Crizotinib was strikingly effective, inducing an 80% response rate, against refractory stage 4 non–small-cell lung adenocarcinoma expressing rearrangements of the c-ros oncogene 1 (ROS1) in a small retrospective cohort study.
The results were published online Feb. 9 in Journal of Clinical Oncology.
This suggests that all patients with lung adenocarcinoma should be screened for ROS1 to allow targeted therapy, much as they are currently screened for EGFR, ALK, and KRAS mutations, said Dr. Julien Mazieres of the thoracic oncology unit, Hopital Larrey, Centre Hospitalier Universitaire Toulouse, France, and his associates.
ROS1 encodes a tyrosine kinase receptor. Crizotinib is an oral tyrosine kinase inhibitor approved for use in advanced lung cancers that have ALK rearrangement or MET amplification. Recent preclinical and phase I studies indicate that the drug also shows “impressive clinical activity” against ROS1-positive lung cancers, “with striking results reported in individual patients,” Dr. Mazieres and his colleagues said.
To characterize the experience to date with crizotinib in this patient population, the researchers assessed the outcomes of all 31 consecutive patients with stage 4 NSCLC carrying ROS1 rearrangements who have been treated with off-label crizotinib at 16 European cancer centers that currently screen for ROS1. In contrast to the typical profile of people with lung cancer, these patients tended to be younger (median age, 50 years), nonsmoking, and female. All but one had already received at least one line of chemotherapy, and most had progressive disease despite receiving two or more lines.
A total of 24 of the 31 patients showed objective responses to crizotinib, including 5 who showed complete responses; 4 patients showed disease progression despite crizotinib. This yielded an overall response rate of 80% and a disease control rate of 86%. The median progression-free survival was 9.1 months. The rate of progression-free survival at 1 year was 44%, the investigators said (J. Clin. Oncol. 2015 Feb. 9 [doi:10.1200/JCO.2014.58.3302]).
These findings confirm the 72% overall response rate reported in a recently published phase I clinical trial involving similar patients. “Thus, we have shown that the findings reported in highly selected patients in a phase I trial can be translated into the routine use of a drug,” Dr. Mazieres and his associates said.
The patient records documented severe (grade 4 or 5) toxicities, and none occurred in this series of patients. No patients discontinued crizotinib because of adverse effects.
The incidence of ROS1 rearrangements in NSCLCs is low, estimated to occur in 2% or fewer of unselected adenocarcinomas. Nevertheless, “we believe that targeted therapies with response rates of more than 50% represent a major breakthrough in lung cancer therapy and should be a priority in drug development,” the researchers said.
At present there are several methods available to test for ROS1, but the best method has not yet been identified, they added.