FDA Approves New Drug for Advanced NSCLC

Roxanne Nelson

August 26, 2011

August 26, 2011 — The US Food and Drug Administration (FDA) has approved crizotinib (Xalkori, Pfizer) for the treatment of late-stage non-small cell lung cancer (NSCLC) in patients who express the abnormal anaplastic lymphoma kinase (ALK) gene.

In patients with ALK rearrangement, crizotinib has shown striking activity and appears to prolong survival. The ALK rearrangement is found in about 4% to 5% of NSCLC cases, which extrapolates to approximately 8000 to 10,000 patients each year in the United States. Worldwide, an estimated 40,000 patients each year are diagnosed with ALK-positive NSCLC.

A companion diagnostic has been developed and was approved alongside crizotinib. The Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc) is a first-of-its-kind genetic test that uses fluorescence in situ hybridization, the standard method for identifying ALK rearrangements in NSCLC tumors. The test will help identify patients who could benefit from crizotinib therapy.

"The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, in a statement. "Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects."

The safety and efficacy of crizotinib were established in 2 multicenter, single-group studies that enrolled 255 patients with locally advanced or metastatic ALK-positive NSCLC: a phase 2 study (PROFILE 1005) and a part 2 expansion cohort of a phase 1 study (Study 1001). The primary efficacy endpoint in both studies was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). The duration of response was also evaluated.

In PROFILE 1005 (n = 136), the ORR was 50%, and that included 1 complete response and 67 partial responses. The median duration of treatment was 22 weeks, and 79% of objective tumor responses were achieved during the first 8 weeks of treatment. The median response duration was 41.9 weeks.

In the second study, Study 1001 (n = 119), the ORR was 61%, and that included 2 complete responses and 69 partial responses. The median duration of treatment was 32 weeks, and 55% of objective tumor responses were achieved during the first 8 weeks of treatment. The median response duration was 48.1 weeks.

The most common adverse reactions (≥25%) observed across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3 or 4 adverse reactions reported in at least 4% of patients in both studies included increased alanine aminotransferase and neutropenia.

Crizotinib was reviewed under the FDA's priority review program, which provides for an expedited 6-month review of drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists. The application for accelerated approval was filed in May 2011.

In July 2011, the FDA issued a draft guidance industry on the agency's policy for reviewing a companion diagnostic and the corresponding drug therapy. The guidance is currently available for public comment.

Pfizer is conducting postmarketing clinical trials to further evaluate the drug's clinical benefit.

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