The Impact of Comprehensive Genomic Profiling (CGP) on the Decision-Making Process in the Treatment of ALK-Rearranged Advanced Non-Small Cell Lung Cancer (aNSCLC) After Failure of 2nd/3rd-Generation ALK Tyrosine Kinase Inhibitors (TKIs)

Abstract

BackgroundThe use of CGP in guiding treatment decisions in aNSCLC with acquired resistance to ALK TKIs is questionable.MethodsWe prospectively assessed the impact of CGP on the decision-making process in ALK-rearranged aNSCLC patients following progression on 2nd/3rd-generation ALK TKIs. Physician’s choice of the most recommended next-line systemic treatment (NLST) was captured before and after receival of CGP results; the percentage of cases in which the NLST recommendation has changed was assessed along with the CGP turnaround time (TAT). Patients were divided into groups: patients in whom the NLST was initiated after (group 1) and before (group 2) receival of the CGP results. Time-to-treatment discontinuation (TTD) and overall survival (OS) with NLST were compared between the groups.ResultsIn 20 eligible patients (median [m]age 63 years [range, 40-89], females 75%, adenocarcinoma 100%, failure of alectinib 90%, FoundationOne Liquid CDx 80%), CGP has altered NLST recommendation in 30% of cases. CGP findings were as follows: ALK mutations 30% (l1171X 10%, G1202R, L1196M, G1269A, G1202R+l1171N+E1210K 5% each), CDKN2A/B mutation/loss 10%, c-met amplification 5%. CGP mTAT was 2.9 weeks [IQR, 2.4-4.4]. mTTD was 11.3 months (95% CI, 2.1-not reached [NR]) and 5.4 months (95% CI, 2.0-NR) in groups 1 and 2, respectively (p-0.34). mOS was 13.2 months (95% CI, 2.9-NR) and 13.0 months (95% CI, 6.0-NR) in groups 1 and 2, respectively (p-0.86).ConclusionCGP has a significant impact on the decision-making process in ALK-rearranged aNSCLC following progression on 2nd/3rd-generation ALK TKIs.

Comparing efficacy and safety of upfront treatment strategies for anaplastic lymphoma kinase-positive non-small cell lung cancer: a network meta-analysis

“…Based on both these mechanistic and practical considerations, lorlatinib is the only drug that does not permit crossing to another ALK inhibitor at the progression disease (PD) [ 30 ], while most patients progressing on all the other drugs could benefit from lorlatinib. Generally, the best sequence strategy should consider systemic activity, CNS activity, ALK variants, mechanisms of resistance, and toxicity profile [ 31 ]. In conclusion, among the currently developed ALK inhibitors, lorlatinib provides the highest probability for the best NSCLC control (both overall and for the CNS metastases), while the best OS and toxicity profile are up to alectinib.…”

“…Typically, this information is derived from retrospective or even preclinical data, relying on the occurrence frequency of molecular resistance mechanisms [28,29]. Based on both these mechanistic and practical considerations, lorlatinib is the only drug that does not permit crossing to another ALK inhibitor at the progression disease (PD) [30], while most patients progressing on all the other drugs could benefit from lorlatinib. Generally, the best sequence strategy should consider systemic activity, CNS activity, ALK variants, mechanisms of resistance, and toxicity profile [31].…”