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Examining Treatment Resistance in RET Fusion–Positive NSCLC

By: Jenna Carter, PhD
Posted: Thursday, February 25, 2021

An article published in the Annals of Oncology highlighted the mechanisms of RET tyrosine kinase inhibitor resistance in patients with RET fusion–positive non–small cell lung cancer (NSCLC). Jessica, J. Lin, MD, of the Massachusetts General Hospital Cancer Center, Boston, and colleagues performed a multi-institutional analysis to examine drug resistance following treatment with selpercatinib and pralsetinib. They found that RET-solvent front mutations, MET amplification, and KRAS amplification were the main resistance mechanisms observed among their patients, and the median progression-free survival was 6.3 months.

“Despite the encouraging efficacy of selective RET [tyrosine kinase inhibitors], experience across the targeted therapy paradigm…suggests that the eventual development of acquired resistance will limit the duration of benefit from RET-selective inhibitors,” stated Dr. Lin and colleagues.

They retrospectively analyzed medical records from five different medical institutions. Eligible patients received pralsetinib and/or selpercatinib as part of their treatment regimen and underwent resistant tumor or liquid biopsy analyses. A total of 23 samples from 18 patients with RET fusion–positive disease was examined using next-generation sequencing or MET fluorescence in situ hybridization. Response evaluation criteria were used to determine response to therapy, and progression-free survival was measured from the time of therapy initiation to disease progression or death.

Overall findings revealed acquired RET mutations in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Additionally, three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. The median progression-free survival for patients given RET inhibitors was 6.3 months (95% confidence interval = 3.6–10.8 months), with a median therapy duration of 7.2 months (95% CI = 3.7–19.0 months).

Disclosure: For full disclosure of the study authors, visit annalsofoncology.org.



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