TY - JOUR
T1 - Sex and Common Germline Variants Affect the Toxicity Profile and Pharmacokinetics of Alectinib
T2 - A Nationwide Cohort Study in Patients With ALK-Positive NSCLC
AU - Heersche, Niels
AU - Lanser, Daan A.C.
AU - Muntinghe-Wagenaar, M. Benthe
AU - Mohmaed Ali, Ma Ida
AU - Ulas, Ezgi B.
AU - Trooster, Tessa M.A.
AU - de Jonge, Evert
AU - Oomen-de Hoop, Esther
AU - Paats, Marthe S.
AU - Bahce, Idris
AU - Croes, Sander
AU - Hendriks, Lizza E.L.
AU - van der Wekken, Anthonie J.
AU - Dingemans, Anne-Marie C.
AU - Huitema, Alwin D.R.
AU - van Schaik, Ron H.N.
AU - Mathijssen, Ron H.J.
AU - Veerman, G.D. Marijn
N1 - Publisher Copyright:
© 2024 International Association for the Study of Lung Cancer
PY - 2024/11/29
Y1 - 2024/11/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85212638662&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2024.11.025
DO - 10.1016/j.jtho.2024.11.025
M3 - Article
C2 - 39617342
SN - 1556-0864
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
ER -