Preclinical cases suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a potential therapy for non-classical EGFR mutant lung cancers with MET amplification acquired resistance. Herein, we report for the first time the effectiveness of novel combination treatment regimens for patients with EGFR G719X/S768I/L861Q. Until the last follow-up assessment, two patients demonstrated improved survival after they switched to afatinib combined with savolitinib (PFS: 10 months) and furmonertinib combined with crizotinib (PFS: 6 months), respectively, that did not observed increased incidence and severity of adverse events. According to the findings of this study and literature review, various responses were observed from the combined therapy in NSCLC patients who harbored uncommon EGFR mutations and MET amplification. Furthermore, Next generation sequencing (NGS) leads to the discovery of uncommon of EGFR and reveals the co-mutations in NSCLC.

EGFR G724S mutation in exon 18 has been shown to be resistant to both first- and third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, we found a rare mutation of EGFR Ex19del/G724S in two patients with lung cancer who demonstrated a favorable response to the combination of afatinib and chemotherapy. Identified by next-generation sequencing (NGS), EGFR G724S was found from a primary and a secondary tumor biopsy, respectively. Treated with afatinib combined with chemotherapy, both patients responded well and achieved progression-free survival. Analysis of acquired mutations developed during treatment using afatinib revealed that the emergence of EGFR T790M or ALK fusion was the potential mechanism of afatinib resistance. Our study lends credence to treatment using afatinib combined with chemotherapy as a viable option for patients with Ex19del/G724S.