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M. Kurasawa
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-005 - Bevacizumab plus Erlotinib in B901L Xenograft Model of EGFR Mut+ NSCLC (ID 484)
09:30 - 09:30 | Author(s): M. Kurasawa
- Abstract
Background:
Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown clinical efficacy in EGFR mutation-positive (EGFR Mut+) non-small-cell lung cancer (NSCLC). However, almost all tumors recur and eventually develop resistance to ERL. Bevacizumab (BEV), a humanized anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody, in combination with standard first-line chemotherapies, has improved clinical outcomes in advanced NSCLC. Recently, the phase II JO25567 study reported that the combination of BEV plus ERL significantly prolonged progression-free survival compared with ERL alone in EGFR Mut+ NSCLC (Seto, et al. Lancet Oncol 2014; 15:1236–44). However, the mechanism by which this combination confers efficacy remains unknown. In the present study, we examined the antitumor activity of BEV in combination with ERL and analyzed the mechanism of action in a human EGFR Mut+ NSCLC xenograft model.
Methods:
Mice (BALB-nu/nu) were subcutaneously inoculated with the human NSCLC cell line B901L harboring EGFR exon 19 deletion. BEV (5 mg/kg) was intraperitoneally administered once a week and oral ERL (60 mg/kg; maximum tolerated dose) was given daily, starting from Day 1. Antitumor activity was evaluated by measuring tumor volume (TV; mm[3]) twice a week. Human VEGF protein was quantified by ELISA, and EGFR signaling in tumor tissues was examined by immunoblot analysis. Statistical analysis was performed using the Wilcoxon test.
Results:
In the initial phase, ERL showed remarkable tumor growth inhibition in the B901L xenograft model. However, tumor regrowth was observed in the ERL-treated group during further treatment. In contrast, no significant tumor regrowth was observed in the BEV plus ERL-treated group (WCLC 2013; P2.05-004). In the ERL-treated group, tumor VEGF protein was significantly increased (p<0.05) on Day 68 (ERL-refractory phase) compared with Day 4 (ERL-sensitive phase) and the levels of phosphorylation of extracellular signal-regulated kinase (ERK), AKT and signal transducer and activator of transcription 3 were markedly increased on Day 75 compared with Day 5, although phosphorylation of EGFR was still inhibited. In contrast, the combination of BEV plus ERL inhibited phosphorylation of ERK on Day 75, although BEV alone did not.
Conclusion:
The combination of BEV plus ERL demonstrated promising efficacy in the B901L xenograft model of EGFR Mut+ NSCLC. The observed continuous inhibition of ERK phosphorylation may contribute to the antitumor activity of BEV plus ERL treatment. Re-induction of VEGF and subsequent VEGF-dependent tumor growth, either directly or indirectly, was suggested as one of the major mechanism of acquired resistance to ERL leading to remarkably prolonged antitumor activity of BEV in combination with ERL in this model. These encouraging preclinical results warrant further investigation in a clinical setting.
