Sex and common germline variants impact the toxicity profile and pharmacokinetics of alectinib: a nation-wide cohort study in patients with ALK-positive non-small cell lung cancer

Abstract

IntroductionAlectinib, a small-molecule kinase inhibitor, is used as first-line treatment for anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC). Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity. MethodsIn this multicenter observational cohort study in patients with advanced ALK+ NSCLC receiving alectinib treatment, we investigated the association between toxicity, pharmacokinetics, and key genetic variants in ABCB1, CYP3A4, PPAR-α, POR, and CYP3A5. Data on demographics, adverse events, and alectinib trough levels were collected from five hospitals. ResultsAmong 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; p=0.001) and also had +35% higher alectinib trough levels (p<0.001). Homozygous carriers of the PPAR-α 209G>A variant exhibited a higher incidence of grade ≥ 3 toxicity (38%) compared to patients who carried at least one wild-type allele (11%) (p=0.004). This remained significant after Bonferroni correction. Patients who experienced severe toxicity had +18.5% (95%CI: 2.9–36.6%; p=0.019) higher trough levels. ConclusionsFemale patients encounter more severe toxicity due to higher alectinib exposure, which warrants further exploration. PPAR-α 209G>A significantly increased relevant alectinib-induced toxicity, most likely due to an increase in alectinib exposure. Pre-treatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.