Crizotinib in ROS1-rearranged non-small-cell lung cancer

Abstract

Background: Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET.

Methods: We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays.

Results: The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC.

Conclusions: In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Figures

Figure 1. Tumor Responses to Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer

Panel A shows the best response of patients treated with crizotinib in the ROS1 expansion cohort. The bars indicate best percent change in the target tumor burden from baseline. Two patients died within 6 weeks after receiving the first dose of crizotinib, so the tumor response was unknown. The asterisk indicates the tumor burden in a patient who had an atypical result on fluorescence in situ hybridization (FISH) for ROS1 (an isolated 5′ green signal). Since this tumor was subsequently shown to be negative for ROS1 rearrangement on next-generation sequencing, an isolated green signal is probably not indicative of a ROS1 rearrangement. The letter A denotes a FISH-positive tumor that was negative for ROS1 rearrangement on next-generation sequencing but positive for ALK rearrangement on FISH and next-generation sequencing. The letter M denotes a FISH-positive tumor that was also positive for MET amplification on FISH (MET-to-CEP7 ratio, 5.34). Panel B shows positron-emission tomographic scans obtained at baseline (left panel) and after 7 weeks of crizotinib treatment (right panel) in a representative patient. On the basis of Response Evaluation Criteria in Solid Tumors, this patient had a partial response (a decrease in tumor burden of 46%), which was ongoing at the time of data cutoff. Panel C shows the duration of response among the 36 patients with a partial or complete response. Arrows indicate patients who had an ongoing response at the time of data cutoff. The letter A indicates that the patient’s tumor was positive for ALK rearrangement.

Figure 2. Progression-free Survival

Shown is the Kaplan–Meier curve for estimated progression-free survival in the ROS1 cohort of patients treated with crizotinib. Progression-free survival was defined as the time from the administration of the first dose of crizotinib to objective disease progression or death from any cause. Data from 27 patients were censored; of these patients, 25 remained in follow-up for progression-free survival at the time of data cutoff. The shaded area represents the 95% Hall–Wellner confidence limits. Vertical lines on the survival curve indicate censoring of data.

Figure 3. Duration of Treatment and ROS1 Fusion Partners

The duration of crizotinib treatment is shown for the 25 patients in whom the ROS1 fusion partner was identified with the use of either a next-generation sequencing assay or a reverse-transcriptase–polymerase-chain-reaction assay. Patients are grouped according to the ROS1 fusion partner, as indicated on the left. The four patients with negative results on next-generation sequencing and the one patient in whom next-generation sequencing failed are indicated by gray bars. One of the four patients with negative results was positive for EML4-ALK rearrangement, as indicated. One patient had negative results on next-generation sequencing and had an atypical FISH pattern (as indicated by an asterisk). The arrows indicate patients who were continuing to receive crizotinib at the time of data cutoff.