Crizotinib may be a powerful weapon against lung cancer

Rachel E. Sanborn, M.D.
Co-medical director, Providence Thoracic Oncology Program
Medical oncologist, Providence Lung Cancer Clinic
Providence Oncology and Hematology Care Clinic-Eastside

Published October 2011

As we start November and Lung Cancer Awareness Month, it is exciting to report the recent addition of a new agent in the armamentarium of drugs available to treat lung cancer.

In August, the U.S. Food and Drug Administration announced accelerated approval of crizotinib (brand name Xalkori), an oral ALK inhibitor, for patients with locally advanced or metastatic non-small cell lung cancer. The drug is for patients whose tumors harbor a rearrangement of the anaplastic lymphoma kinase, or ALK, gene.

Based upon eligibility screening for the crizotinib studies, rearrangements in the ALK gene seem to occur in about 5 percent of U.S. patients with non-small cell lung cancer. The rearrangements are most commonly found in younger patients, or in patients who have adenocarcinoma or a history of minimal tobacco use. The population is not exclusive, however; ALK rearrangements also have been identified in patients with histories of heavier tobacco use. ALK rearrangements do seem to occur exclusive of KRAS or EGFR mutations.

The initial phase I study involved 82 patients with ALK rearrangements (identified with FISH testing). The response rate was a striking 57 percent. When patients with stable disease were included, 87 percent of this heavily pretreated patient population had disease control at eight weeks.

The median progression-free survival had not been reached at the time of initial publication, but the probability of progression-free survival at six months was estimated at 72 percent probability. Given the expected response rate of less than 10 percent with standard chemotherapy agents in the salvage setting for advanced lung cancer, the results were significantly exciting.

Results of an expanded phase I study, reported at the American Society of Clinical Oncology’s annual meeting in June, confirmed the 88 percent disease control rate. Preliminary data on progression-free survival was available for 94 patients, with a median progression-free survival of 10 months. Overall survival had not yet been reached.

Toxicities of crizotinib include gastrointestinal side effects of nausea, vomiting, diarrhea or constipation (generally mild). Elevations in transaminases have been reported in 5 to 6 percent of patients, with improvement after holding the drug.

QTc prolongation has been noted, as has a 1.6 percent rate of treatment-related pneumonitis. Visual disturbances, a unique side effect of this agent, have been reported in approximately 40 percent of patients.

Phase III study under way

Crizotinib is currently undergoing evaluation in comparison with second-line chemotherapy for patients with an ALK rearrangement and advanced non-small cell lung cancer in a phase III trial. It is hoped that this study will develop a better understanding of the agent’s effects on overall survival.

Approximately 160,000 patients are diagnosed with lung cancer yearly in the United States alone, and roughly 85 percent have non-small cell lung cancer. Unfortunately, most of these patients have advanced disease.

Despite the small percentage of patients with tumors harboring an ALK rearrangement, this still leaves potentially 7,000 people eligible for the drug and potentially longer survival than with standard chemotherapy.

Whether crizotinib will work concurrently with chemotherapy or other targeted agents remains to be seen, and its role for patients without ALK rearrangements is still unknown.

The recent approval of crizotinib is a very exciting moment for the management of lung cancer. Two different targeted agents with superior outcomes are now available for patients with specific activating mutations (erlotinib for EGFR mutations and crizotinib for ALK rearrangements). This, coupled with proven differences in survival with different chemotherapy agents for lung cancer of different histologies, further emphasizes the importance of obtaining adequate tumor tissue at the time of diagnosis.

Gone are the days when “non-small cell lung cancer” was enough to determine treatment. Molecular medicine is now firmly established, with potential for further development of patient-specific therapies as science continues to advance.

Although it’s not a cure, crizotinib may offer more patients hope and time, and with it, quality of life. For clinical researchers and scientists working to advance cancer care, it underscores the importance of understanding the genetic basis of cancers of all different types. The challenges of research have really just begun.

Clinical articles by Rachel E. Sanborn, M.D.