Crizotinib Highly-Effective in ROS1-Rearranged NSCLC

Silas Inman @silasinman
Published: Monday, Sep 29, 2014

Alice T. Shaw, MD, PhD

Alice T. Shaw, MD, PhD

Treatment with crizotinib (Xalkori) demonstrated an overall response rate (ORR) of 72% in patients with ROS1-rearranged non–small cell lung cancer (NSCLC), according to phase I data presented at the 2014 ESMO Congress and published in The New England Journal of Medicine.

“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 in a statement. “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.”

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 test, 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.

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.

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.

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.

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

“This is a great example of success in personalized medicine," senior study author John Iafrate, MD, PhD, medical director of the Massachusetts General Hospital Center for Integrated Diagnostics, said in a statement. "While NSCLC patients with ROS1 fusions are rare, if you devote the diagnostic laboratory resources to find that 1 to 2 percent of patients, you will make a real difference.”


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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