27P Influence of single nucleotide polymorphisms (SNPs) in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer

Abstract

Brain metastases (BM) are present in >30% of patients with metastatic epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The tyrosine kinase inhibitor (TKI) osimertinib (OSI) and its active metabolites are substrates of ABCB1 and ABCG2 and metabolized by CYP3A4. In this study, we investigated the relationships between the SNPs ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4*22 and the progression and new occurrence of BM in EGFRm+ NSCLC patients treated with OSI. This observational cohort study was performed in six Dutch hospitals from Nov 2014 until Oct 2021. For patients with baseline BM, the primary study endpoint was cerebral progression-free survival (CNS-PFS), c.q. time from OSI start to cerebral disease progression. For patients with no or unknown baseline BM, the primary endpoint was cerebral disease-free survival (CNS-DFS), c.q. time from OSI start to the occurrence of new BM. OSI stop for other causes was considered a competing risk. The relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks Cox regression. Variables with p<0.20 in the univariable analysis were included in a multivariable analysis with backward selection. From 571 included patients, 201 had baseline BM. The table shows the statistical significant associations with CNS-PFS and CNS-DFS.Table: 27PCNS-PFSHR95% CIp-valuePrimary EGFR mutation (L858R vs exon 19 deletion)2.061.34-3.160.001Presence of T790M at baseline0.600.40-0.890.011Any prior treatment other than an EGFR-TKI1.551.02-2.350.042CNS-DFSHR95% CIp-valuePrimary EGFR mutation (L858R vs exon 19 deletion)3.011.44-6.310.004Haplotype ABCB1 3435C>T wild type orABCG2 34G>A variant(present in 35%)0.270.10-0.710.007Performance status (grade >1 vs 0-1)2.601.14-5.940.023Age0.970.94-1.000.040Single ABCG2 421C>A variant(present in 21%)2.171.03-4.580.042 Open table in a new tab In EGFRm+ NSCLC patients treated with OSI, the SNPs ABCG2 421C>A, ABCB1 3435C>T and ABCG2 34G>A can impact CNS-DFS, and not CNS-PFS. Genotyping these patients may guide monitoring strategies aimed at early detection of brain metastases.