Combination Treatment Of A Dual Igf-1r/Ir Kinase Inhibitor, Osi-906, With Egfr Inhibitor Erlotinib In Models Of Non-Small Cell Lung Cancer With An Egfr Activating Mutation

Erlotinib is a tyrosine kinase inhibitor of EGFR approved for use in non-small cell lung cancer (NSCLC) and pancreatic cancer in combination with Gemcitabine. Within the context of NSCLC it has been observed that patients harboring an activating mutation within the kinase domain of EGFR demonstrate a high response to treatment. However, their disease often progresses within 1 year. OSI-906 targets IGF-1R and IR receptor tyrosine kinases and has shown combination efficacy with erlotinib in preclinical models of NSCLC with wild type EGFR. Here we report preclinical data suggesting that the combination of erlotinib and OSI-906 is more efficacious in NSCLC models expressing an EGFR mutation than either single agent. A panel of NSCLC cells lines with confirmed mutations in the EGFR kinase domain was screened for erlotinib and OSI-906 single agent drug sensitivities. All mutant EGFR models exhibited sensitivity to EGFR inhibition by erlotinib (IC50 7–33 nM) while none showed sensitivity to OSI-906 (IC50 7gt;10 uM). In vitro, the combination of erlotinib and OSI-906 resulted in synergistic inhibition of cell proliferation and induction of apoptosis in PC3 (JCP-1) cells. Mechanistically we found the combination had enhanced inhibition of signaling through the PI3K/AKT pathway compared to treatment with either single agent. We also observed that while OSI-906 showed no induction of cell death, erlotinib treatment caused almost complete cell death. However after 9 days of erlotinib treatment small colonies of viable cells still remained. Removal of drug allowed the cells to grow and expand. When cells were treated with both erlotinib and OSI-906, complete cell death occurred without any evidence of cell regrowth following removal of both drugs. In order to evaluate this combination effect in vivo the EGFR mutant human tumor xenograft models NCI-H1650 and PC-14 were employed. Both lines are highly sensitive to erlotinib single agent treatment but show no anti-tumor activity with OSI-906 single agent treatment. The combination of 100 mg/kg erlotinib and 10 mg/kg OSI-906 demonstrated enhanced tumor growth delay when compared to either single agent dosed at MTD. However, as a first step towards understanding preclinical mechanism of this interaction we investigated the combination of 25 mg/kg of erlotinib with 30 mg/kg of OSI-906 and identified potential in vivo synergy. These studies with 25 mg/kg of erlotinib and 30 mg/kg of OSI-906 showed initial tumor regressions, enhanced tumor inhibition and substantially prolonged tumor growth delay when compared to either single agent. Drug-drug interaction PK studies suggest that OSI-906 is not acting to enhance erlotinib exposure. This data provides preclinical proof-of-concept for the use of OSI-906 in combination with erlotinib to obtain greater anti-tumor activity in the mutant EGFR setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-388. doi:10.1158/1538-7445.AM2011-LB-388