Treatment outcomes with first-line EGFR tyrosine kinase inhibitors in Vietnamese metastatic NSCLC patients harboring compound EGFR mutations.

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Background: Compound EGFR mutations represent a heterogeneous group of genetic alterations with inferior clinical outcomes. While next-generation sequencing has increased their identification, real-world data on first-line TKI efficacy remain limited in Vietnam. This study aimed to investigate time-to-treatment failure (TTF), overall survival (OS) and associated factors in metastatic compound EGFR-positive NSCLC. Methods: An observational study was conducted at the National Cancer Hospital (Vietnam) in compound EGFR-mutated metastatic lung adenocarcinoma patients between 2018 and 2025. Patients received first-line EGFR-TKIs (1st, 2nd, or 3rd generation). Kaplan-Meier curves of TTF and OS from the start of EGFR-TKIs were plotted. Associated factors were evaluated with hazard ratios estimated using univariable and multivariable Cox models. Results: Of 86 patients, the median age was 63.0 years and 61.6% were male. Most patients (95.3%) had a PS 0-1. Brain and liver metastasis presented in 43.0% and 15.1% of patients, respectively. Compound EGFR mutations were categorized into three subgroups: common plus uncommon (64.0%), double uncommon (27.9%), and de novo T790M compound mutations (8.1%). Afatinib was the most commonly used (n = 41, 47.7%), followed by erlotinib/gefitinib (n = 27, 31.4%), and osimertinib (n = 18, 20.9%). Median TTF (mTTF) was 16.0 (95% CI, 12.8 – 19.2) months. Median OS (mOS) was 23.0 (95% CI, 16.0–30.0) months. TTF was comparable across TKI generations (mPFS: 15.0, 19.0, and 15.0 months for first-, second- and third-generation TKIs, respectively; p = 0.788). Similarly, OS did not differ among groups (mOS: 56.0, 23.0, and 20.0 months, respectively; p = 0.576). In multivariable analysis, PS 2 (HR 5.03, p = 0.008), liver metastases (HR 2.99, p = 0.003), and adrenal metastases (HR 2.77, p = 0.003) were independently associated with shorter TTF. Multivariable analysis showed an inferior OS with smoking history (HR 2.56, p = 0.011), PS 2 (HR 6.67, p = 0.009), and liver metastases (HR 2.84, p = 0.007). Conclusions: In a real-world Vietnamese clinical setting, the efficacy of first-line EGFR-TKIs was demonstrated in metastatic NSCLC patients harboring compound EGFR mutations, with a mTTF of 16.0 months and mOS of 23.0 months. Survival outcomes were comparable across EGFR-TKI generations. Poor performance status and liver metastasis were independently associated with worse TTF and OS.