Objective responses occurred in 72% of patients with mutation-specific non-small cell lung cancer (NSCLC) treated with crizotinib (Xalkori), final results from a small clinical trial showed.
Median response duration approached 1½ years, and median progression-free survival (PFS) had reached 19.2 months with follow-up ongoing.
All 50 patients enrolled in the study had chromosomal rearrangements in ROS1, which several lines of evidence suggested would be susceptible to ALK inhibitors such as crizotinib, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston, reported here at the European Society of Medical Oncology.
“ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active,” Shaw and colleagues concluded in an article published simultaneously in the New England Journal of Medicine. “In the majority of patients, crizotinib induced durable clinical responses and was associated with grade 2 or lower toxic effects.
“These results highlight the importance of screening for this genetic alteration in patients with advanced NSCLC.”
The report corroborates data initially reported 2 years ago at the American Society of Clinical Oncology meeting.
Though distinct from ALK, ROS1 encodes a tyrosine kinase receptor similar to ALK. ROS1 rearrangements occur in about 1% of NSCLC worldwide, representing 15,000 of the estimated 1.5 million new cases of NSCLC diagnosed each year. As with ALK rearrangements, ROS1 rearrangements occur more often in patients who are nonsmokers or light smokers and have adenocarcinoma histology, Shaw and colleagues noted in the journal article.
Though sharing certain characteristics, ALK and ROS1 rarely occur in the same tumor. Instead, each type of abnormality defines a molecular subgroup of NSCLC.
Preclinical studies have shown that crizotinib inhibits ROS1 signaling and cell viability, and case reports have documented major responses to crizotinib in patients with ROS1-rearranged NSCLC, the authors continued.
The accumulation of evidence provided a rationale to conduct a formal evaluation of crizotinib in patients with NSCLC characterized by ROS1 rearrangements. Investigators in a phase I dose-escalation trial of crizotinib in ALK-positive NSCLC amended the protocol to include an expansion cohort of patients with ROS1 rearrangements.
The presence of ROS1 rearrangement was confirmed in all 50 patients by fluorescence in situ hybridization assay. Almost 90% of the patients had received at least one previous line of standard therapy for NSCLC.
The primary endpoint was overall response rate. Shaw reported that three patients (6%) had a complete response, 33 (66%) patients had a partial response, and nine patients (18%) had stable disease as their best response. The median time to response was 7.9 weeks, and response was ongoing in 23 of 36 (64%) at the time of data cutoff.
The patients had an estimated median duration of response of 17.6 months (upper limit of confidence intervals not reached). Median PFS was 19.2 months (95% CI 14.4 months to not reached).
The adverse event profile of crizotinib was consistent with previously reported findings. The most common adverse events were visual impairment (82%), diarrhea (44%), nausea (40%), peripheral edema (40%), constipation (34%), vomiting (34%), elevated aspartate aminotransferase (22%), fatigue (20%), dysgeusia (18%), and dizziness (16%).
More than 90% of adverse events were grade 1 or 2 in severity, and all of the reported episodes of visual impairment were grade 1.
The most common grade 3 adverse events were hypophosphatemia (10%), neutropenia (10%), and elevated alanine aminotransferase (4%). No treatment-related grade 4 or grade 5 adverse events occurred during the study.
Standard mutation analysis for newly diagnosed NSCLC included EGFR mutations and ALK translocation. EGFR mutations are found in about 15% of NSCLC cases and ALK translocation in 5% to 6%, said Edward Kim, MD, of Carolinas Healthcare System’s Levine Cancer Institute in Charlotte, N.C. ROS1 rearrangements add another 1% to the targetable population of NSCLC.
“The activity of ALK inhibition in this molecularly specific patient population is impressive and would certainly warrant clinical consideration,” Kim told MedPage Today in an email. “Currently ROS1 is not tested standardly, and this is something the medical oncology community should give consideration to.
“The rarity of this rearrangement brings into questions how rigorous a clinician should be to test for molecular aberrations. This discussion parallels conversations regarding testing EGFR mutations, for instance, in patients with squamous histology but with limited smoking histories.”
Outlet Full Name: MedPage Today
Author: Charles Bankhead