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

Abstract

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.

• Authors: Chen Zhang, Honggang Cao, Yanan Cui, Shidai Jin, Wen Gao, Chenjun Huang, Renhua Guo
• Journal: Thoracic cancer (Thorac Cancer) Vol. 12 Issue 19 Pg. 2574-2584 (10 2021) ISSN: 1759-7714 [Electronic] Singapore
• PMID: 34510760 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Chemical References

• Indoles
• Protein Kinase Inhibitors
• Quinolines
• anlotinib
• EGFR protein, human
• EGFR protein, mouse
• ErbB Receptors
• Gefitinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Disease Models, Animal
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• Drug Therapy, Combination
• ErbB Receptors (genetics)
• Female
• Gefitinib (pharmacology)
• Humans
• Indoles (pharmacology)
• Lung Neoplasms (drug therapy, genetics)
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Protein Kinase Inhibitors (pharmacology)
• Quinolines (pharmacology)
• Retrospective Studies