Genetic correlation of crizotinib efficacy and resistance in ALK- rearranged non-small-cell lung cancer

Objectives: Crizotinib remains one of the most commonly used targeted therapies for ALK fusion-positive patients. However, the mutational profiles and mechanisms of resistance to first-line crizotinib treatment remain to be thoroughly examined. Materials and Methods: We retrospectively reviewed 125 ALK-positive patients with histological and/or cyto-logical diagnosis of NSCLC. Of these, baseline samples were available from 62 patients and 63 had resistance samples following first-line crizotinib treatment, with 18 patients having paired baseline and resistance samples. All patients were genetically profiled by NGS using a 139 lung cancer gene panel (Pulmocan (R), Nanjing Geneseeq Technology Inc.). Survival associations of progression-free survival (PFS) and resistance mechanisms were evaluated in relation to ALK fusion variants and background genetic alterations. Results: The median age of the cohort was 53 years old (range 26-78; 46.4 % females). Three novel ALK fusion partners were identified, including PSME4, cullin3 (CUL3) and coiled-coil domain containing 85A (CCDC85A). Among the different ALK fusion genes, patients carrying the v3 variant experienced worse PFS outcome compared with other non-v3 fusions (P = 0.01) in response to first-line crizotinib. Profiling of the genetic landscape revealed TP53 as the most frequently co-mutated gene, alterations of which were associated with unfavorable outcome (P = 0.024) and were among the secondary acquired mutations in the resistance samples. Examinations of the resistance mechanisms showed that the v3 variant was more likely to acquire ALK activating mutations (P = 0.04). Off-target resistance mechanisms included mutations in genes in the RAS/MAPK and its parallel pathway genes, such as ERBB2, BRAF, KRAS, FGFR3, NF1 and CREBBP. Conclusion: In this study, through profiling of the mutational landscape of ALK-positive advanced NSCLCs both at baseline and disease progression, we characterized resistance mechanisms and molecular correlations of PFS in response to first-line crizotinib. Our findings may facilitate rational selection of subsequent ALK TKIs in the clinic.

Automated summary

In this study, the mutational landscape of ALK-positive advanced NSCLCs both at baseline and disease progression was profiled, and resistance mechanisms and molecular correlations of progression-free survival (PFS) in response to first-line crizotinib were characterized. Rational selection of subsequent ALK TKIs may be facilitated by these findings.