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FDA Grants Crizotinib Priority Review for ROS1-positive NSCLC

Silas Inman @silasinman
Published: Wednesday, Dec 09, 2015

Dr. Mace Rothenberg

Mace Rothenberg, MD

The FDA has granted a priority review to crizotinib (Xalkori) as a treatment for patients with ROS1-positive metastatic non–small cell lung cancer (NSCLC), based on the demonstration of substantial efficacy in a phase I study. A final decision for crizotinib is expected from the FDA by April 2016.

In data from study, which were published in The New England Journal of Medicine (NEJM), treatment with crizotinib elicited an overall response rate (ORR) of 72% in patients with ROS1-rearranged NSCLC. The median progression-free survival with crizotinib was 19.2 months. At a median follow-up for overall survival (OS) of 16.4 months, the 12-month OS rate was 85%. The median had not been reached.

“The development of Xalkori in this subgroup of patients is an example of the capability of precision medicine to identify treatments for patients whose tumors contain rare genetic mutations, such as ROS1-positive metastatic NSCLC,” Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology, the company developing 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.

The ORR of 72% 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.

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 April 2015, crizotinib was granted a breakthrough therapy designation as a potential treatment for patients with ROS1-rearranged NSCLC. Crizotinib was initially granted an accelerated approval as a treatment for patients with ALK-rearranged NSCLC in 2011, based on an ORR of up to 61%. In November 2013, a full approval was granted to the drug following the demonstration of improvement in PFS and ORR when compared with chemotherapy.

ROS1 represents the second molecular subgroup of NSCLC in which Xalkori has demonstrated a level of anti-tumor activity that can potentially make a meaningful difference for patients,” said Rothenberg.

While crizotinib is not currently approved as a treatment for patients with ROS1-rearranged NSCLC, evidence from a variety of studies has eluded to its efficacy for this rare type of cancer. These findings have already led to the NCCN recommending crizotinib for patients with advanced NSCLC who harbor a ROS1 rearrangement.


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.



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