Abstract A28: SPACEWALK: Plasma NGS for remote evaluation of ALK drug resistance in advanced NSCLC

Abstract

Abstract Introduction: Precision therapy for cancer drug resistance requires detection of resistance mutations and treatment with appropriate targeted therapies. This paradigm is well established in EGFR-mutant NSCLC, yet our understanding of drug resistance in ALK-positive NSCLC is limited. Next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) now permits noninvasive interrogation of drug resistance. To facilitate improved understanding of ALK drug resistance and the effectiveness of treatment strategies, we launched this remote participation study. Methods: The SPACEWALK study offers plasma NGS to patients with advanced NSCLC with systemic progression on a next-generation ALK TKI to assess for mechanisms of resistance. Patients consent, enroll, and participate remotely, permitting a larger cohort of ALK positive patients to be studied. Remote phlebotomists can be dispatched to the patient’s home when necessary to ease the burden of study participation and to ensure study compliance. Blood is sent to Resolution Biosciences for ctDNA extraction and hybrid capture NGS, with results returned to the study team and the patient’s physician. Patients are followed for 2 years and blood is collected again after starting a new treatment or at progression. This study is supported by the Addario Lung Cancer Medical Institute (ALCMI). Results: Of 143 patients contacting us via the study website, 61 were offered consent and 53 signed consent. 46 enrolled from 23 different US states and 38 different medical centers. Plasma NGS results were returned a median of 13 days after blood draw (range 8-21). Of the 46 patients, the known ALK fusion was detected in 20 (43%) with a median ALK fusion AF of 3.5% (range 0.3%-37%). 10 patients also underwent plasma NGS with Guardant360, with a median time between the two plasma NGS draws of 1.5 weeks (range 0-22.6). In 4 cases, Resolution Bioscience identified an ALK fusion (AF 0.2-37%) not detected on Guardant360. Among the 20 patients with ALK fusions detected, 12 (60%) were found to carry ALK resistance mutations, 5 with G1202R; 2 patients had 2 or more ALK mutations detected. In addition, 6 participants (30%) had a MET amplification detected with a median of 8 copies (range 3-22) and 1 had a KRAS G12V mutation detected (10% AF). One patient with high MET amplification received combination therapy with alectinib and crizotinib and had dramatic radiographic response. Conclusions: Plasma NGS permits the detection of targetable resistance mechanisms in patients with ALK-positive NSCLC and drug resistance. Sensitivity of different plasma NGS assays for ALK fusions varies. This assay may help guide oncologists across the country to select best treatment options after resistance. Such remote-participation studies may offer a new mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations. Citation Format: Marissa N. Lawrence, Rubii M. Tamen, Alicia Sable-Hunt, Seyed Ali Hosseini, George R. Simon, Jonathan W. Riess, Geoffrey R. Oxnard. SPACEWALK: Plasma NGS for remote evaluation of ALK drug resistance in advanced NSCLC [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A28.