhibitor; cohort analysis; continuous infusion; pathology; breast neoplasms; phosphatidylinositol 3 kinase; cancer resistance; cancer hormone therapy; hyperglycemia; rash; protein kinase inhibitors; maculopapular rash; multicenter study; breast tumor; diabetes mellitus; glucose blood level; open study; receptor, erbb-2; receptors, estrogen; receptors, progesterone; glucose; estrogen receptor; progesterone receptor; drug therapy; thiazoles; good clinical practice; cyclin dependent kinase 4; fulvestrant; cyclin-dependent kinase 4; cyclin dependent kinase 6; erbb2 protein, human; cyclin-dependent kinase 6; thiazole derivative; overall response rate; hemoglobin a1c; response evaluation criteria in solid tumors; advanced breast cancer; cdk4 protein, human; pik3ca protein, human; phosphatidylinositol 4,5 bisphosphate 3 kinase; humans; human; female; hormone receptor positive breast cancer; alpelisib; electronic health record; ecog performance status; class i phosphatidylinositol 3-kinases; hormone receptor-positive, her2-negative breast cancer; date of death; cdk6 protein, human; cyclin dependent kinase 4/6 inhibitor; phosphatidylinositol 3 kinase catalytic subunit alpha; fasting blood glucose level
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