Crizotinib Shows Promise for Lung Cancer Patients With ALK Genetic Abnormality
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Reviewed By Laura J. Martin, MD
June 7, 2010 (Chicago) -- An experimental pill shrank tumors in lung cancer patients who have a specific genetic abnormality.
After treatment with the drug crizotinib, tumors shrank or stopped growing in more than 90% of 82 advanced lung cancer patients with the genetic abnormality. In 57%, tumors shrank by 30% or more. Side effects were generally mild.
"That's huge for a population of lung cancer patients where most treatments have only a 10% response (tumor shrinkage) rate, with considerable toxicity," says Indiana University's George W. Sledge Jr., MD, incoming president of American Society of Clinical Oncology (ASCO).
It's too early to know if the drug actually extends lives. And only the 4% of lung cancer patients worldwide with the gene abnormality targeted by the drug are typically helped by crizotinib.
Still, that translates to more than 8,000 people in the U.S. each year, Sledge tells WebMD.
The findings were presented at ASCO's annual meeting.
How Crizotinib Works in Lung Cancer
Crizotinib blocks an aberrant protein called ALK that is critical for the growth and survival of cancer cells.
In some people, an aberration causes the ALK gene to fuse with another gene, typically EML4 in lung cancer.
This, in turn, inappropriately turns on the ALK gene so it produces more and more of the ALK protein, driving tumor growth.
No one knows exactly why it happens, but lung cancer patients with the abnormality are generally nonsmokers. And they're typically younger, in their 50s on average. The abnormality is not inherited.
It's easy to test for ALK aberration, "so we can tell right away if you're likely to respond to the drug," says Roy Herbst, MD, chief of thoracic medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. He was not involved with the work.
Only 28% Chance of Lung Cancer Progression
People in the study had advanced non-small-cell lung cancer (NSCLC), the most common type of cancer. In many cases, the disease had already spread to other parts other body. They had failed to respond to an average of three, and up to seven, drugs.
Most were former light smokers or never-smokers, and all had the ALKgene fusion.
After an average of six months of treatment, there was only a 28% chance that the cancer got worse, and responses to crizotinib have lasted for up to 15 months, says one of the study's leaders, Yung-Jue Bang, MD, of the Seoul National University College of Medicine in South Korea.
About 50% of patients on crizotinib had mild diarrhea or nausea that generally occurred early on and resolved after a few weeks. Ten percent had elevated liver enzymes that sometimes required stopping treatment, usually temporarily.
Crizotinib for Lung Cancer: Hope Warranted
Cancer doctors don't usually get excited about a drug that's in such early phase I testing; they prefer to see long-term safety results and how well it works when pitted against existing treatments, or at least placebo.
But in this case, enthusiasm is warranted, Herbst tells WebMD.
Although some drugs fail to live up to their promise, crizotinib appears to shrink tumors and keep cancer at bay in a large portion of patients that carry the gene defect targeted by the drug, he says.
"It's hard to argue that a response rate this high in these selected patients is not due to a specific effect of this agent on the ALK pathway," Herbst says.
And because crizotinib is targeted at an abnormality on cancer cells, it doesn't cause the systemic side effects associated with chemotherapy, which kills cancer and healthy cells alike, says Alice Shaw, MD, of the Massachusetts General Hospital who worked on the study.
Herbst says that two other gene-targeted treatments, Tarceva and Iressa, help another 10% to 20% of lung cancer patients.
"We're chipping away at the pie," he says.
Still, more testing is needed to establish long-term safety and to see how the drug compares to existing treatments, how long any benefits last, and whether it extends lives, Herbst says.
Pfizer, which makes the drug and sponsored the work, is enrolling patients in a late-stage, phase III study, which will compare crizotinib to standard chemotherapy.
The company hopes to submit an application for FDA approval next year, says a company spokesperson, adding that no price has been set.
Crizotinib is also being tested for the treatment of some lymphoma, sarcomas, and brain cancer patients with the ALK aberration.
This study was presented at a medical conference. The findings should be considered preliminary as they have not yet undergone the "peer review" process, in which outside experts scrutinize the data prior to publication in a medical journal.
SOURCES: American Society of Clinical Oncology Annual Meeting 2010, Chicago, June 4-8, 2010.
Yung-Jue Bang, MD, PhD, professor, department of internal medicine, Seoul National University College of Medicine, Seoul, Korea.
George W. Sledge Jr., MD, professor of oncology, professor of pathology and laboratory medicine, Indiana University School of Medicine, Indianapolis.
Roy Herbst, MD, chief of thoracic medical oncology, University of Texas M.D. Anderson Cancer Center, Houston.
Alice Shaw, MD, Massachusetts General Hospital, Boston.
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