The ARIA Study:activity of next-generation ALK TKIs based on ALK resistance mutations detected by liquid biopsy in ALK positive NSCLC patients

Abstract

Introduction: Detection of resistance mechanisms to tyrosine kinase inhibitors (TKI), in particular ALK mutations (ALKm), could help to select the subsequent treatment in ALK-positive NSCLC patients. Liquid biopsy can identify these ALKm from ctDNA in up to 29% of patients after 2nd-generation TKI-failure. We assessed the activity of next-gen TKIs based on the presence of ctDNA ALKm. Methods: Patients with ALK-positive advanced NSCLC pretreated with 1st and/or 2nd-generation ALK-TKI were selected in 9 European centers. Liquid biopsy was collected immediately before starting brigatinib or lorlatinib. ALKm were defined by commercial or homemade next-generation sequencing run on ctDNA and covering ALK exon 22/23/25. We correlated the activity of brigatinib or lorlatinib based on three ctDNA molecular groups: presence ALKm (if one: single; if 2: complex); other mutations and no detectable mutations. We assessed progression-free survival (PFS), objective response rate (ORR), intracranial ORR according to the clinical routine of each center and overall survival (OS). Results: 62 patients were identified, 58 evaluable at cutoff data (Jul-20): 16 before brigatinib and 42 before lorlatinib. Median age was 53 [27-80], 64% were female, 67% nonsmoker; 97% with adenocarcinoma; 7% and 10% with isolated thoracic and brain disease, respectively. The median (m) number of TKIs was 3 [2-7]; 90% received 2nd-generation TKIs. The mFU since liquid biopsy was 24.8 months. ALKm were detected in 28% (3 brigatinib; 13 lorlatinib), 9 single and 7 complex; others were detected in 17% (n¼10) and none in 55% (n¼32). The most common mutation was G1202R (7 before lorlatinib), followed by G1269A and F1174L in 3 cases each, all pretreated with 2nd-generation TKIs. The TKI outcomes according to the ctDNA molecular groups is summarized in table 1. In the ALKm group, lorlatinib showed an ORR of 46% and 56% of intracranial ORR with mPFS of 6.5 months (7¼single/ 6¼complex) while no responses were observed in the 3 cases treated with brigatinib, with mPFS of 3.5 months (2¼single/1¼complex). Those 7 cases harboring the G1202Rmut (4¼complex) had an ORR of only 14% but an intracranial ORR of 50%; mPFS was 3.6 mo. No differences were observed among ctDNA molecular groups. Conclusion: In our study, lorlatinib showed activity in heavily-pretreated patients with ALK-positive NSCLC, regardless the ctDNA molecular groups. Poor outcomes were observed for brigatinib in 3 heavily-pretreated patients with ctDNA ALKm. The recent use of 2ndgen TKI upfront calls for similar studies to confirm if ctDNA may be a biomarker for guiding the sequential therapy.