Abstract 2593: Combination therapy with EGFR-TKI and cMET-TKIs in non-small cell lung cancer: the golden duo

Abstract

Abstract Intro: The use of targeted therapies confers great responses in non-small cell lung cancer patients, but ultimately results in acquired resistance, e.g. against epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) due to cMET amplification. Therefore, combination therapy with EGFR-TKI and cMET TKIs in cell lines with a different EGFR and cMET background was investigated. Materials & methods: All experiments were performed in 5 cell lines with a different EGFR and cMET background: the cMET amplified squamous lung cancer cell line EBC-1, the HGF-secreting myeloma cell line JJN3, the HCC827 and H1975 lung adenocarcinoma cell lines with an activating EGFR exon 19 deletion and an L858 as well as a T790M resistance mutation, respectively. Finally LUDLU-1 is a squamous lung cancer cell line, wild-type for both EGFR and cMET. The cytotoxicity of combination therapy with erlotinib (EGFR-TKI) and crizotinib (cMET-ALK-ROS1-TKI) or PHA665752 (cMET-TKI) was determined by the sulforhodamine B assay after 72h of simultaneous/sequential treatment (Table 1). Results: For all treatments, the JJN3, EBC-1 and HCC827 cell lines showed no synergistic effect. For the H1975, a decrease in resistance could be observed, albeit not significant. For LUDLU-1, a trend towards synergism was observed when erlotinib was administered simultaneously with crizotinib (p = 0.074) and PHA665752 (p = 0.055). Also a significantly synergistic effect was observed when treatment with erlotinib was followed by PHA665752 (p = 0.014). Discussion: Synergism between erlotinib and crizotinib/PHA665752 depends on the genetic background of the cells and the treatment schedule. This was most pronounced in the EGFR and cMET wild-type cell line. These results open up the discussion to include EGFR and cMET wild-type patients into future clinical trials. Cell lineErlotinib (μM)Crizotinib (μM)PHA665752 (μM)Erlo+CrizErlo = >CrizCriz = >ErloErlo+PHAErlo = >PHAPHA = >ErloEBC-10-100-0.025-0.050-0.1-0.150-0.025-0.050-0.1-0.20-0.3-0.40-0.1-0.2JJN30-100-2-30-2-30-2-30-5-70-5-70-5-6HCC8270-50-3-50-3-50-1-20-7-90-7-90-4-5H19750-100-2-30-2-30-1-20-6-70-6-70-2-3LUDLU-10-100-3-50-3-50-2-30-7-80-7-80-3.5-4 Table 1: Therapeutic concentrations per cell line & treatment schedule: control-IC20-IC40. Citation Format: Nele Van Der Steen, Vanessa Deschoolmeester, An Wouters, Filip Lardon, Christian Rolfo, Patrick Pauwels. Combination therapy with EGFR-TKI and cMET-TKIs in non-small cell lung cancer: the golden duo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2593. doi:10.1158/1538-7445.AM2015-2593