EC Approves Crizotinib for ROS1-Positive NSCLC

New York, September 2016:
The European Commission (EC) has approved crizotinib (Xalkori) as a treatment for patients with advanced ROS1-positive non–small cell lung cancer (NSCLC), based on an improvement in objective response rate (ORR) in a phase I study.
Findings from the single-arm 50-patient study that led to the approval were published in The New England Journal of Medicine in 2014. In this study, crizotinib showed an ORR of 66% with a median duration of response of 18.3 months by independent review.
The approval decision followed a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP). In Europe, crizotinib is also indicated as both a first- and second-line treatment option for patients with ALK-positive NSCLC.
“The European Commission’s decision to approve Xalkori for ROS1-positive advanced NSCLC represents an important milestone for patients who previously had limited treatment options,” Andreas Penk, MD, Regional President, International Developed Markets, Pfizer Oncology, the company that developed the drug, said in a statement.

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.
“We now know that NSCLC is not a single disease, but includes a number of molecularly defined tumors with different clinical characteristics and treatment options," said Penk. "With EU approvals in two distinct molecular targets in advanced NSCLC, ROS1 and ALK, Xalkori continues to break new ground and exemplify our commitment to precision drug development and patients.”
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. Onclive