Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma—A Retrospective Analysis of a Multicenter Clinical Study

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.

Clinical outcomes and safety of osimertinib plus anlotinib for patients with previously treated EGFR T790M‐positive NSCLC: A retrospective study

“…The overall adverse reactions of the combination regimen were acceptable and tolerable, which was consistent with the previous study regarding the combination therapy of antiangiogenic TKI plus osimertinib in EGFR‐positive NSCLC 25 . Interestingly, the incidence of grade ≥3 TRAEs was 36.4%, which was higher than that of osimertinib monotherapy (grade ≥3 TRAEs was 23.0%) and lower than that of osimertinib plus bevacizumab (grade ≥3 TRAEs was ≥40%).…”

“…least, our study preliminarily suggested that osimertinib plus anlotinib instead of antiangiogenic monoclonal antibody might be of valuable therapeutic significance for patients with EGFR T790Mpositive NSCLC. In addition, the results in present study were consistent with another exploratory retrospective study initiated by Yang and colleagues 25. They included a total of 39 patients with EGFR-positive NSCLC and investigated the efficacy and safety of combination administration with apatinib plus osimertinib after osimertinib resistance, which resulted in an ORR of 12.9% and median PFS of 4.0 months.…”

The exploration of three different treatment models of osimertinib plus antiangiogenic agents in non‐small cell lung cancer: A real‐world study

“…Patients from Group B all progressed after treatment with osimertinib, then combined with antiangiogenic agents, the median PFS was 9.2 months, which was comparable with the PFS results (10.1 months) of the AURA3 trial. 12 The ORR, DCR, and median PFS2 of combination therapy were 15.8%, 84.2%, and 5.0 months (95% CI: 4.5-5.5), respectively, which was also comparable with a retrospective study, 23 in which the efficacy of apatinib with osimertinib F I G U R E 4 A forest-graph of the association between different clinical characteristics and OS of all the enrolled patients in our cohort. OS, overall survival; EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitors after the progression of osimertinib in EGFR positive LUAD patients was explored, and the ORR, DCR, and median PFS of combination therapy were 12.8%, 79.5%, and 4 months, respectively.…”

Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance

“…Dual inhibition of VEGF and EGFR pathways had the potential advantage of reversing EGFR-TKI resistance ( Larsen et al, 2011 ). A retrospective analysis of patients with advanced NSCLC who failed osimertinib treatment showed that osimertinib rechallenge combined with apatinib reached a median PFS of 4 months (95% CI: 3.5–4.5 months) ( Yang et al, 2021 ). How about the combination of osimertinib and bevacizumab in osimertinib resistance?…”