The Committee for Medicinal Products for Human Use (CHMP) has adopted a positive option for crizotinib (Xalkori) as a treatment for adults with ROS1
-positive advanced non–small cell lung cancer (NSCLC), suggesting an approval may be imminent.
The positive opinion was based on findings from a phase I study, which included 50 patients with the rare alteration. In findings from the single-arm study that were published in The New England Journal of Medicine
, crizotinib showed an overall response rate (ORR) of 66% with a median duration of response of 18.3 months by independent review.
The positive CHMP opinion will be sent to the European Commission (EC) for a final regulatory decision, which will be issued within 67 days. The EC initially approved crizotinib as a treatment for patients with ALK
-positive NSCLC in October 2012. The agent is currently approved as both a first- and second-line treatment option for patients with ALK
"The availability of Xalkori has changed treatment outcomes for patients with ALK
-positive advanced NSCLC throughout the world," a representative from Pfizer told OncLive
. "If validated by the European Commission, Xalkori will be the first and only regulatory-approved biomarker-driven therapy for both the treatment of ALK
-positive and ROS1-positive metastatic NSCLC in the EU."
In the phase I trial, 50 patients at a median age of 53 were treated with crizotinib at 250 mg twice daily in a continuous 28-day cycle. A majority of patients had an ECOG performance status of 0 or 1 (98%), had never smoked (78%), and had adenocarcinoma histology (98%). Half of patients were white (54%) and 42% were Asian. The majority of patients (86%) had received previous treatment, with 44% having received more than 1 prior therapy.
In total, ROS1
was detected in approximately 1% of screened patients with NSCLC. The ROS1 rearrangement was confirmed in all but one patient using a break-apart FISH assay, with the remaining patient identified by RT-PCR.
Next-generation sequencing (NGS) of the tumor identified by RT-PCR would later reveal the absence of a ROS1
rearrangement. One patient who tested positive by the break-apart test was found to be ALK
-positive but not ROS1
-positive by NGS. Additionally, one patient had a coexisting amplification in MET.
In data from study, by investigator assessment treatment with crizotinib elicited an ORR of 72% in patients with ROS1
-rearranged NSCLC. By this review, the ORR was comprised of 3 complete responses (6%) and 33 partial responses (66%). An additional 9 patients (18%) had stable disease as their best response for an overall disease control rate of 90%.
The median time to first response was 7.9 weeks and the median duration of response was 17.6 months. At the time of the analysis, 64% of patients were still responding to therapy, with a median duration of treatment of 64.5 weeks. The median progression-free survival with crizotinib was 19.2 months. At a median follow-up for overall survival of 16.4 months, the 12-month OS rate was 85%. The median had not been reached.
Crizotinib’s safety profile was similar to previous studies in patients with ALK
-rearranged NSCLC. The most common events with crizotinib were visual impairment (82%), diarrhea (44%), nausea (40%), peripheral edema (40%), constipation (34%), vomiting (34%), an elevated aspartate aminotransferase level (22%), fatigue (20%), dysgeusia (18%), and dizziness (16%).
The most common grade 3 adverse events were hypophosphatemia (10%), neutropenia (10%), and an elevated alanine aminotransferase level (4%). Additionally, one patient (2%) discontinued crizotinib because of treatment-related nausea.
In the United States, crizotinib was granted an accelerated approval for patients with ALK
-positive NSCLC in August 2011, which was followed by a full approval in November 2013. In March 2016, the FDA extended the label for crizotinib to include the treatment of patients with ROS1-mutant NSCLC.
Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer [published online ahead of print October 4, 2014]. N Engl J Med. doi:10.1056/NEJMoa1406766.