Osimertinib plus anlotinib in untreated, EGFR-mutated, advanced non-small-cell lung cancer with concurrent alterations: a multicenter phase II study.

The standard first-line treatment for advanced EGFR-mutated non-small cell lung cancer (NSCLC) is EGFR tyrosine kinase inhibitors. However, concurrent mutations facilitate resistance evolution in EGFR-mutant lung adenocarcinoma and combination therapies may offer a superior approach. This study explores the efficacy and safety of osimertinib plus anlotinib as first-line treatment for advanced NSCLC with EGFR co-mutations. This study prospectively enrolled patients with advanced NSCLC harboring EGFR (19Del/21L858R) mutations and ≥1 mutation in TP53, PIK3CA, or RB1, who had not undergone systemic treatment. Kaplan-Meier survival analysis tested the differences among patients with different concurrent mutations. ctDNA test was administered before and after treatment and its correlation with efficacy. A total of 38 patients were enrolled, with co-mutations in TP53 (76.3%), PIK3CA (26.3%), and RB1 (2.6%). With a median follow-up of 25.6 months, the median progression-free survival (PFS) was 29.0 months (95% CI,18.6-NR), and 1-year PFS rate was 85% (95% CI, 70.4-94.5%). Objective response rate was 73.7% (95% CI, 56.9-86.3%), and disease control rate was 97.4% (95% CI, 85.8-99.9%). Adverse events of any grade occurred in all patients. Seven (18.4%) patients experienced grade 3 treatment-related adverse events (TRAEs), with no grade 4 TRAEs or treatment-related deaths. Osimertinib plus anlotinib shows promising efficacy and manageable toxicity as first-line treatment for advanced NSCLC with EGFR co-mutations (ChiCTR2300070023). This study was registered in the Chinese Clinical Trial Registry (ChiCTR) under the registration number ChiCTR2300070023 on March 31, 2023 (https://www.chictr.org.cn).