99TiP A randomized phase II study of lazertinib alone versus lazertinib plus bevacizumab for advanced non-small cell lung cancer with epidermal growth factor receptor activating mutations and smoking history

Lazertinib, a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is one of the first-line treatment options in patients with advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. Bevacizumab, a vascular endothelial growth factor inhibitor, plays a critical role in tumor angiogenesis and is recognized for its interaction with EGFR-signaling pathways. While several studies have shown that combinations of anti-angiogenic agents with erlotinib can extend progression-free survival (PFS) compared to erlotinib monotherapy, these findings are not consistently observed with third-generation EGFR TKIs. A previous meta-analysis, investigating the differential impact of smoking status on the benefits of adding an angiogenesis inhibitor to EGFR TKI, revealed significantly prolonged PFS and overall survival (OS) for smokers but not for nonsmokers. Consequently, we designed this study to assess the efficacy and safety of combining lazertinib with bevacizumab in NSCLC patients with EGFR mutations and a history of smoking. This multicenter, open-label, randomized phase II trial is conducted at five study sites in Korea. Previously untreated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) harboring EGFR sensitizing mutations (exon 19 deletion or exon 21 L858R) with a smoking history receive either lazertinib (240 mg daily) plus bevacizumab (15 mg/kg every 3 weeks) or lazertinib monotherapy through random assignment (1:1). Patients are stratified according to brain metastasis status and EGFR mutation type. The treatment will be administered until disease progression, intolerability to lazertinib and/or bevacizumab. The important eligibility criterion 'patient with smoking history' is defined as someone who has smoked more than 100 cigarettes in their lifetime. The primary endpoint is PFS. Secondary endpoints include OS, objective response rate, and adverse events. For exploratory analysis, pre/post-plasma next-generation sequencing will be conducted to reveal prognostic biomarkers and resistance mechanisms. NCT06156527. National Cancer Center. Y. Boryung.