Purpose Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those that do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in ALK+ non-small cell lung cancer (NSCLC) patients. Experimental Design We analyzed tissue obtained from 14 ALK+ NSCLC patients demonstrating evidence of radiologic progression while on crizotinib in order to define mechanisms of intrinsic and acquired resistance to crizotinib. Results Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK kinase domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient demonstrated outgrowth of EGFR mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient demonstrated the emergence of an ALK gene fusion negative tumor compared to the baseline sample, but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism. Conclusions Crizotinib resistance in ALK+ NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.

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Introduction Many patients with oncogene driven non-small cell lung cancer treated with TKIs experience limited sites of disease progression. This study investigated retrospectively the benefits of local ablative therapy (LAT) to CNS and/or limited systemic disease progression and continuation of crizotinib or erlotinib in patients with metastatic ALK gene rearrangement (ALK+) or EGFR-mutant (EGFR-MT) NSCLC, respectively. Materials and Methods Patients with metastatic ALK+ NSCLC treated with crizotinib (n=38) and EGFR-MT NSCLC treated with erlotinib (n=27) were identified at a single institution. Initial response to the respective kinase inhibitors, median progression free survival (PFS1) and site of first progression were recorded. A subset of patients with either non-leptomeningeal CNS and/or ≤4 sites of extra-CNS progression (oligoprogressive disease) suitable for LAT received either radiation or surgery to these sites and continued on the same TKI. The subsequent median progression free survival from the time of first progression (PFS2) and pattern of progression were recorded. Results PFS1 in ALK+ patients on crizotinib was 9.0 months, and 13.8 months for EGFR-MT patients on erlotinib. 25 of 51 (49%) patients who progressed were deemed suitable for local therapy (15 ALK+, 10 EGFR-MT; 24 with radiotherapy, 1 with surgery, and continuation of the same targeted therapy. Post LAT, 19/25 patients progressed again, with median PFS2 of 6.2 months Discussion Oncogene addicted NSCLC with CNS and/or limited systemic disease progression (oligoprogressive disease) on relevant targeted therapies is often suitable for LAT and continuation of the targeted agent, and is associated with >6 months of additional disease control.