Spectrum of Resistance Mechanisms to ALK TKIs in NSCLC: Largest Single-Center Experience from India

Abstract

Abstract Introduction Anaplastic lymphoma kinase (ALK) rearranged non-small cell lung carcinoma (NSCLC) has emerged as a distinct entity with growing number of potent ALK tyrosine kinase inhibitors (TKIs). Despite showing durable responses and promising survival rates, resistance to these ensue. This 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 and histology, we describe the spectrum of various resistance mechanisms encountered. Methods 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 next-generation sequencing (NGS). Results Thirty-two 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). Twenty-seven (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, and 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. Sixteen patients have been offered lorlatinib therapy, the median progression-free survival of which has not yet been reached. Conclusion This is the largest series depicting ALK resistance mechanisms from a single center to date. The SPACEWALK study which demonstrated ALK TKI resistance mechanisms using plasma-based genotyping was a multicentric study. The spectrum encountered in this study is distinct from the rest of the world, thus highlighting heterogeneity within ALK-rearranged tumors. Comprehensive clinical evaluation at disease progression coupled with NGS-based genotyping will pave the way for lucid understanding of disease biology, thus aiding in the institution of optimal therapy.