Circulating tumor (ct) DNA analysis to monitor response and resistance to ensartinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC)

Abstract

Background: Pts with anaplastic lymphoma kinase (ALK)-rearranged NSCLC have benefited from ALK tyrosine kinase inhibitors (TKIs); however, most pts eventually acquire resistance. Identification of resistance mutations informs subsequent therapy but has typically required invasive repeat biopsies. Here, we assessed the utility of ctDNA analysis and the ability to monitor response longitudinally and detect resistance mutations during therapy with ensartinib, a potent second-generation ALK TKI. Methods: Blood samples were collected frompts at the start of and during treatment with ensartinib in the eXalt2 trial (NCT01625234).DNAfromplasma samples was hybridized to a panel of probes using the Resolution Biosciences targeted hybrid-capture system. Archival tumor tissue froma subset of pts was analyzed for comparison. Efficacy assessments included response rate (RR) and median progression-free survival (mPFS). Results: As of April 1, 2018, baseline plasma samples from 76 pts with ALK+NSCLC were analyzed. Among these pts, 22% were ALK-TKI naive, 49% received prior crizotinib, and 29% received crizotinib and ≥ 1 second-generation ALK TKI. There was a high concordance rate (91%) between plasma and tissue analysis of ALK fusions. Among 69 efficacy-evaluable pts, the EML4-ALK variant 1 (V1) and V3 were detected at baseline in 17 pts (24%) and 7 pts (10%), respectively, and 12 pts (17%) had non-V1 or non-V3 fusions. Both RR and mPFS with ensartinib were more favorable in pts with V1 vs V3 fusions (9/17 [53%] vs 1/7 [14%] and 8.2 vs 1.9 months, respectively). The pooled RR of pts with other EML4-ALK variants was 7/12 (58%). Longitudinal plasma samples were analyzed in 11 pts. In general, reduced allelic frequencies (AFs) of ALK fusions were detected during clinical response, followed by increased AFs and/or the emergence of new mutations in ALK at or before disease progression. Conclusions: Overall, the data suggest that plasma ctDNA analysis can potentially identify a subgroup of pts with ALK+ NSCLC who may derive clinical benefit fromensartinib. Furthermore, serial assessments of ctDNA during therapy offer a convenient method to track tumor response and identify the mutational landscape of acquired resistance.