Pharmacokinetics and Pharmacogenomics of Ribociclib in Race-Based Cohorts (LEANORA)

Underrepresented populations' participation in clinical trials remains limited, and the potential impact of genomic variants on drug metabolism remains elusive. This study aimed to assess the pharmacokinetics (PK) and pharmacogenomics (PGx) of ribociclib in self-identified Black women with hormone receptor positive (HR+)/human epidermal growth factor receptor 2-negative (HER2) advanced breast cancer. LEANORA (NCT04657679) was a prospective, observational, multicenter cohort study involving 14 Black women. PK and PGx were evaluated using tandem mass spectrometry and PharmacoScan microarray. CYP3A5*3, CYP3A5*6, and CYP3A5*7 variants were genotyped and CYP3A5 phenotypes were constructed from these data. We observed 7 poor metabolizers (PM), 6 intermediate metabolizers (IM), and one normal metabolizer (NM). The area under the curve of plasma concentration versus time curve (AUC) of ribociclib did not differ between PMs (39,230 hr*ng/mL) and IM/NMs (43,546 hr*ng/mL; P=0.38). The incidence of adverse events (AEs) was also similar. We found no association between CYP3A5 genotype and ribociclib exposure. Continued efforts are needed to include diverse populations in clinical trials to ensure equitable treatment outcomes. ]]>
Key Inclusion Criteria:Histologically or cytologically proven diagnosis of HR+/HER2- breast cancer with evidence of metastatic or locally advanced disease, not amenable to curative treatment by surgery or radiotherapy Women age ≥ 18 years Self identify as Black, African American, or non-Hispanic White Signed informed consent form Adequate hepatic, hematologic, and renal function as defined below in the body of the protocol Normal baseline QTc (<450 ms) Asymptomatic and treated brain metastases are permitted Key Exclusion Criteria:Patient on active treatment with CDK4/6 inhibitors Any other prior neo-/adjuvant anti-cancer therapy must be stopped at least 5 half-lives or 7 days, whichever is longer, before the date of ribociclib initiation. Patient is concurrently using other anti-cancer therapy (including systemic therapy or radiation) Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drug Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, as defined below in the body of the protocol Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1: strong inducers or inhibitors of CYP3A4/5 -including herbal medications-, chronic dosing of corticosteroids and medications that prolong the QTc interval Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's judgment. Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to ribociclib initiation and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patients with central nervous system (CNS) involvement unless they meet specific stability criteria Liver or allogeneic bone marrow transplant ]]>
11/2020 - IRB approved at Georgetown05/2021 - First participant started the study09/2023 – Study closed to accrual10/2023 - Last participant completed follow up06/2024 – Trial results shared at American Society of Clinical Oncology Annual Meeting]]>