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Crizotinib Granted Breakthrough Designation for ROS1-positive NSCLC

Silas Inman @silasinman
Published: Tuesday, Apr 21, 2015

Dr. Mace Rothenberg

Mace Rothenberg, MD

The FDA has granted a breakthrough therapy designation to crizotinib (Xalkori) as a potential treatment for patients with ROS1-positive non–small cell lung cancer (NSCLC), based on phase I findings published in the New England Journal of Medicine (NEJM).

In the study, treatment with crizotinib demonstrated an overall response rate (ORR) of 72% in patients with ROS1-rearranged NSCLC. The median progression-free survival (PFS) 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.

“We are excited that the FDA has granted breakthrough therapy designation for Xalkori as a potential treatment for patients with ROS1-positive NSCLC,” said Mace Rothenberg, MD, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology, the company developing the drug. “Xalkori pioneered precision medicine for ALK-positive metastatic NSCLC, and ROS1 represents a second molecular subgroup of NSCLC in which Xalkori has demonstrated a level of anti-tumor activity that can potentially make a real difference for patients.”

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%).

ROS1 rearrangements were confirmed in all but one patient using a break-apart FISH assay, with the remaining patient identified by RT-PCR. The majority of patients (86%) had received previous treatment, with 44% having received more than 1 prior therapy.

The ORR of 72% was comprised of 3 complete responses (6%) and 33 partial responses (66%). The median time to first response was 7.9 weeks and the median duration of response was 17.6 months. Nine patients (18%) had stable disease following treatment. At the time of the analysis, 64% of patients were still responding to therapy.

Crizotinib’s safety profile was similar to previous studies in patients with ALK-rearranged NSCLC, the authors noted. 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.

“Prior to this study, there were a handful of reports describing marked responses to crizotinib in individual patients with ROS1-positive lung tumors,” lead author Alice T. Shaw, MD, PhD, from the Massachusetts General Hospital Cancer Center, said when the NEJM results were published. “This is the first definitive study to establish crizotinib’s activity in a large group of patients with ROS1-positive lung cancer and to confirm that ROS1 is a bona fide therapeutic target in those patients.”

The FDA granted an accelerated approval to crizotinib 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.

Pfizer plans to work closely with the FDA to "provide the information needed to support a potential regulatory submission," according to a statement from the company.

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 in this space. NCCN guidelines recommend treatment with crizotinib for patients with advanced NSCLC who harbor a ROS1 rearrangement, which occurs in approximately 1% of patients.


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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