Osimertinib plus anlotinib for advanced NSCLC with acquired EGFR T790M mutation: results from a multicenter phase II study with ctDNA analysis

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BACKGROUND: Osimertinib is a standard treatment for first- or second-line therapy in patients with non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR). However, options are limited for patients with acquired EGFR T790M mutations resistant to first- or second-generation EGFR-tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of combining osimertinib with anlotinib in this patient population and explored circulating tumor DNA (ctDNA) as a biomarker of treatment outcomes. METHODS: In this prospective, single-arm, phase II trial, 31 patients with advanced NSCLC resistant to prior first- or second-generation EGFR-TKIs therapy received osimertinib (80 mg daily) and anlotinib (12 mg daily on days 1-14 of each 21-day cycle). Efficacy endpoints included progression-free survival (PFS) and overall survival (OS). ctDNA was analyzed using next-generation sequencing (NGS) to monitor mutation status and treatment response. RESULTS: The median PFS was 16.2 months (95% confidence interval [CI] 9.8-23.6, 90% CI 14.2-20.9), and the median OS was 31.4 months (95% CI 27.3-not reached). The objective response rate (ORR) was 45.2% (95% CI 30.6-66.6%), with a disease control rate (DCR) of 96.8% (95% CI 86.3-100.0%). ctDNA analysis showed that activating EGFR mutation clearance after two treatment cycles correlated with significantly longer PFS and OS. The regimen was well-tolerated, with no grade 4 or higher adverse events observed. CONCLUSIONS: Osimertinib combined with anlotinib demonstrates promising long-term efficacy and manageable safety in EGFR T790M-positive NSCLC. Clearance of ctDNA, particularly of EGFR mutations, could serve as a valuable predictive biomarker, supporting the implementation of personalized treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04029350.

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