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The ARIA Study:activity of next-generation ALK TKIs based on ALK resistance mutations detected by liquid biopsy in ALK positive NSCLC patients
Mezquita, L. Swalduz, A. Auclin, E. Carter, Mathew Steendam, C. Aldea, M. Scheffler, M. Corral, J. Viteri, S. Segui, E.
Mezquita, L.
Swalduz, A.
Auclin, E.
Carter, Mathew
Steendam, C.
Aldea, M.
Scheffler, M.
Corral, J.
Viteri, S.
Segui, E.
Citations
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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.
Description
Date
2021
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Mezquita L, Swalduz A, Auclin E, Carter M, Steendam C, Aldea M, et al. P84.01 The ARIA Study: Activity of Next-Generation ALK TKIs Based on ALK Resistance Mutations Detected by Liquid Biopsy in ALK Positive NSCLC Patients. Journal of Thoracic Oncology. 2021 Mar;16(3):S655.