Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in -Positive Non-Small-Cell Lung Cancer.

PURPOSE

The ROS1 tyrosine kinase is activated through gene rearrangements in 1-2% of non-small cell lung cancer (NSCLC), conferring sensitivity to treatment with the ALK/ROS1/MET inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among -positive patients are limited.

PATIENTS AND METHODS

We reviewed clinical and radiographic imaging data of patients with - and -positive NSCLC in order to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we also analyzed repeat biopsies from a cohort of -positive patients progressing on crizotinib.

RESULTS

We identified 39 and 196 patients with advanced and positive NSCLC, respectively. -positive patients had significantly lower rates of extrathoracic metastases ( 59.0%, 83.2%, =0.002), including lower rates of brain metastases ( 19.4%, 39.1%; = 0.033), at initial metastatic diagnosis. Despite similar overall survival between and positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; =0.786), positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; <0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. mutations included: G2032R (41%), D2033N (6%), and S1986F (6%).

CONCLUSIONS

Compared to rearrangements, rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, underscoring the need to develop novel ROS1 inhibitors with activity against these resistant mutants.