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. 2023 Apr 13:59:101955.
doi: 10.1016/j.eclinm.2023.101955. eCollection 2023 May.

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  1   2 , Rene J Boosman  3 , Merel Jebbink  4 , Esther Oomen-de Hoop  1 , Anthonie J van der Wekken  5 , Idris Bahce  6 , Lizza E L Hendriks  7 , Sander Croes  7   8 , Christi M J Steendam  2   9 , Evert de Jonge  10 , Stijn L W Koolen  1   11 , Neeltje Steeghs  12 , Ron H N van Schaik  10 , Egbert F Smit  4   13 , Anne-Marie C Dingemans  2 , Alwin D R Huitema  3   14   15 , Ron H J Mathijssen  1
Affiliations

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 et al. EClinicalMedicine. .

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.

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Conflict of interest statement

G.D.M.V. reports grants from Eli Lilly; outside the submitted work. A.C.D. reports grants from Boehringer-Ingelheim; outside the submitted work (paid to institution). R.H.J.M. reports an unrestricted grant from Boehringer-Ingelheim (paid to institution) and grants from Astellas, Bayer, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Sanofi, and Servier; outside the submitted work (paid to institution). L.E.L.H. has no relationship to disclose in relation to this manuscript. Outside of the current manuscript: research funding Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda (all institution, Beigene under negotiation); advisory board: BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer Ingelheim, Amgen, Janssen (all institution, Roche one time self); speaker: MSD, Lilly (institution); travel/conference reimbursement: Roche Genentech (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Benecke, Medtalks, VJOncology (self), high5oncology (institution); interview sessions funded by Roche Genentech, Bayer, Lilly (institution); local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD, Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Pharmaceuticals, Mirati, Abbvie, Gilead. A.J.v.d.W. reports grants and advisory board from AstraZeneca, grants and advisory board from Boehringer-Ingelheim, advisory board from Janssen, advisory board from Novartis, grants and advisory board from Pfizer, grants and advisory board from Roche, grants and advisory board from Takeda, all outside the submitted work; all payment to the UMCG. N.S. provided consultation or attended advisory boards for Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma, Luszana. N. Steeghs received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, Incyte, InteRNA, Janssen, Kinnate Biopharma, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute. E.F.S. has no relationship to disclose in relation to the manuscript. Outside the submitted work (all institutional): research grants from Astra Zeneca, MSD, BMS, Roche Genentech, advisory boards Astra Zeneca, BMS, Boehringer Ingelheim, Bayer, DSI, MSD, Takeda, Roche, Merck, Novartis, Amgen, Janssen. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Possible effects of single nucleotide polymorphisms in ABCB1 and ABCG2 on the osimertinib concentration in the central nervous system. The blue spheres represent osimertinib. The red arrows in the left circle show the possible decreased (--|) or normal (-->) function of the osimertinib transporting enzymes ABCB1 and ABCG2, which could lead to altered osimertinib concentrations in the central nervous system (right circle).
Fig. 2
Fig. 2
Central nervous systemefficacy of osimertinib in patients without known brain metastases. Cumulative incidence of central nervous system metastases in patients which are divided based on the combined genotype ABCB1 3435C>T - ABCG2 34G>A. The blue line represents patients with ABCB1 3435CC and/or ABCG2 34GA/AA (combined genotype +), the red line represents patients with ABCB1 3435CT/TT and ABCG2 34GG (combined genotype -). The 12-months incidence for the combined genotype + cohort was 3.3%, compared to 9.5% in the combined genotype - cohort.
See this image and copyright information in PMC

References

    1. Peters S., Bexelius C., Munk V., Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev. 2016;45:139–162. - PubMed
    1. O'Kane G.M., Su J., Tse B.C., et al. The impact of brain metastases and associated neurocognitive aspects on health utility scores in EGFR mutated and ALK rearranged NSCLC: a real world evidence analysis. Oncologist. 2019;24(7):e501–e509. - PMC - PubMed
    1. Hendriks L.E., Smit E.F., Vosse B.A., et al. EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases? Lung Cancer. 2014;84(1):86–91. - PubMed
    1. Reungwetwattana T., Nakagawa K., Cho B.C., et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018;36(33):3290–3297. - PubMed
    1. Heon S., Yeap B.Y., Britt G.J., et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010;16(23):5873–5882. - PMC - PubMed