Impact of EML4-ALK variants and co-occurring TP53 mutations on duration of first-line ALK tyrosine kinase inhibitor treatment and overall survival in ALK fusion–positive NSCLC: Real-world outcomes from the GuardantINFORM database

Abstract

Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Factors such as variant allele frequencies (VAF), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting. Adults with advanced/metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated. 307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n=280), brigatinib (n=15), lorlatinib (n=9), or ceritinib (n=3); 150 patients (49%) had ALK-fusion VAF ≥1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF <1% versus ≥1% had median TTD of 32.2 (95% CI: 20.7-NE) versus 14.7 months (10.4-19.9; HR: 1.57 [95% CI: 1.09-2.26]; P=0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-not estimable [NE]) in patients with versus without TP53mt detected (HR: 1.53 [1.07-2.19]; P=0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR: 1.29 [0.83-2.01]; P=0.2641). Patients with TP53mt and v3 had median TTD of 7.4 months (95% CI: 4.2-31.1). High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.