Abstract 5198: Combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer
Authors: Kayatani Hiroe , Ohashi Kadoaki , Imao Takeshi , Kudo Kenichiro , Kato Yuka , Ninomiya Takashi , Kubo Toshio , Sato Akiko , Hotta Ktsuyuki , Tanimoto Mitsune , Kiura Katsuyuki 
Published: July 2016

Abstract
Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have excellent effects on non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, EGFR mutant NSCLC inevitably acquires resistance to EGFR-TKIs such as gefitinib, erlotinib, or afatinib. Previously, we found that bevacizumab, an anti-vascular endothelial growth factor-A (VEGF-A) antibody, enhanced the antitumor effects of gefitinib and afatinib in preclinical lung cancer models (Ichihara et al., Caner Res 2009; Ninomiya et al., Mol Cancer Ther 2013). In a phase II trial of OLCSG1001, we demonstrated relatively longer progression-free survival by adding bevacizumab to gefitinib in the treatment of patients harboring an EGFR exon 19 deletion. Seto et al. (Lancet Oncol 2015) also reported that adding bevacizumab to erlotinib in patients harboring EGFR mutations significantly prolonged progression-free survival. A new anti-angiogenic agent, the anti-human VEGF receptor-2 (VEGFR-2) antibody ramucirumab, has also been used clinically (Garon et al., Lancet 2014). We investigated the effect of an anti-VEGFR-2 antibody combined with erlotinib on the growth of lung cancers harboring EGFR mutations.
Materials and Methods: NSCLC cell lines PC-9, which harbors EGFR exon 19 deletion and H3255, which harbors EGFR L858R mutation, were used in this study. Ramucirumab and the anti-murine VEGFR-2 antibody DC101 were kindly provided by Eli Lilly (Indianapolis, IN, USA). BALB/c nu/nu or transgenic mice expressing the delE748-752 mutant version of mouse Egfr driven by the SP-C promoter, which is equivalent to the delE746-A750 mutation of humans (C57BL/6/Egfr15DEL) (Ohashi et al. Cancer Sci 2009), were used for in vivo experiments. For xenograft models, PC-9 or H3255 cells were injected subcutaneously into BALB/c mice. The mice were divided into four treatment groups: vehicle, erlotinib, DC101, or erlotinib combined with DC101.
Results: DC101 alone moderately inhibited the growth of PC-9 or H3255 tumor in the xenograft mouse models or suppressed lung cancers in C57BL/6/Egfr15DEL mice. Combined erlotinib and DC101 therapy inhibited the growth of PC-9 tumor in the xenograft mouse models more markedly than did erlotinib or DC101 alone. There were no differences in toxicity between monotherapy and combination therapy.
Conclusion: Combination therapy with erlotinib and an anti-VEGFR-2 antibody had a stronger antitumor effect than those of the respective monotherapies in lung cancers harboring EGFR mutations in vivo.
Citation Format: Hiroe Kayatani, Kadoaki Ohashi, Takeshi Imao, Kenichiro Kudo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Ktsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura. Combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5198.