Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in patients with advanced EGFR‐mutant non‐small cell lung cancer

BACKGROUND: Acquired resistance development is a major challenge in the epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR–TKI) treatment of non–small cell lung cancer (NSCLC). Here, we investigated the potential effects of the concurrent use of anlotinib and EGFR‐TKI to overcome acquired resistance. METHODS: We conducted a preclinical study to evaluate the antitumor effects of gefitinib + anlotinib in gefitinib‐resistant lung adenocarcinoma models in vitro and in vivo. We then investigated the treatment effect of EGFR–TKI + anlotinib therapy in 24 advanced EGFR‐mutant NSCLC patients after EGFR‐TKI acquired resistance between January 2018 and August 2020. RESULTS: Anlotinib reversed gefitinib resistance in gefitinib‐resistant lung adenocarcinoma models by enhancing the antiproliferative and proapoptotic effects of gefitinib. The gefitinib + anlotinib treatment exerted a synergistic antitumor effect by downregulating the activation of VEGFR2 and downstream effectors, Akt and ERK. The EGFR–TKI + anlotinib therapy exhibited an objective response rate of 20.8% and a disease control rate of 95.8%. Median progression‐free survival (PFS) was 11.53 ± 2.41 months, but median overall survival was not reached. The median PFS was longer in patients experiencing gradual progression (13.30 ± 1.69 months) than in patients with dramatic progression (6.80 ± 1.75 months, p = 0.017). One grade 3 adverse event was noted (diarrhea, n = 2, 8.3%), and grade 4 or 5 adverse events were absent. CONCLUSIONS: EGFR–TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and in vivo. Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in advanced EGFR‐mutant NSCLC patients.