LaserTinib and Amivantamab superior effectiveness in treating atypical EGFR lung cancer
Feb 13, 2025
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A research team led by researchers Hong Min-hee of Yonsei Cancer Hospital's lung cancer center, Yoon Mi-ran of Yonsei University's Medical Life Sciences Department, and Oh Seung-yeon and Park Se-won said that laser-tinib and amivantamab combinations are superior to laser-tinib monotherapy.
The findings were published in the international journal Cell Reports Medicine.
Three to four out of 10 patients with non-small cell lung cancer have EGFR mutations. Of these, 90% are classified as L858R and exon19 deletion variants, and the rest are classified as atypical EGFR variants. Representatively, there are G719X, S768I, and L861Q, and more than one variation may appear simultaneously.
As a treatment for atypical EGFR mutations, the second-generation EGFR-targeted anticancer drug afatinib has been approved by the FDA, but its effectiveness against some mutations is limited and alternative options are lacking if resistance occurs. Osimertinib, a third-generation EGFR-targeted anticancer drug, has also demonstrated therapeutic effects, but the effects seen in each mutation are different.
The research team tried a new treatment that simultaneously targets MET mutation, a mechanism that causes resistance to EGFR mutation drugs. The third-generation EGFR-targeted anticancer drug lasertinib and EGFR-MET double-targeted antibody amivantamab were used in combination to confirm the possibility of overcoming the limitations of existing treatments.
In an experiment with mouse-derived cell lines, patient-derived organoids (PDOs), and patient-derived cell (PDC) models designed to express EGFR-active mutations, combination therapy had better tumor suppression effects than conventional EGFR inhibitor monotherapy.
The PDO experiment identified the drug concentration (IC50) required to reduce cancer growth-induced EGFR phosphorylation activity by half.
The IC50 values of the monotherapy and combination therapy were 19.5 nanomoles (nM) and 3 nanomoles, respectively, and approximately six times less doses were required than the monotherapy in order for the combination therapy to have the same effect. In addition, the growth cycle of cancer cells stopped in the G1 phase (the beginning of the next cycle for cells to proliferate).
Through PDC made from patient cells that acquired resistance to monotherapy, antibody-dependent cytotoxicity (ADCC) effects were confirmed. ADCC is a mechanism that helps immune cells kill cancer cells.
In animal experiments, combination therapy showed tumor suppression persistence. In monotherapy, tumor growth resumed immediately after treatment was discontinued, but in combination therapy, the tumor did not grow for about 90 days after discontinuation. It was the result of lasertinib enhancing the efficacy of amivantamab by increasing target receptor expression. When it came to actual patients, about 40% showed tumor reduction, and progression-free survival was recorded more than 16 months, much longer than conventional monotherapy.
Professor Min-Hee Hong said, "The combination therapy is a mechanism that activates antibody-dependent cytotoxicity that helps human immune cells kill cancer cells, and overcomes resistance to conventional treatments."The results of this study are also significant in that they laid the groundwork for an atypical cohort study published last year at the American Society of Clinical Cancer (ASCO) and presented the level of MET mutation expression as a biomarker for predicting treatment responses."
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This article was translated by Naver AI translator.
