Abstract 2595: Efficacy of cetuximab and mutant selective EGFR inhibitor WZ4002 in EGFR T790M and non-T790M models of erlotinib resistant non-small cell lung cancer

Background: EGFR kinase inhibitors, including erlotinib, are effective treatments for patients with EGFR mutant lung cancer. However, resistance inevitably develops, most commonly (60%) mediated by an EGFR secondary mutation EGFR T790M. Mutant selective EGFR inhibitors (WZ4002, AZD9291, CO-1686) are effective in preclinical models and clinically (AZD9291 & CO-1686) in EGFR T790M patients (response rates (RR) > 50%) but are less effective in patients with non-T790M mediated drug resistance (AZD9291 RR ∼10%). Combination of afatinib and cetuximab is effective in both T790M (32% RR) and non-T790M (25% RR) mediated resistance but is associated with significant toxicity. We evaluated whether cetuximab could add to the efficacy of a mutant selective EGFR inhibitor and whether the combination was also effective in a model of non-T790M mediated resistance. Methods: Mice harboring xenografts from PC9GR (EGFR Del 19/T790M), H1975 (EGFR L858R/T790M), HCC827GR (EGFR Del 19/MET amplification) cells or genetically engineered mouse models (GEMMS) expressing EGFR L858R/T790M were treated with vehicle, WZ4002 alone, cetuximab alone or the combination. We compared the efficacy of the treatments and evaluated for tumor cures (defined as tumor disappearance and lack of regrowth following 6 weeks of drug withdrawal). In addition, we evaluated the impact of the treatments on EGFR signaling and apoptosis. Results: In the EGFR T790M xenograft models (PC9GR and H1975), the combination of WZ4002 and cetuximab was more effective than either single agent. Only the combination led to tumor cures (5/15 in PC9GR and 3/18 in H1975) while none were observed with the single agents. In the HCC827GR xenografts, the combination of WZ4002/cetuximab was more effective than the single agents but did not lead to any cures. Evaluation of the tumors from treated mice revealed that the efficacy of the combination correlates with effective degradation of EGFR and MET (in HCC827GR). In the L858R/T790M GEMMs, the combination led to significantly greater tumor shrinkage compared to single agents. Evaluation of treated tumors revealed enhanced apoptosis in the combination treated mice. Conclusions: The addition of cetuximab enhances the efficacy of the mutant selective EGFR inhibitor WZ4002 in vivo by increasing the single agent efficacy in both EGFR T790M and non-T790M models. Clinical trials of mutant selective EGFR inhibitors and cetuximab are warranted. Citation Format: Erin M. Tricker, Chunxiao Xu, Kwok-Kin Wong, Pasi A. Janne. Efficacy of cetuximab and mutant selective EGFR inhibitor WZ4002 in EGFR T790M and non-T790M models of erlotinib resistant non-small cell lung cancer. [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 2595. doi:10.1158/1538-7445.AM2015-2595