P24.03 Dynamic Circulating Tumor DNA Interim Results From The ALKternate Clinical Trial

Abstract

The ALKternate clinical trial is a proof-of-concept study enrolling patients with advanced ALK-rearranged NSCLC, harboring secondary resistance to 2ndgeneration ALK-inhibitor therapy (Trial in Progress#1012). Patients receive induction lorlatinib and at confirmed disease control enter an active phase alternating lorlatinib with crizotinib testing the hypothesis that via altering selection pressure and suppressing emerging resistance clones, sustained sensitivity to lorlatinib and improved disease control may be achieved. Patients prospectively enrolled in ALKternate receive sequential plasma sampling, analyzed real-time via the Resolution Bioscience ctDxTM NGS liquid biopsy platform. Results are correlated with prior therapy, clinical and radiological course on trial. Interim censor date was April 07, 2021. 14 patients have been screened for trial, 3 screen failed, 2 due to ctDNA confirming non-ALK drivers, 1 without prior resistance. N=2/11 were ineligible for the alternating arm due to primary lorlatinib resistance. N=6/9 proceeding to alternating ALKi had baseline CNS disease. The ALK fusion variant was identified in N=7/9, 1+ ALK KDMs in N=7/9, 1+ ALK bypass variants (co-occurring) in N=6/9. The variant allelic frequency (VAF) of ctDNA decreased in N=7/9, N=2/9 harboring MET amplification. Complete temporal ctDNA VAF data will be presented via stream-plots accompanying the results of Table 1, as in Figure 2. At immature median(m) follow-up 12.1mo, m-time on alternating therapy is 7.8mo. In those with persisting positive ctDNA at 6mo, time to treatment failure (TTTF) was 6.1mo and not reached in those with no detectable ctDNA. All with PD on alternating (N=5/9) crossed-over to continuous lorlatinib, PFS 5.6mo.Figure 2ALK5 VAF stream-plotView Large Image Figure ViewerDownload Hi-res image Download (PPT) Preliminary analysis of the ALKternate clinical trial dynamic plasma ctDNA profiles on alternating therapy indicate the inherent genetic heterogeneity in ALK NSCLC at drug resistance and with clearing of plasma ctDNA when alternating ALK-inhibitor therapy, an efficacy advantage is suggested.