Lung Cancer Resistance Mutations Point to New Treatment Approaches

Two novel mutations in the anaplastic lymphoma kinase (ALK) gene in ALK-positive lung cancer patients that confer resistance to the ALK inhibitor alectinib, have been identified. Alectinib is being developed by Roche, and has been granted a breakthrough therapy designation from the Food and Drug Administration (FDA) as a second-generation ALK inhibitor for patients who develop resistance to crizotinib, the first ALK inhibitor approved for ALK-positive lung cancer.

Patients whose tumors harbor either of these mutations are sensitive to other next-generation oral, ALK inhibitors, including ceritinib (Zykadia), which was granted accelerated approval this past April by the FDA for ALK-positive patients who had progressed on crizotinib.

The results are published in the September 2014 edition of  Clinical Cancer Research.

Discussing these results at a press teleconference that also included the release of the 2014 American Association for Cancer Research annual Cancer Progress Report, was study author Jeffrey A. Engelman, MD, PhD, Director of the Center for Thoracic Cancers at the Massachusetts General Hospital Cancer Center in Boston. He noted that the discovery of the ALK mutation in a subset of lung cancer in 2007 to patient impact, and the approval of crizotinib in 2011, has been very short. “This has transformed the lives of patients with lung cancer with this abnormality,” said Engelman.

Engelman underscored the importance of such resistance studies as novel therapies that may help combat drug resistance, which can be developed and made available during the course of a cancer patient’s disease. “Options can appear a year or two after diagnosis that did not exist at the time of diagnosis. To me, that really speaks to the rapidity of the progress. This is why continued funding (for cancer research) is so crucial," Engelman said.

Approximately 4% to 5% of lung cancer patients harbor a mutation in the ALK gene.

Still, while most ALK-positive lung cancer patients initially respond to an ALK inhibitor from 12 months to several years, resistance is almost inevitable. “Patients go into remission, but that lasts from one to a few years before the cancer starts to progress and this is a theme in many different types of tumors,” said Engelman. “So now we need to understand how the cancer has evolved, and have led to new drugs that can put patients back into remission.”

The authors developed a cell line resistance to alectinib and analyzed tumor samples from patients who had relapsed on alectinib therapy, testing the response of these cells to other ALK inhibitors. The cell line model harbored the novel, previously unidentified mutation in the ALK gene, V1180L, while one of the tumor samples harbored the novel I1171T mutation. Both mutations were resistant to treatment with crizotinib and alectinib, but responded to ceritinib or AP26113 treatment. Computational models then showed that the mutations result in structural alterations in the ALK protein that decreases the binding affinity of alectinib.

An ALK-positive non-small cell lung cancer patient who had developed resistance to alectinib has so far had a seven-month response to ceritinib.