You are here
Non-invasive detection of crizotinib resistance in ALK-rearranged lung adenocarcinoma directs treatment with next-generation ALK inhibitors.
Background: Somatic mutations (SNVs) in ALK are a common mechanism of resistance to crizotinib, and may respond to next-generation ALK inhibitors. Historically, identification of these ALK SNVs required repeat tissue biopsies because they are absent in pre-treated tissue samples. Circulating tumor DNA (ctDNA) next-generation sequencing (NGS) may provide a non-invasive way to identify these SNVs. Methods: Guardant360 is a ctDNA NGS test that sequences complete exons in the ALK gene and the intronic breakpoints needed to identify ALK fusions. It includes other guideline-recommended somatic genomic targets: SNVs in 70 genes, select fusions, indels and amplifications. Results: In the first 10,000 advanced-solid-cancer patients (pts) tested by Guardant360, ALK SNVs and fusions were detected in 6% of pts. EML4 was the most common ALK fusion partner (81%); STRN (9%), KIF5B (5%), VCL (2.5%), KCL (2.5%). Among 24 pts with ALK-fusion-driven lung adenocarcinoma (LUAD), mutant allele fraction (MAF) of ALK fusion ranged from 0.06% to 12.5%. We found several co-occurring SNVs, of which 10% were known resistance SNVs in ALK (detected in 4 pts): F1174C/V (3), G1202R (2), L1198F (1), I1171T (1), and L1196M (1). We also found co-occurring SNVs in other genes that are absent in treatment-naïve pts, suggesting possible novel crizotinib-resistance mechanisms. ALK L1198F, a rare alteration shown to re-sensitize to crizotinib, was detected in a patient who expired before re-treatment. In a case with serial draws, pre-treated ALK fusion MAF was 0.91%; at progression, ALK fusion MAF was 0.4% and F1174C was detected at 1.0%. Tissue results from both time points were concordant with ctDNA. The patient started alectinib in January 2016, and response scans are pending. Conclusions: We comprehensively cataloged mutations that likely arose at progression in ALK-fusion-positive LUAD pts treated with crizotinib, including five well-described crizotinib-resistance alterations. These results add to the growing body of literature demonstrating that comprehensive ctDNA assays provide a non-invasive means of detecting known and novel resistance mechanisms that inform treatment decisions.