Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in ROS1-Positive Non–Small-Cell Lung Cancer

Abstract

PURPOSE The ROS1 tyrosine kinase is activated through ROS1 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 ROS1-positive patients are limited. PATIENTS AND METHODS We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-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 ROS1-positive patients progressing on crizotinib. RESULTS We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. ROS1-positive patients had significantly lower rates of extrathoracic metastases (ROS1 59.0%, ALK 83.2%, P=0.002), including lower rates of brain metastases (ROS1 19.4%, ALK 39.1%; P = 0.033), at initial metastatic diagnosis. Despite similar overall survival between ALK- and ROS1-positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; P=0.786), ROS1-positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; P<0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. ROS1 mutations included: G2032R (41%), D2033N (6%), and S1986F (6%). CONCLUSIONS Compared to ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 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.

Recent Advances in Targeting ROS1 in Lung Cancer

“…Notably, not all clinicopathologic features are shared between ALK - and ROS1 -rearranged NSCLCs. For example, one recent series comparing 39 ROS1 -rearranged and 196 ALK -rearranged NSCLC patients found that ROS1 rearrangements were associated with a significantly lower rate of extrathoracic and brain metastases at the time of diagnosis, in addition to a lower cumulative incidence of brain metastases (42). Although the number of patients included in this series was limited, particularly for the ROS1 -rearranged subset, the findings suggest that patterns of metastases may be distinct for ROS1 - versus ALK -rearranged lung cancer.…”

“…Mutations within the ROS1 kinase domain occur in ~50–60% of crizotinib-resistant tumors (42). This is higher than the frequency of ALK kinase domain mutations (~20–25%) observed in crizotinib-resistant ALK -rearranged lung cancers (60, 61), and may reflect differences in crizotinib binding characteristics or its higher potency against ROS1 versus ALK (55).…”

“…The most frequently observed resistant mutation has been the ROS1 G2032R mutation in the solvent front (i.e., solvent-exposed region of the kinase), analogous to ALK G1202R (Figure 4A) (42, 62, 63). G2032R was the first crizotinib-resistant mechanism reported in a patient with ROS1 -rearranged lung adenocarcinoma (62).…”

Lorlatinib in ALK- and ROS1-positive NSCLC: the future has a start

“…Brain and meningeal sites of disease both at diagnosis and after first-and second-generation inhibitors represent a critical issue in ALK-positive patients and, to a lower extent, in ROS1-positive ones (10). Although the sites of disease progression before lorlatinib were not recorded in the study, we can easily speculate that a significant proportion of ALK-rearranged NSCLC patients had previously developed central nervous system (CNS) progression.…”

Personalized therapy for lung cancer: Striking a moving target

“…A number of secondary ROS1 resistance mutations have been identified, with the most common being G2032R in approximately 40% of crizotinib-treated patients (75). More recently, entrectinib, a novel multikinase inhibitor, has demonstrated robust PFS of 30 months in a small cohort of patients with ROS1-positive NSCLC (76).…”