Introduction: Alectinib, a small-molecule kinase inhibitor, is used as first-line treatment for ALK-positive (ALK+) NSCLC. Albeit generally well-tolerated, a considerable subset of patients requires dose adjustments due to drug-related toxicity. Single-nucleotide polymorphisms in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity.
Methods: In 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.
Results: Among 215 patients, 47% experienced severe toxicity. Women experienced more severe toxicity (female versus male: 56% versus 34%; p = 0.001) and had +35% higher alectinib trough levels (p < 0.001). Homozygous carriers of the PPAR-α 209G>A variant exhibited a higher incidence of grade greater than or equal to 3 toxicity (38%) compared with 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% confidence interval: 2.9%-36.6%; p = 0.019) higher trough levels.
Conclusions: Female 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. Pretreatment testing for genetic variants with a subsequent dose reduction could provide a viable approach to reduce alectinib-related toxicity.
Keywords: Alectinib; NSCLC; Pharmacokinetics; Single-nucleotide polymorphisms; Toxicity.
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