Osimertinib plus anlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer with concurrent gene alterations: A single-arm, prospective, multicenter phase II study.

Abstract

8627 Background: The standard first-line treatment for advanced EGFR-mutated non-small cell lung cancer (NSCLC) is EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, co-existing mutations can reduce the efficacy of EGFR-TKIs, and combination treatments may offer superior outcomes. Some studies suggest that the combination of Osimertinib and Anlotinib may enhance anti-tumor activity. This study explores the efficacy and safety of this combination as a first-line treatment for advanced NSCLC with EGFR co-existing mutations. Methods: This prospective, multicenter phase II trial enrolled patients (pts) with untreated, advanced NSCLC carrying EGFR exon 19 deletions or L858R mutations plus at least one additional mutation in TP53, PI3KCA, or RB1. pts received oral Osimertinib (80 mg daily) and Anlotinib (10 mg daily for 2 weeks, followed by 1 week off), repeated every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included median overall survival (mOS), median PFS (mPFS), objective response rate (ORR), disease control rate (DCR), and safety. Exploratory analyses evaluated changes in circulating tumor DNA (ctDNA) and their correlation with clinical outcomes. Results: As of June 24, 2024, 38 pts (median age 65 years; 39.5% male; 78.9% ECOG PS 1) were enrolled. EGFR mutations included exon 19 deletions (47.4%) and L858R (52.6%), with co-existing mutations in TP53 (78.9%), PI3KCA (28.9%), and RB1 (2.6%). At baseline, 47.4% of pts had brain metastases. With a median follow-up of 14.5 months, the 1-year PFS rate was 85% (95% CI: 70%-95%), and median PFS was 29.0 months (95% CI: 22.5-NA). The ORR was 76.7%, and DCR was 97.4%. Among the 18 pts with brain metastases, the ORR was 83.3%, and median PFS was 22.3 months (95% CI: 14.6-30.4). All pts experienced treatment-related adverse events (TRAEs), with 18.3% having Grade 3 or higher TRAEs. Common TRAEs included rash (81.6%), hand-foot syndrome (71.1%), oral mucositis (50.0%), hypertension (60.5%), liver function impairment (47.4%), decreased appetite (44.7%), and diarrhea (36.8%). In the 11 pts monitored via next-generation sequencing (NGS), ctDNA clearance post-treatment correlated significantly with improved PFS (median PFS: NR vs. 17.8 months, P=0.015). Conclusions: The combination of Osimertinib and Anlotinib shows promising efficacy and manageable toxicity as a first-line treatment for advanced NSCLC with EGFR co-existing mutations, particularly in pts with brain metastases. Post-treatment ctDNA clearance appears to be a potential biomarker for predicting therapeutic response and prognosis. Further investigation is warranted to confirm these findings and explore personalized treatment strategies in NSCLC. Clinical trial information: ChiCTR2300070023 .