Drug Targets 'Achilles' Heel' of Some Lung Cancers
Article date: October 27, 2010
By Karen Patterson
Taking aim at a genetic trait found in some tumors, new research has hit its target, with a promising drug emerging to treat a subset of patients with advanced lung cancer.
The drug, called crizotinib (PF-02341066), inhibits the effects of chemical rearrangement of a gene called ALK. While only a small percentage of non-small cell lung cancers have ALK gene rearrangements, early testing has found that about 90% of patients with these gene changes benefited from the medicine, with their tumors either shrinking or remaining stable.
Uncommon mutation, but still large numbers of patients
“Crizotinib finds the Achilles' heel of these types of lung cancers,” says study lead author Eunice Kwak, M.D., Ph.D., a medical oncologist at Massachusetts General Hospital. The study was published today in The New England Journal of Medicine. Its findings also were reported earlier this year at a meeting of the American Society of Clinical Oncology.
“Unfortunately, crizotinib will not cure advanced cancers with ALK abnormalities, and it is not yet known how long most patients can expect to remain on crizotinib with their disease controlled,” Kwak adds. Most patients in the study are continuing to receive therapy, and some have been on the drug as long as 2 years.
Only an estimated 2% to 7% of non-small cell lung cancers have ALK aberrations. But that still adds up to nearly 10,000 U.S. patients who could be helped annually by crizotinib, an editorial accompanying the study estimates. Also, other people with ALK-positive cancers—including subsets of patients with non-Hodgkin lymphomas, inflammatory myofibroblastic tumors and neuroblastomas—might someday benefit from the medicine.
Crizotinib is not yet FDA-approved and is currently only available through clinical trials.
Tumors shrank in 57% of patients
Based on previous lab-dish testing with hundreds of cancer cell lines, researchers knew that inhibiting ALK, which stands for anaplastic lymphoma kinase, could quell the growth of cells with a rearranged ALK gene. The first part of the new study focused on the safety and optimal dose of crizotinib in cancer patients with various tumors. There, the researchers noted the drug’s dramatic activity in 2 patients whose lung cancers had ALK rearrangements.
Next the researchers checked tumor samples from some 1,500 patients with non-small cell lung cancer and found that about 5%, or 82 people, had ALK-positive cancers. Those patients—who generally were younger than other lung cancer patients, had minimal or no smoking history, and had tumors of a type known as adenocarcinomas—were enrolled in the second part of the study, to see whether the drug could specifically attack their advanced cancers.
Tumors shrank significantly in 57% of the people in the study group, including one patient whose cancer could no longer be detected, even though almost all of these patients had had previous treatments. “Tumor shrinkage can occur even after the lung cancers have already progressed through multiple lines of prior therapy,” Kwak says.
The 57% response rate compares favorably to that of second-line chemotherapy, which usually helps only about 10% of such patients, the researchers note. Also in the study, tumor growth was halted in an additional 33% of participants.
Lung cancer symptoms minimized
Crizotinib is given as a pill, twice a day. The average time the patients received crizotinib on the study was about 6 months, although many are still getting it. Side effects during the study were mostly manageable, and included nausea and vomiting, diarrhea, and visual disturbances appearing as trails of light following moving objects. A few patients had elevated liver function tests, which was managed by a temporary stoppage of the drug and then a resumption at a lower dose.
At the same time, many patients saw improvements in their lung cancer symptoms.
“It has been gratifying to see patients no longer having to struggle with shortness of breath, pain or cough,” Kwak says. “Patients overall seem to feel very well because they are no longer dealing with the side effects of their disease. We have patients who are taking care of their young families, who are working full-time, or who are out hiking or bike riding, as if they didn’t have cancer at all.”
More research needed
Experts agree that more research into crizotinib is needed. The study, for instance, does not show whether patients taking the medicine actually live longer, and it did not directly compare patients on crizotinib to patients not receiving the drug. Also, participants had a varied history of previous treatments, so it’s unclear what impact those treatments may have had on the results. Nor is it clear whether crizotinib is best used by itself or along with other cancer drugs. Larger studies now under way will help address these issues.
Further studies may also shed light on a finding from separate new research, which suggested that new ALK mutations could develop in some patients that might make their cancers resistant to crizotinib.
None of the patients with the ALK rearrangement also had a mutation in a gene called EGFR, which is the target of different lung cancer therapies such as erlotinib (Tarceva). That finding suggests ALK variation defines a second, separate group of lung cancer patients who respond to targeted therapy with a different mechanism of action.
Eventually, non-small cell lung cancers may be tested for ALK and other gene changes at the time of diagnosis to help guide the choice of treatment. “It is important to test tumors ahead of time so as to give patients the best chance of receiving therapies that will work,” Kwak says. “It’s like needing to have the right key to lock or unlock a door.”
The study was funded by the drug’s developer, Pfizer, along with various non-commercial grants and awards. Participating sites in the initial trial were the University of Chicago, University of Colorado, and Mass General along with Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center. The expanded study also included the University of California, Irvine, and Memorial Sloan-Kettering Cancer Center as well as sites in Australia and Korea.
Reviewed by members of the ACS Medical Content Staff
Citation: "Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer." Published in the Oct. 28, 2010 issue of the New England Journal of Medicine (Vol. 363, No. 18). First author: Eunice L. Kwak, M.D., Ph.D., Massachusetts General Hospital Cancer Center, Boston, Mass.
"Crizotinib — Latest Champion in the Cancer Wars?" Published in the Oct. 28, 2010 issue of the New England Journal of Medicine (Vol. 363, No. 18). First author: Bengt Hallberg, Ph.D., Department of Molecular Biology, Umeå University, Umeå, Sweden.
ACS News Center stories are provided as a source of cancer-related news and are not intended to be used as press releases.
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