A combined strategy of EGFR-MET bispecific antibody and HER3 ADC to overcome osimertinib resistance in NSCLC.

PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as the standard-of-care first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, EGFR-TKI resistance has become a major challenge for almost all patients with EGFR-mutated NSCLC. Both amivantamab (EGFR-MET bispecific antibody) and patritumab deruxtecan (HER3 antibody-drug conjugate) have shown promising efficacy in clinical trials for NSCLC resistant to osimertinib. This study aimed to evaluate a novel therapeutic strategy combining amivantamab and patritumab deruxtecan to overcome osimertinib resistance in NSCLC. METHODS: Three osimertinib-resistant non-small cell lung cancer cell lines were established in vitro. Changes in relevant targets between pre- and post-resistance states were explored at the RNA and protein levels. Subsequently, the efficacy and safety of combination therapy were verified in vitro and in vivo respectively. Changes in treated mice immune microenvironment post-combination therapy were analyzed by flow cytometry, while bulk-RNA sequencing was conducted on tumor tissues. RESULTS: We found that in vitro studies, when combined, amivantamab and patritumab deruxtecan both exhibited a synergistic effect on cell lines that were sensitive or resistant to Osimertinib, and the use of amivantamab increases the expression of HER3 in certain cell lines. Furthermore, the combination therapy polarized macrophages toward the M1 phenotype in vivo, thereby constructing an immune microenvironment unfavorable for tumor growth. CONCLUSION: In conclusion, we have proposed a new therapeutic strategy for NSCLC after osimertinib resistance. The combined strategy of amivantamab and patritumab deruxtecan highlight a promising therapeutic avenue, warranting future clinical trials to validate safety and efficacy.