Perspective from Edward S. Kim, MD
October 07, 2014
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Two novel mutations linked to ALK inhibitor resistance in NSCLC

Perspective from Edward S. Kim, MD
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Two novel ALK mutations, V1180L and I1171T, were associated with resistance to crizotinib and alectinib but were sensitive to other next-generation ALK tyrosine kinase inhibitors for non–small-cell lung cancer, according to study results.

Although crizotinib (Xalkori, Pfizer) is the standard therapy for ALK-rearranged non–small cell lung cancer (NSCLC), patients often develop resistance to this agent and the next-generation ALK tyrosine kinase inhibitor (TKI) alectinib (CH5424802/RO5424802; Chugai Pharmaceuticals, Roche), according to study background information.

For this reason, Ryohei Katayama, PhD, of the Cancer Chemotherapy Center at the Japanese Foundation for Cancer Research in Tokyo, and colleagues sought to evaluate mechanisms of resistance to next-generation ALK TKIs.

Katayama and colleagues developed a human NSCLC cell line and generated resistant H3122 cells by increasing their exposure to alectinib over 7 months. They then examined coding sequencing of H3122 parental cells and resistant H3122 CHR-A1 cells, and identified the novel V1180L gatekeeper mutation.

Researchers also examined a tumor specimen from a patient who developed resistance to and relapsed on crizotinib and alectinib. Through fluorescent in situ hybridization analysis, they identified the novel I1171T mutation.

An analysis of EML4-ALK–expressing Ba/F3 cells that harbored V1180L and I1171T mutations confirmed that the mutations conferred resistance to crizotinib and alectinib. However, V1180L was associated with stronger resistance.

Using the Ba/F3 cells, the next-generation ALK TKI ceritinib (Zykadia, Novartis) demonstrated activity against the mutations. Ceritinib treatment of the patient from whom the cells were derived conferred a partial response that lasted for longer than 7 months.

Katerina Politi, PhD

Katerina Politi

“Until now, it was unknown whether patients could continue to derive benefit from ALK inhibition after failure of a next-generation ALK inhibitor,” Katayama and colleagues wrote. “Our results suggest that patients may benefit from multiple, sequential ALK inhibitor therapies, depending on the underlying mechanism of resistance.”

The findings suggest the need for routine biopsies in the management of patients with ALK-rearranged NSCLC, Katerina Politi, PhD, and Scott Gettinger, MD, both of Yale University School of Medicine and Yale Cancer Center, wrote in an invited commentary.

“These data highlight the need for repeat tumor biopsies at the time of resistance to each individual agent to determine if ALK mutations are present in the tumor, and if so, which ones,” Politi and Gettinger wrote. “This practice will allow subsequent treatment to be tailored to the most current mutational state of the tumor.”

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Disclosure: The researchers report consultant/advisory roles with, as well as research grants and honoraria from Chugai, Genentech, Ignyta, Novartis, Pfizer and Ventana. Politi reports a consultant/advisory role with Takeda and a patent relating to EGFR T790M licensed to MolecularMD. Gettinger reports a consultant/advisory role with Ariad Pharmaceuticals.