Abstract
Currently, there are limited treatment options for patients who developed resistance to osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor. Resistance to EGFR inhibitors is frequently associated with enhanced vascular endothelial growth factor (VEGF) levels. This multicenter, retrospective study aimed to evaluate the efficacy of the combination treatment with apatinib and osimertinib in 39 patients with EGFR-mutant non-small cell lung carcinoma (NSCLC) who developed osimertinib resistance. The patients received the combination of oral apatinib 250 mg qd and osimertinib 80 mg qd. The efficacy was evaluated after the first month then every 2 months thereafter. The primary endpoint was progression-free survival (PFS). The overall response rate (ORR) and the disease control rate (DCR) of the combination of apatinib and osimertinib was 12.8% (5/39) and 79.5% (31/39), respectively. The median PFS was 4 months [95% confidence interval (CI): 3.5–4.5 months]. Fourteen patients were administered with at least 6 months of combination therapy, and 11 of them remained on treatment programs. The 6-month PFS rate was 38%. Nine patients underwent biopsies after failing osimertinib treatment, and five of six patients with TP53 mutations had PFS of less than 3 months. The spectrum of resistance to osimertinib mechanisms included c-mesenchymal-epithelial transition factor (c-Met) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gain-of-function mutation, phosphatase and tensin homolog (PTEN) loss-of-function mutation, Erb-B2 receptor tyrosine kinase 2 (ERBB2) amplification, and insulin-like growth factor 1 receptor (IGF1R) mutation. The most common adverse events were hypertension (30.7%, 12/39), diarrhea (15.4%, 6/39), and proteinuria (12.8%, 5/39). The combination of apatinib and osimertinib improved the ORR and the DCR of patients with osimertinib-refractory EGFR-positive NSCLC, thus making it a reasonable treatment choice after the development of osimertinib resistance.
Highlights
Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), can selectively block mutations that are sensitive to EGFR-TKI
Given the broad range of resistance mechanisms currently emerging with osimertinib, the potential role of combination therapy in certain osimertinib-refractory settings warrants further investigation
This multicenter retrospective analysis demonstrated that treating patients with the combination of osimertinib and apatinib resulted in a 13% overall response rate (ORR) and a median progression-free survival (PFS) of 4 months, together with a safety profile (Lin et al, 2018)
Summary
Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), can selectively block mutations that are sensitive to EGFR-TKI. In patients with non-small cell lung carcinoma (NSCLC) who had EGFR T790M mutations that are resistant to both first- and second-generation EGFR-TKIs, it can help achieve a median progression-free survival (PFS) of approximately 10 months (Mok et al, 2017). We previously reported good efficacy and prolonged PFS benefit of using the combination of apatinib and a first-generation EGFR-TKI in cases of EGFR mutation-positive NSCLC (Li et al, 2017) progression. There are no data about the efficacy of the combination of a VEGFR inhibitor and osimertinib after third-generation EGFR-TKI failure. This study aimed to evaluate the efficacy of the combination of apatinib and osimertinib in patients with EGFR-mutant NSCLC who developed osimertinib resistance
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