Circulating tumor (ct) DNA analysis to monitor response and resistance to ensartinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) (2019)

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 from pts at the start of and during treatment with ensartinib in the eXalt2 trial (NCT01625234). DNA from plasma samples was hybridized to a panel of probes using the Resolution Biosciences targeted hybrid-capture system. Archival tumor tissue from a 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 from ensartinib. Furthermore, serial assessments of ctDNA during therapy offer a convenient method to track tumor response and identify the mutational landscape of acquired resistance. Clinical trial identification: NCT01625234. Editorial acknowledgement: Writing and editorial support was provided by Chrysalis Medical Communications funded by Xcovery Holding Company, LLC. Legal entity responsible for the study: Xcovery Holding Company, LLC. Funding: Xcovery Holding Company, LLC. Disclosure: L. Horn: Consultant/Advisory board member: AbbVie, AstraZeneca, Bristol-Myers Squibb, Merck, Roche-Genentech, Xcovery; Commercial research support: Boehringer Ingelheim. H. Wakelee: Commercial research grants: Genentech/Roche, Novartis, Pfizer, Xcovery; Consultant/advisory board member: AstraZeneca, Genentech/Roche (uncompensated), Merck (uncompensated), Novartis (uncompensated), ARIAD (uncompensated); Commercial research grants to institution for conduct of clinical trial work: Genentech/Roche, Novartis, Pfizer, Lilly, Celgene, Astrazeneca/Medimmune, Exelixis, Clovis Oncology, BMS, Gilead, Pharmacyclics, ACEA biosciences, Merck, Xcovery. K.L. Reckamp: Consultant/advisory board member: ARIAD; Commercial research grants: Xcovery; Consultant/advisory board member: ARIAD Takeda, Exelixis, Guardant, Loxo, Genentech; Commercial research grants: Xcovery, AbbVie, Acea, Adaptimmune, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Guardant, Janssen, Loxo Oncology, Seattle Genetics, Takeda, Zeno. C.M. Lovly: Consultant: Pfizer, Novartis, AstraZeneca, Genoptix, Sequenom, ARIAD, Takeda, Foundation Medicine, Blueprints Medicine, Cepheid; Research funding: Novartis, AstraZeneca, Xcovery (through Vanderbilt University); Work in the CML laboratory is supported through the National Institutes of Health (NIH) and National Cancer Institute (NCI) R01CA121210 and P01CA129243, the Damon Runyon Foundation, the LUNGevity Foundation, the V Foundation, the Lung Cancer Foundation of America, and the International Association for the Study of Lung Cancer. CML was also supported through P30CA6848. J. Hernandez, T. Shaffer, K. Garg, L.P. Lim, M. Li: Employee, shareholder: Resolution Bioscience. S. Patel: Sci Ad Board member: AZ, BMS, Illumina, Tempus, Novartis; Research funding: BMS, Eli Lilly, Fate, Incyte, AZ/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance; Research funds through UCSD. R.E. Sanborn: Consultant/advisory board member: ARIAD, Takeda. A. Holzhausen: Employee: Xcovery Holdings, Inc. K. Harrow, C. Liang: Employee, ownership interests (including patents): Xcovery Holding, Inc. All other authors have declared no conflicts of interest.