Next-generation ALK Inhibitor Overcomes Resistance to Crizotinib in Lung Cancer

PHILADELPHIA —The targeted cancer drug crizotinib is very effective in causing rapid regression of a particular form of lung cancer, but patients’ tumors inevitably become resistant to the drug. A pair of studies published in The New England Journal of Medicine and Cancer Discovery, a journal of the American Association for Cancer Research, found that a new drug called ceritinib, tested in a phase I clinical trial, is effective against advanced ALK-positive non-small cell lung cancer (NSCLC), both in tumors that have become resistant to crizotinib and in those never treated with the older drug. Laboratory studies found ceritinib is able to overcome several known ALK mutations that confer resistance to crizotinib.

NSCLC is the leading cause of cancer death in the United States, and around 5 percent of cases are driven by mutations in the ALK gene, which lead to uncontrolled tumor growth. In 2011, crizotinib received accelerated approval to treat ALK-positive NSCLC, but as with other drugs directed against cancer-driving gene mutations, its effectiveness proved to be temporary. Laboratory studies indicated that ceritinib, which has a different molecular structure than crizotinib, could be as much as 20 times stronger; and animal studies suggested it would be effective against both crizotinib-sensitive and crizotinib-resistant tumors.

As in trials of crizotinib, ceritinib produced often-dramatic shrinkage in the size and number of tumors in around 60 percent of study participants, with similar effectiveness in those who had and those who had not previously been treated with crizotinib. But also as with the crizotinib, most patients developed resistance to ceritinib in the phase I trial, after an average of around seven months.

In the study that appeared in Cancer Discovery, Jeffrey A. Engelman, M.D., Ph.D., director of the Center for Thoracic Cancers at the Massachusetts General Hospital Cancer Center, and colleagues used cell lines established from biopsies of crizotinib-resistant NSCLC patients, and showed that ceritinib is able to overcome several known ALK mutations that confer crizotinib resistance. However, they found that the drug was not able to overcome two crizotinib-resistant ALK mutations, G1202R and F1174C. They identified one of these mutations in five out of 11 biopsies from patients with acquired resistance to ceritinib. The authors report that future studies should identify mechanisms of resistance to ceritinib other than the two mutations they identified, in order to maximize the clinical benefit afforded by next-generation, ALK-targeted therapies.

“Our study findings help us understand both the benefit and limitations of ceritinib and the need to develop ALK inhibitors that can overcome these more recalcitrant mutants,” said Engelman.

This study was funded by the National Institutes of Health, the V Foundation for Cancer Research, the National Cancer Institute, and the Japan Society for the Promotion of Science. Engelman is a consultant for Novartis and receives research support from Novartis.

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