Reversal of Acquired Resistance to EGFR–TKI in T790M-negative Patients With Non–small-cell Lung Cancer Using Anlotinib

Background: Treatment options for epidermal growth factor receptor (EGFR) T790M-negative patients with non–small-cell lung cancer (NSCLC) and acquired resistance (AR) to EGFR–tyrosine kinase inhibitor (EGFR–TKI) are limited. The efficacy of EGFR–TKI and anti-angiogenic drug combination therapy in these patients is known. We investigated the effectiveness of EGFR–TKI+anlotinib combination therapy in patients with T790M-negative NSCLC. Method: We evaluated the antitumor effects of gefitinib combined with anlotinib in gefitinib-resistant lung adenocarcinoma cells. We also investigated the treatment effect and absence of adverse events of EGFR–TKI+anlotinib therapy in 22 T790M-negative patients after EGFR–TKI treatment failure between January 2018 and August 2020. Results: Anlotinib reversed gefitinib resistance in the gefitinib-resistant cell line, PC9/GR, by enhancing anti-proliferative and pro-apoptotic 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 18.2% and a disease control rate of 95.5%. The median progression-free survival (PFS) was 11.53 ± 1.94 months, whereas the median overall survival was not reached. The median PFS was longer in patients exhibiting gradual progression (13.30 ± 1.69 months) than in patients with dramatic progression (8.60 ± 5.39 months, p = 0.041). One Grade 3 adverse event was noted (diarrhea, n = 2, 9.1%), and Grade 4 or 5 adverse events were absent.Conclusion: EGFR–TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and excellent treatment effect in T790M-negative NSCLC patients after AR.