Gangnam Severance Hospital (GSH) researchers demonstrated that antibody drug conjugate (ADC), REGN5093-M114, can overcome mesenchymal-epithelial transition (MET) gene-based EGFR target mutant non-small cell lung cancer (NSCLC).
Lung cancer is classified into NSCLC and small cell lung cancer (SCLC) according to the size of cancer cells, but 80 to 85 percent are NSCLC patients. Genetic mutations are found in EGFR in about 50 percent of NSCLC in Asia, including Korea.
Osimertinib is used to inhibit the tyrosine kinase activity of EGFR and is widely used as a primary treatment for EGFR mutant lung cancer, but most patients develop resistance within one to two years.
Modification of the MET gene is the most common resistance mechanism of osimertinib treatment. When resistance occurs due to the MET gene, EGFR target therapy and MET tyrosine kinase inhibitors (TKIs) are administered together. However, this produces a low treatment response rate and leads to secondary resistance of MET inhibitors, said the research team at GSH.
Accordingly, the research team led by Professors Yun Mi-ran and Lim Sun-min analyzed the effects of REGN5093-M114, an ADC targeting METs, to present an improved treatment strategy.
ADCs selectively deliver cytotoxic agents to cancer cells expressing target proteins through powerful cytotoxic agents attached to antibodies which target proteins on the cancer cells surface.
A preclinical model derived from lung cancer patients who developed MET-based acquisition resistance after using EGFR target therapy was produced. Subsequently, the effect was analyzed by administering REGN5093-M114, a new treatment that promotes apoptosis by transferring potent cytotoxins to tumor cells overexpressing METs.
REGN5093-M114 demonstrated strong anti-tumor activity in MET-based EGFR-targeted therapy resistance models and tumor models that acquired resistance to MET TKIs.
Specifically, when comparing the tumor growth inhibition (TGI) of the MET Y1230C mutation with different osimertinib was inhibited by 25.8 percent, cabozantinib by 94.7 percent, and osimertinib plus cabozantinib by 97.6 percent. However, REGN5093-M114 alone reduced these tumors most effectively at 202.1 percent.
Currently, REGN5093-M114 is undergoing phase 1/2 clinical trials in patients with advanced non-small cell lung cancer who overexpress MET in the U.S.
"Through the patient-derived preclinical model, we confirmed that REGN5093-M114 can be an effective treatment option to overcome MET gene-based EGFR mutations in NSCLC," Professor Yun Mi-ran said. "This is the basis for continuous evaluation of REGN5093-M114 in various clinical-related scenarios."
Professor Lim Sun-min added that ADCs can be applied to treat various diseases caused by MET gene mutations along with lung cancer.
The results were published in the cancer research journal of the American Association for Cancer Research.