FDA Approves Xalkori for ROS1-Positive NSCLC

The FDA has approved Xalkori (crizotinib) 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 1 study.

The approval was based on data from 50 patients with ROS1-positive NSCLC, in which the overall response rate (ORR) was 66 percent with a median duration of response of 18.3 months by independent review. The approval was preceded by a breakthrough therapy designation and arrived approximately one month ahead of a deadline set under the Prescription Drug User Fee Act.

“Lung cancer is difficult to treat, in part, because patients have different mutations, some of which are rare,” Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “The expanded use of Xalkori will provide a valuable treatment option for patients with the rare and difficult to treat ROS-1 gene mutation by giving health care practitioners a more personalized way of targeting ROS-1 positive NSCLC.”

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 an ECOG performance status of 0 or 1 (98 percent), had never smoked (78 percent), and had adenocarcinoma histology (98 percent). Half of patients were white (54 percent) and 42 percent were Asian. The majority of patients (86 percent) had received previous treatment, with 44 percent having received more than one prior therapy.

In total, ROS1 was detected in approximately 1 percent 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, which were published in The New England Journal of Medicine (NEJM), treatment with Xalkori elicited an ORR of 72 percent in patients with ROS1-rearranged NSCLC by investigator assessment. The ORR was comprised of three complete responses (6 percent) and 33 partial responses (66 percent). An additional nine patients (18 percent) had stable disease as their best response for an overall disease control rate of 90 percent.

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 percent of patients were still responding to therapy, with a median duration of treatment of 64.5 weeks. 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.

Xalkori's safety profile was similar to previous studies in patients with ALK-rearranged NSCLC. The most common events with Xalkori were visual impairment (82 percent), diarrhea (44 percent), nausea (40 percent), peripheral edema (40 percent), constipation (34 percent), vomiting (34 percent), an elevated aspartate aminotransferase level (22 percent), fatigue (20 percent), dysgeusia (18 percent), and dizziness (16 percent).

The most common grade 3 adverse events were hypophosphatemia (10 percent), neutropenia (10 percent), and an elevated alanine aminotransferase level (4 percent). Additionally, one patient (2 percent) discontinued Xalkori because of treatment-related nausea.

Xalkori was initially granted an accelerated approval for patients with ALK-positive NSCLC in August 2011, which was followed by a full approval in November 2013. The full approval was based on the demonstration of superior PFS and ORR for Xalkori compared with chemotherapy in ALK-positive NSCLC. The median PFS with Xalkori was 7.7 versus 3.0 months with chemotherapy. ORR was 65 percent with Xalkori versus 20 percent with chemotherapy.

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.