ALK rearranged NSCLC has emerged as a distinct entity with growing number of potent ALK tyrosine kinase inhibitors. Despite showing durable responses and promising survival rates, resistance to these ensue. ReWARD is the largest series of repeat biopsies from patients of ALK-positive NSCLC progressing on ALK directed therapy from this part of the world. Using a combinatorial approach of genomics, histology we describe the spectrum of various resistance mechanisms encountered.
This is a cross sectional study recruiting ALK-positive NSCLC cases who have progressed on any line ALK TKI and have undergone repeated biopsies followed by genomic sequencing by NGS.
32 ALK-positive NSCLC patients progressed on TKI were enrolled. Median age was 53 years (range:36-75 years) with a male predilection (male: female- 1.3:1). 27 (84.4%) cases harbored an additional resistance mechanism. Eighteen of these harbored an on-target ALK alteration, with L1196M gatekeeper mutation being the most common, in 11 cases, G1202 alteration in 3 cases. In 9 cases an off-target alteration was detected, the most frequent being TP53 mutation in 8 cases, KRAS mutation in 4 cases and MET amplification in 3 cases. Four patients underwent sequential NGS testing and allele frequency changes in ALK fusion and resistance mechanisms were demonstrated. 16 patients have been offered lorlatinib therapy, the median PFS of which has not yet been reached. Table: 159P
|Post resistance treatment given|
ReWARD is the largest series depicting ALK resistance mechanisms from a single center to date. SPACEWALK study which demonstrated ALK TKI resistance mechanisms using plasma-based genotyping was a multicentric study. The spectrum encountered in ReWARD is distinct from the rest of the world, thus highlighting heterogeneity within ALK-rearranged tumors. Comprehensive clinical evaluation at disease progression coupled with next-generation sequencing-based genotyping will pave the way for lucid understanding of disease biology, thus aiding in the institution of optimal therapy.
Legal entity responsible for the study
Has not received any funding.
All authors have declared no conflicts of interest.