Crizotinib Granted FDA Priority Review for ROS1 mNSCLC

The FDA has granted a priority review for a supplemental new drug application for crizotinib (Xalkori). The indication is for patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC).

D. Ross Camidge, MD, PhD

The FDA has granted a priority review for a supplemental new drug application (sNDA) for crizotinib (Xalkori). The application is for an indication in patients with metastatic non—small cell lung cancer (NSCLC), whose tumors are ROS1-positive, according to a press release posted by Pfizer Inc.1

"ROS1 is another gene rearrangement. It is like ALK in that it is structurally related, but rarer. ROS1 occurs in about 1% of [NSCLC] patients, but [it has] also been seen in other types of rare cancers," said D. Ross Camidge, MD, PhD, director, Thoracic Oncology Clinical Program, University of Colorado Cancer Center, in an interview withTargeted Oncology. He added that crizotinib, originally an ALK inhibitor, may be even more effective as a ROS1 inhibitor. "It's great for that small population of patients."

Crizotinib is currently indicated for treatment in patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive. A priority review by the FDA means an acceleration of review time from 10 months to 6 months from the date of its acceptance for filing by the agency. The FDA is expected to take further action on crizotinib by April 2016.

"ROS1 represents the second molecular subgroup of NSCLC in which XALKORI has demonstrated a level of antitumor activity that can potentially make a meaningful difference for patients," said Mace Rothenberg, MD, senior vice president of clinical development and medical affairs, chief medical officer, Pfizer Oncology, in a statement. "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."

According to the press release, the sNDA is based on data from a multicenter, single-arm phase I study (Study 1001) of crizotinib in a cohort of 53 patients. Each of these patients were diagnosed with ROS1-positive metastatic NSCLC, and in data from the study, crizotinib showed impressive antitumor activity in patients with ROS1-positive metastatic NSCLC.

In a phase I trial, 50 patients, median age 53, were treated with crizotinib at 250 mg twice daily on 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 one prior therapy.

The study showed 3 complete responses (6%) and 33 partial responses (66%), with the median time to first response being 7.9 weeks and the median duration of response being 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 safety profile of crizotinib in ROS1-positive metastatic NSCLC was the same as that observed in patients treated who had ALK-positive metastatic NSCLC. According to the press release, adverse reactions to crizotinib evaluated in a phase III study in previously untreated patients with ALK-positive metastatic NSCLC were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal side effects occured in 2.3% of patients, those side effects being septic shock, acute respiratory failure, and diabetic ketoacidosis. The study randomized patients to either a crizotinib arm (n = 171) or chemotherapy arm (n = 169). Some of the most common side effects reported were visual impairments such as photopsia, blurred vision, or vitreous floaters.

The press release stated that ROS1 rearrangement occurs in patients with NSCLC when the ROS1 gene attaches to another gene and alters the way each gene normally functions. These alerations can cause an expedited cancer growth. Of the estimated 1.5 million new cases of NSCLC worldwide each year, roughly 15,000 may be driven by oncogenic ROS1 fusions.


  1. Pfizer announces U.S. FDA acceptance and priority review of supplemental new drug application for XALKORI® (crizotinib) for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer | Pfizer: One of the world's premier biopharmaceutical companies. 2015. Accessed December 8, 2015.