Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer

G D Marijn Veerman; Rene J Boosman; Merel Jebbink; Esther Oomen-de Hoop; Anthonie J van der Wekken; Idris Bahce; Lizza E L Hendriks; Sander Croes; Christi M J Steendam; Evert de Jonge; Stijn L W Koolen; Neeltje Steeghs; Ron H N van Schaik; Egbert F Smit; Anne-Marie C Dingemans; Alwin D R Huitema; Ron H J Mathijssen

doi:10.1016/j.eclinm.2023.101955

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer

G D Marijn Veerman^*
, Rene J Boosman
, Merel Jebbink
, Esther Oomen-de Hoop
, Anthonie J van der Wekken
, Idris Bahce
, Lizza E L Hendriks
, Sander Croes
, Christi M J Steendam
, Evert de Jonge
, Stijn L W Koolen
, Neeltje Steeghs
, Ron H N van Schaik
, Egbert F Smit
, Anne-Marie C Dingemans
, Alwin D R Huitema
, Ron H J Mathijssen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated ( EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients.

METHODS: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics.

FINDINGS: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010).

INTERPRETATION: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment.

FUNDING: No funding was received for this trial.

Original language	English
Article number	101955
Number of pages	11
Journal	EClinicalMedicine
Volume	59
DOIs	https://doi.org/10.1016/j.eclinm.2023.101955
Publication status	Published - May 2023

Keywords

Brain metastases
Drug transporters
Non-small cell lung cancer
Osimertinib
Pharmacokinetics
Single-nucleotide polymorphism

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Veerman, G. D. M., Boosman, R. J., Jebbink, M., Oomen-de Hoop, E., van der Wekken, A. J., Bahce, I., Hendriks, L. E. L., Croes, S., Steendam, C. M. J., de Jonge, E., Koolen, S. L. W., Steeghs, N., van Schaik, R. H. N., Smit, E. F., Dingemans, A.-M. C., Huitema, A. D. R., & Mathijssen, R. H. J. (2023). Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer. EClinicalMedicine, 59, Article 101955. https://doi.org/10.1016/j.eclinm.2023.101955

@article{94f4128c9e4846359a01137636846796,

title = "Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer",

abstract = "BACKGROUND: Central nervous system (CNS) metastases are present in approximately 40\% of patients with metastatic epidermal growth factor receptor-mutated ( EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. METHODS: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. FINDINGS: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35\% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95\% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0\% versus 16.5\%; p = 0.010). INTERPRETATION: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. FUNDING: No funding was received for this trial.",

keywords = "Brain metastases, Drug transporters, Non-small cell lung cancer, Osimertinib, Pharmacokinetics, Single-nucleotide polymorphism",

author = "Veerman, \{G D Marijn\} and Boosman, \{Rene J\} and Merel Jebbink and \{Oomen-de Hoop\}, Esther and \{van der Wekken\}, \{Anthonie J\} and Idris Bahce and Hendriks, \{Lizza E L\} and Sander Croes and Steendam, \{Christi M J\} and \{de Jonge\}, Evert and Koolen, \{Stijn L W\} and Neeltje Steeghs and \{van Schaik\}, \{Ron H N\} and Smit, \{Egbert F\} and Dingemans, \{Anne-Marie C\} and Huitema, \{Alwin D R\} and Mathijssen, \{Ron H J\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = may,

doi = "10.1016/j.eclinm.2023.101955",

language = "English",

volume = "59",

journal = "EClinicalMedicine",

issn = "2589-5370",

publisher = "Elsevier",

}

Veerman, GDM, Boosman, RJ, Jebbink, M, Oomen-de Hoop, E, van der Wekken, AJ, Bahce, I, Hendriks, LEL, Croes, S, Steendam, CMJ, de Jonge, E, Koolen, SLW, Steeghs, N, van Schaik, RHN, Smit, EF, Dingemans, A-MC, Huitema, ADR & Mathijssen, RHJ 2023, 'Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer', EClinicalMedicine, vol. 59, 101955. https://doi.org/10.1016/j.eclinm.2023.101955

TY - JOUR

T1 - Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer

AU - Veerman, G D Marijn

AU - Boosman, Rene J

AU - Jebbink, Merel

AU - Oomen-de Hoop, Esther

AU - van der Wekken, Anthonie J

AU - Bahce, Idris

AU - Hendriks, Lizza E L

AU - Croes, Sander

AU - Steendam, Christi M J

AU - de Jonge, Evert

AU - Koolen, Stijn L W

AU - Steeghs, Neeltje

AU - van Schaik, Ron H N

AU - Smit, Egbert F

AU - Dingemans, Anne-Marie C

AU - Huitema, Alwin D R

AU - Mathijssen, Ron H J

PY - 2023/5

Y1 - 2023/5

N2 - BACKGROUND: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated ( EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. METHODS: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. FINDINGS: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). INTERPRETATION: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. FUNDING: No funding was received for this trial.

AB - BACKGROUND: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated ( EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+ NSCLC patients. METHODS: Patients who started treatment with osimertinib for EGFRm+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. FINDINGS: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010). INTERPRETATION: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. FUNDING: No funding was received for this trial.

KW - Brain metastases

KW - Drug transporters

KW - Non-small cell lung cancer

KW - Osimertinib

KW - Pharmacokinetics

KW - Single-nucleotide polymorphism

UR - https://www.scopus.com/pages/publications/85152142912

U2 - 10.1016/j.eclinm.2023.101955

DO - 10.1016/j.eclinm.2023.101955

M3 - Article

C2 - 37125403

SN - 2589-5370

VL - 59

JO - EClinicalMedicine

JF - EClinicalMedicine

M1 - 101955

ER -

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer

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