Xalkori Granted Breakthrough Designation for ROS1-Positive Lung Cancer

The Food and Drug Administration (FDA) has granted a breakthrough therapy designation to Xalkori (crizotinib) as a potential treatment for patients with ROS1-positive non—small cell lung cancer (NSCLC), based on phase 1 findings published in the New England Journal of Medicine (NEJM).

In the study, treatment with Xalkori demonstrated an overall response rate (ORR) of 72 percent in patients with ROS1-rearranged NSCLC. The median progression-free survival (PFS) with Xalkori was 19.2 months. At a median follow-up for overall survival (OS) of 16.4 months, the 12-month OS rate was 85 percent. 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, 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 1 trial, 50 patients at a median age of 53 were treated with Xalkori at 250 mg twice daily in a continuous 28-day cycle. A majority of patients had never smoked and had adenocarcinoma histology.

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 percent) had received previous treatment, with 44 percent having received more than one prior therapy.

The ORR of 72 percent was comprised of three complete responses (6 percent) and 33 partial responses (66 percent). The median time to first response was 7.9 weeks and the median duration of response was 17.6 months. Nine patients (18 percent) had stable disease following treatment. At the time of the analysis, 64 percent 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 percent), diarrhea (44 percent), nausea (40 percent), peripheral edema (40 percent), constipation (34 percent) and vomiting (34 percent).

The most common grade 3 adverse events were hypophosphatemia, neutropenia and an elevated alanine aminotransferase level. Additionally, one patient discontinued Xalkori 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, 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 Xalkori as a treatment for patients with ALK-rearranged NSCLC in 2011, based on an ORR of up to 61 percent. 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 Xalkori 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. National Comprehensive Cancer Network guidelines recommend treatment with Xalkori for patients with advanced NSCLC who harbor a ROS1 rearrangement, which occurs in approximately 1 percent of patients.