Crizotinib Receives Conditional Marketing Approval in Europe

Roxanne Nelson


October 25, 2012

The European Commission has given conditional marketing authorization for crizotinib (Xalkori, Pfizer) for the treatment of adults in the European Union with previously treated anaplastic lymphoma kinase (ALK)-positive advanced nonsmall-cell lung cancer (NSCLC).

According to the manufacturer, conditional marketing authorization is similar to accelerated approval in the United States. This type of authorization is granted to medicinal products when a positive benefit/risk assessment has been demonstrated, the drug addresses unmet medical needs, and availability would result in a significant public health benefit. Conditional marketing authorization is renewable on an annual basis; the timing of drug availability in individual countries varies, depending on local regulations.

"In the field of metastatic nonsmall-cell lung cancer, [crizotinib] represents a major advancement," said Jean-Charles Soria, MD, professor of medicine and medical oncology at South-Paris University and cancer specialist at Institut Gustave Roussy, France, in a statement. It offers patients "with ALK-translocated tumors an oral compound that can achieve tumor shrinkage and delay disease progression," he added.

Crizotinib is an oral ALK inhibitor that binds to and inhibits ALK kinase and ALK fusion proteins. It also inhibits c-Met kinase and disrupts the c-Met signaling pathway, which, taken together, inhibits tumor cell growth.

In August 2011, crizotinib received approval from the US Food and Drug Administration for the treatment of late-stage NSCLC in patients who express the abnormal ALK gene.

ALK rearrangement is found in about 4% to 5% of NSCLC cases; globally, an estimated 40,000 patients each year are diagnosed with ALK-positive NSCLC.

Crizotinib is also approved in Canada, Japan, and South Korea.

Clinical Trial Data

The safety and effectiveness 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).

However, there are currently no data demonstrating improvements in patient-reported outcomes or survival with this agent.

Now that the conditional marketing authorization has been granted, the manufacturer is required to submit data from the recently completed PROFILE 1007 study to the European Medicines Agency (EMA). PROFILE 1007 was a head-to-head comparison of crizotinib and standard chemotherapy (pemetrexed or docetaxel) in a selected population of patients with ALK-positive NSCLC. All 347 patients had previously received 1 line of chemotherapy.

The PROFILE 1007 data, which were presented at the 2012 European Society for Medical Oncology Congress, showed that crizotinib doubled progression-free survival to a median of 7.7 months, compared with 3.0 months for chemotherapy (hazard ratio, 0.49; P < .0001). In addition, crizotinib trebled the response rate (65% vs 20%; P < .0001) and improved symptom control and quality of life.

After the EMA Committee for Medicinal Products for Human Use reviews the PROFILE 1007 data, the European Commission will decide whether or not the conditional marketing authorization should be updated to a normal marketing authorization.

Adverse events reported with crizotinib include hepatotoxicity and pneumonitis, both of which have been associated with fatalities in clinical trials. Also reported are QT interval prolongation, neutropenia, vision disorders, nausea, diarrhea, vomiting, constipation, and peripheral neuropathy.