Triplet therapy with afatinib, cetuximab, and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo. Issue 6 (2nd May 2017)

• Record Type: Journal Article
• Authors: Kudo, Kenichiro; Ohashi, Kadoaki; Makimoto, Go; Higo, Hisao; Kato, Yuka; Kayatani, Hiroe; Kurata, Yasuko; Takami, Yoichiro; Minami, Daisuke; Ninomiya, Takashi; Kubo, Toshio; Ichihara, Eiki; Sato, Akiko; Hotta, Katsuyuki; Yoshino, Tadashi; Tanimoto, Mitsune; Kiura, Katsuyuki
• Is Part Of: Molecular oncology. Volume 11:Issue 6(2017)
• Page Start: 670
• Page End: 681
• Publication Date: 2017-05-02
• Subjects: afatinib -- bevacizumab -- cetuximab -- deep remission -- EGFR T790M; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12063
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR‐mutant lung cancers; however, resistance usually occurs due to a secondary mutation, T790M, in EGFR. Combination therapy using afatinib and cetuximab has had good results in lung tumors harboring EGFR T790M mutations in clinical trials. The effect of bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, combined with EGFR‐TKIs has also been investigated. We hypothesized that the dose of afatinib and cetuximab could be reduced by combination with bevacizumab and that the triplet therapy may result in better tumor inhibition with tolerable toxicity. Using a xenograft mouse model with H1975‐harboring EGFR L 858R+T790M and RPC‐9‐harboring EGFR 19DEL+T790M, we tested the efficacy of the triplet therapy with a modified dose of afatinib, cetuximab, and bevacizumab, and compared this therapy to single and double therapies. Triplet therapy with afatinib, cetuximab, and bevacizumab induced pathological complete remission in xenograft tumors with H1975 and RPC‐9 cells versus tumors treated with single or double therapies. We saw no body weight loss in the mice. The triple therapy induced a significant reduction in CD31‐positive vascular endothelial cells and increased cleaved caspase‐3‐positive cells in the tumors. This suggests that one mechanism underlying the deep remission could be suppression of neovascularization and induction of apoptosis by intensive inhibition of driver oncoproteins and VEGF. These results highlight the potential of afatinib, cetuximab, and bevacizumab to induce deep remission in tumors harboring EGFR T 790M mutations. Therefore, clinical trials of this combination therapy are warranted. Abstract : Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment strategy for EGFR‐mutant lung cancers. In this study, we tried a triplet therapy, combining bevacizumab, an antivascular endothelial growth factor (VEGF) antibody, with reduced doses of the TKIs afatinib and cetuximab in a xenograft mouse model of EGFR‐mutant lung cancer. The triplet therapy has the potential to induce deep remission in tumors harboring EGFR T790M mutations.