Analysis of resistance mechanisms to ALK kinase inhibitors in ALK+ NSCLC patients.

Abstract

7504 Background: Patients with anaplastic lymphoma kinase (ALK) gene fusions derive significant clinical benefit from crizotinib, an ALK inhibitor; moreover, next generation ALK kinase inhibitors are in development. Unfortunately, drug resistance develops after initial benefit (acquired) or occurs in patients who never derive a benefit (intrinsic). This study aimed to define molecular mechanisms of resistance to ALK kinase inhibitors in ALK+ non-small cell lung cancer (NSCLC) patients. Methods: 30 ALK+ crizotinib-treated NSCLC patients experienced radiologic disease progression, of whom 7 progressed only in the CNS. Of the 23 patients with extra-CNS progression, a biopsy was attempted on 19. One of the patients without tissue post-crizotinib then proceeded to a second generation ALK inhibitor and tissue was obtained post progression on this drug. We performed molecular analysis and initiated cell lines from tumor tissue for these 19 patients. Results: 15 patients had material evaluable for molecular analysis. Six patients (40%) developed secondary mutations in the kinase domain of ALK. Two novel mutations were identified in samples from ALK+ NSCLC patients, F1174C and D1203N. Two patients each demonstrated G1269A or L1196M mutations. Two patients each, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). Four patients demonstrated the presence of another oncogenic driver (1 with EGFR mutation; 3 with KRAS mutation) with or without a persistent ALK gene rearrangement. One patient lacked an ALK gene fusion on progression biopsy, but had no identifiable alternate oncogene alteration. 3 patients retained ALK positivity with no identifiable resistance mechanism. Data on additional patients and an in vitro model of copy number gain will be presented. Conclusions: ALK kinase inhibitor resistance in ALK+ NSCLC occurs through a diverse array of kinase domain mutations, ALK gene fusion CNG, and emergence of second (same cell) or separate (different cell) oncogenic drivers. In order to overcome resistance it will be important to differentiate patients that preserve ALK dominance (secondary mutations and CNG) versus those that have diminished ALK dominance (separate or second oncogenic drivers).