Abstract 4818: In vivo efficacy of triplet therapy with osimertinib, cetuximab and bevacizumab for lung cancer cells harboring EGFR T790M
Authors: Nishii Kazuya , Ohashi Kadoaki , Makimoto Go , Higo Hisao , Ninomiya Kiichiro , Kayatani Hiroe , Ninomiya Takashi , Kubo Toshio , Rai Kammei , Ichihara Eiki , Hotta Katsuyuki , Tabata Masahiro , Kiura Katsuyuki 
Published: August 2018

Abstract
Background
Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is the standard treatment for patients with lung cancer harboring EGFR T790M (Mok T et al. N Engl J Med. 2017). However, acquired resistance to osimertinib is inevitable, and alternative strategies are needed. We recently reported that triplet therapy with afatinib, cetuximab and bevacizumab induced deep remission in lung tumors with EGFR T790M in vivo (Kudo K, et al. Mol Oncol. 2017). Therefore, we hypothesized that the combination of osimertinib with cetuximab and/or bevacizumab is a more effective treatment than osimertinib monotherapy for lung tumors harboring EGFR T790M.
Materials and Methods
RPC-9 cells (5 × 106) harboring EGFR 19DEL+T790M were injected subcutaneously into nude mice as xenograft models. The mice were treated with osimertinib (5 mg/kg, 5 times/week), cetuximab (1 mg/mouse, twice/week) and/or bevacizumab (5 mg/kg, twice/week) for 1 month, and observed for an additional month without treatment. The efficacy and toxicity of the triplet therapy (osimertinib, cetuximab, and bevacizumab) were compared with each of the single and double therapies.
Results
The cell proliferation assay confirmed that RPC-9 cells were sensitive to osimertinib in vitro. In the xenograft model, the doublet therapies (osimertinib plus bevacizumab or osimertinib plus cetuximab) had stronger antitumor effects than osimertinib monotherapy 56 days after drug administration (i.e., 28 days after discontinuation of the treatment). However, no significant differences were observed in inhibitory or CR ratios between mice receiving triplet therapy and those receiving doublet therapies
(osimertinib plus bevacizumab or cetuximab). No intolerable toxicity was observed with the doublet or triplet therapies.
Conclusions
Doublet therapy (osimertinib plus bevacizumab or osimertinib plus cetuximab), induced a significant reduction in lung tumors with EGFR T790M in vivo compared with osimertinib monotherapy. We were not able to prove the superiority of the triplet therapy over the doublet therapy. In future studies, we will examine the effects of the doublet and triplet therapies in other models, including an EGFR-driven transgenic lung cancer mice model.
Citation Format: Kazuya Nishii, Kadoaki Ohashi, Go Makimoto, Hisao Higo, Kiichiro Ninomiya, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura. In vivo efficacy of triplet therapy with osimertinib, cetuximab and bevacizumab for lung cancer cells harboring EGFR T790M [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4818.