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Study Identifies Two Novel ALK Mutations Causing Lung Cancer Resistance to ALK Inhibitors

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Key Points

  • Researchers have identified two novel mutations that cause lung cancer resistance to the ALK inhibitors alectinib and crizotinib, but are still sensitive to ceritinib.
  • The ability of ceritinib to overcome alectinib resistance suggests a potential role for sequential therapy with multiple next-generation ALK tyrosine kinase inhibitors in the treatment of ALK-positive lung cancer.
  • About 84% of lung cancers are non–small cell lung cancers (NSCLCs), and 3% to 5% of NSCLCs have mutations in the ALK gene.

In a recent study investigating alectinib resistance in ALK-positive lung cancers, researchers identified two novel ALK mutations that are sensitive to ceritinib (Zykadia), a next-generation ALK tyrosine kinase inhibitor approved by the FDA earlier this year for advanced non–small cell lung cancer (NSCLC). The ability of ceritinib to overcome alectinib resistance suggests a potential role for sequential therapy with multiple next-generation ALK tyrosine kinase inhibitors in the treatment of ALK-positive lung cancer. The research by Katayama et al is published in Clinical Cancer Research.

Study Methods

To determine how cancers develop resistance to alectinib, the researchers established a cell line model of acquired resistance to alectinib and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. Computational thermodynamic simulation with MP-CAFEE was performed in order to learn the structure-activity relationships of ALK mutations,

Results

The researchers identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who had developed resistance to alectinib. Both ALK mutations were resistant to alectinib as well as to crizotinib (Xalkori), but were sensitive to ceritinib and other next-generation ALK tyrosine kinase inhibitors. The researchers treated the lung cancer patient with ceritinib, resulting in a marked response that lasted 7 months.

Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.

“This type of research has led to discoveries understanding how cancers have changed and has led to new drugs that can put patients back into remission and are effective against these cancers that were resistant to the first drug,” said Jeffrey A. Engelman, MD, PhD, Director of the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center, Associate Professor of Medicine at Harvard Medical School in Boston; and a coauthor of the study, during a press conference announcing the study results. “Ceritinib is effective in cancers that have become resistant to crizotinib. And we are continually trying to understand how cancers will get through different therapies, because, ultimately, the goal is to develop therapeutic strategies that will block the development of resistance from the beginning … [and have] patients going back into remissions and leading longer and better lives.”

“Overall, these findings highlight the importance of drug resistance, and to enable the rational selection of therapies most likely to be effective based on the underlying molecular alterations,” concluded the study authors.

According to the National Cancer Institute, each year approximately 200,000 people in the U.S. are diagnosed with lung cancer and more than 159,000 die from the disease. About 84% of lung cancers are NSCLCs, and 3% to 5% of NSCLCs have mutations in the ALK gene.

Naoya Fujita, PhD, of the Japanese Foundation for Cancer Research, and Jeffrey A. Engelman, MD, PhD, and Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, are the corresponding authors for the Clinical Cancer Research article.

Funding for the study was provided by the National Cancer Institute and the Japan Society for the Promotion of Science KAKENHI grants.

A. John Iafrate, MD, is a consultant/advisory board member for Chugai and Pfizer. Kengo Takeuchi, MD, PhD is a consultant/advisory board member for and reports receiving a commercial research grant and speakers bureau honoraria from Chugai. Dr. Engelman reports receiving a commercial research grant from Novartis and is a consultant/advisory board member for Chugai, Genentech, Novartis, and Ventana. Dr. Shaw is a consultant/advisory board member for Ignyta, Genentech, Novartis, and Pfizer.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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