Crizotinib Yields High Response Rates in ROS1-Rearranged Lung Cancer

March 23, 2015

A retrospective analysis showed that crizotinib is highly active in lung cancer with ROS1 rearrangements, which are present in about 1% of lung adenocarcinomas.

A retrospective analysis showed that crizotinib is highly active in lung cancer patients with a ROS1 rearrangement. About 1% of lung adenocarcinomas are driven by such rearrangements.

“Interestingly, ROS1-positive patients share similar characteristics with ALK-positive patients, such as adenocarcinoma histology, histomorphology, young age, and a high prevalence of nonsmoker status,” wrote study authors led by Julien Mazieres, MD, PhD, of Centre Hospitalier Universitaire Toulouse in France.

Early suggestion that crizotinib, a tyrosine kinase inhibitor with affinity for ALK, MET, and ROS1 kinase domains, could be effective against ROS1-positive lung cancer led to a phase I trial and testing in routine clinical practice. The authors noted that this yielded “striking results reported in individual patients.” In the absence of a large prospective clinical trial, though, the researchers looked retrospectively at the EUROS1 cohort to see if crizotinib is effective in these patients.

The study identified 32 eligible patients, one of whom was excluded because next-generation sequencing was negative for ROS1 fusion. Most of the cohort were women (64.5%), and most also were never-smokers (67.7%); 30 patients were evaluable for progression-free survival (PFS), and 29 were evaluable for best response. Results were published in the Journal of Clinical Oncology.

The median PFS was 9.1 months, and the cohort had a 12-month PFS rate of 44%. There were 5 complete responses, and 24 overall objective responses; 2 patients had stable disease and 4 had disease progression. This yielded a response rate of 80% and a disease control rate of 86.7%. The authors noted that these results mirror the recently published phase I data, which showed a 72% response rate.

“Crizotinib seems to be the current treatment of choice for ROS1-positive patients,” the authors wrote. Recent larger trials have been initiated to test this, including prospective phase II trials in several European countries.

The low prevalence of ROS1 rearrangement makes testing for the mutations a challenge. The authors note that because ROS1 rearrangement “occurs almost exclusively with other genomic aberrations, it should be preferentially analyzed in triple-negative (EGFR, ALK, and KRAS) patients.”

Resistance to ROS1 inhibition is also an issue that needs to be addressed, and little is known about the mechanisms at present. “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,” they concluded, adding that the rarity of this mutation suggests patients with a ROS1 fusion should have accelerated access to trials, international programs, and national registries.