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.
Single group
Osimertinib
DrugEtoposide Soft Capsules Dosage：25mg/tablet, 2 tablets/time, taken continuously for 21 days, and stopped for one week. Osimertinib Dosage：80mg/tablet, 1 tablet/time, QD, taken for two cycles.
Objective Remission Rate (ORR) as assessed by RECIST v1.1
To evaluate the efficacy of osimertinib combined with etoposide as first-line treatment in patients with osimertinib-resistant or -insensitive, advanced EGFR-mutant non-small cell lung cancer. ORR will be defined as the proportion of patients achieving complete response (CR) or partial response (PR) according to RECIST v1.1 criteria.
Two-Year Overall Survival Rate
To observe the two-year overall survival rate of the treatment group receiving osimertinib combined with etoposide. OS will be measured from the start of treatment to the time of death from any cause.
One-Year Progression-Free Survival Rate
To observe the one-year tumor progression-free survival time in the treatment group receiving osimertinib combined with etoposide. PFS will be defined as the time from the start of treatment to the time of disease progression or death, whichever occurs first, as assessed by RECIST v1.1.
Disease Control Rate (DCR) within One Month
To observe the disease control rate in the treatment group receiving osimertinib combined with etoposide. DCR will be defined as the proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1.
Number of Participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0
To observe the safety of osimertinib combined with etoposide in the treatment group. Safety will be assessed by the number of participants with treatment-related adverse events (AEs), graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
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