Two novel mutations linked to ALK inhibitor resistance in NSCLC
Two novel ALK mutations,
Although crizotinib (Xalkori, Pfizer) is the standard therapy for
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
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
An analysis of EML4-ALK–expressing Ba/F3 cells that harbored
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.
“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
“These data highlight the need for repeat tumor biopsies at the time of resistance to each individual agent to determine if
For more information:
- Katayama R.
Clin Cancer Res.2014;doi:10.1158/1078-0432.CCR-14-1511.
- Politi K.
Clin Cancer Res.2014;doi:10.1158/1078-0432.CCR-14-2306.
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.