Relevance of detection of mechanisms of resistance to ALK inhibitors in ALK-rearranged NSCLC in routine practice

Background ALK Tyrosine Kinase Inhibitors (ALK TKIs) have demonstrated efficacy in the treatment of ALK-rearranged Non-Small Cell Lung Cancer (NSCLC), but the disease eventually progresses in all patients. In many cases, resistance to ALK TKIs arises through ALK mutations. Although clinical and biological data suggest variations in TKI efficacy according to the mechanism of resistance, ALK mutations are still rarely investigated in routine practice. Material and methods We performed a retrospective multicentric study aiming to determine the frequency and clinical relevance of ALK alterations detected by targeted Next-Generation Sequencing (t-NGS) in patients with advanced ALK-rearranged NSCLC following progression on an ALK TKI. Clinical, pathological, and molecular characteristics and patient outcomes were collected. Results We identified 23 patients with advanced ALK-rearranged NSCLC who, between January 2012 and May 2017, had undergone at least one repeat biopsy at progression on an ALK TKI. A resistance mechanism was identified in 9 of the 23 patients (39%). The anomalies involved included 9 ALK mutations in 8 patients and one ALK amplification. The ALK mutation rate was 15% after failure of a first ALK TKI and 33% after failure of two ALK TKIs. Five out of seven patients who received a different ALK TKI following detection of an ALK mutation achieved an objective response. All the patients who received a TKI presumed to act on the detected ALK mutant achieved disease control. Conclusions Targeted NGS is suitable for detecting ALK resistance mutations in ALK-rearranged NSCLC patients in routine practice. It may help select the best treatment at progression on an ALK TKI.