Crizotinib Gets New Indication in Lung Cancer

Crizotinib (Xalkori) has been approved by the FDA as a treatment for patients with ROS1-positive metastatic non–small cell lung cancer.

Alice T. Shaw, MD, PhD

Crizotinib (Xalkori) has been approved by the FDA as a treatment for patients with ROS1-positive metastatic non—small cell lung cancer (NSCLC), based on an overall response rate (ORR) of 66% and a median duration of response of 18.3 months according to an independent review of findings of a phase I study.

“The approval of crizotinib for metastatic ROS1-positive non—small cell lung cancer represents another significant step forward in biomarker-driven cancer care,” lead investigator Alice T. Shaw, MD, PhD, associate professor of medicine at Massachusetts General Hospital and Harvard Medical School, said in a statement. “As with ALK-positive lung cancer, ROS1-positive lung cancer defines a distinct subset of patients for whom crizotinib is efficacious.”

In the phase I trial, 50 patients with ROS1-positive NSCLC 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%). Half of patients were white (54%) and 42% were Asian. The majority of patients (86%) had received previous treatment, with 44% having received more than 1 prior therapy. The median age of participants was 53.

Data from the study were also reported based on investigator assessment, and treatment with crizotinib elicited an ORR of 72% in patients with ROS1-rearranged. The ORR was comprised of 3 complete responses (6%) and 33 partial responses (66%). An additional 9 patients (18%) had stable disease as their best response for an overall disease control rate of 90%.

At the time of the analysis, 64% of patients were still responding to therapy, with a median duration of treatment of 64.5 weeks. 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%.

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

“Lung cancer is difficult to treat, in part, because patients have different mutations, some of which are rare,” Richard Pazdur, MD, 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.”

Crizotinib 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 crizotinib compared with chemotherapy in ALK-positive NSCLC. The median PFS with crizotinib was 7.7 versus 3.0 months with chemotherapy (HR, 0.49; P <.0001). ORR was 65% with crizotinib versus 20% with chemotherapy.

Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-rearranged non—small-cell lung cancer. N Engl J Med. 2014;371(121):1963-1971.