Osimertinib, though a standard first-line treatment for EGFR-mutant advanced NSCLC, shows primary resistance in 10-30% of patients, leading to disease progression within 3-4 months. This resistance is linked to co-mutations in genes like TP53, RB1, and PIK3CA, among others. Studies indicate that Topo II inhibitor Etoposide (VP-16) can reduce cell survival, enhance DNA damage, and delay resistance in Osimertinib-resistant cells, suggesting a potential combination therapy to manage resistance.This study is a single-center, prospective, single-arm study evaluating the efficacy and safety of osimertinib combined with etoposide as a first-line treatment in patients with osimertinib-resistant or -insensitive advanced non-small cell lung cancer (NSCLC). The study focuses on patients with advanced NSCLC (stage IIIB or IV) with EGFR-sensitive mutations who developed slow resistance to osimertinib and for whom secondary biopsy after resistance did not identify any therapeutic targets.
Age 18 to 79 years.
Locally advanced (stage IIIB) or metastatic (stage IV) EGFR-mutant NSCLC.
Harboring an EGFR sensitizing mutation (Exon 19 deletion or L858R).
Received at least two cycles of first-line osimertinib treatment, with a best response of stable disease or slow progression.
Currently receiving or planning to receive other anti-cancer therapies.
Having contraindications to osimertinib or etoposide.
Harboring known targetable osimertinib resistance mechanisms.