Abstract 761: Changing the paradigm for treating drug resistance in NSCLC: Novel combinations of AZD6094, a selective MET inhibitor, and an irreversible, selective (EGFRm/T790M) EGFRTKI, AZD9291

Abstract

Abstract Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression across myriad cancer types, where the MET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here we explore the therapeutic potential of AZD6094, a highly potent and selective MET inhibitor, in EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC). Although many EGFRm NSCLC patients receiving first-line EGFR Tyrosine Kinase Inhibitors (TKI) benefit from therapy initially, the majority of patients will acquire resistance in 9-14 months1,2. Of this patient population, ∼10-15% of patients with emerging resistance to early generation EGFRm-TKI will have MET amplification3. Using xenograft models (HCC827) of resistance to erlotinib or gefitinib, both first-generation EGFRm-TKI, we assessed the efficacy of AZD6094 in models with varying copy number gain for MET. We demonstrate that the combination of AZD6094 with gefitinib, or AZD9291, an irreversible, selective (EGFRm/T790M) EGFR TKI, results in tumor growth inhibition (TGI) of >100% in 3 models (HCC827-ER1, PCS030 clone 1 and 2)4, suggesting that the combination is necessary and sufficient to address acquired resistance due to MET gene amplification. Moreover, we explore efficacy of AZD6094 in models representative of resistance to first-line treatment with EGFRm-TKIs, harboring MET amplification and T790M EGFR mutations. In NCI-H820 xenografts (EGFRm/T790M/MET), we demonstrate for the first time that combining MET and EGFRm/T790M TKIs (AZD6094 with AZD9291) induces tumor regressions (TGI% >100%, 94% regressions) and the loss of palpable tumors in 5/7 animals as compared to AZD9291 (TGI 48%) or AZD6094 treatment alone (TGI >100%). Pharmacodynamic analysis of tumor lysates demonstrated potent and durable inhibition of pMET in all AZD6094 treatment groups. Due to the clinical importance of understanding acquired resistance to targeted TKIs, we then generated a model of resistance to AZD6094 in MET-amplified NSCLC NCI-H1993 cells and analyzed several resistant clones (H1993R). Interestingly, MET phosphorylation remains strongly inhibited in AZD6094-treated H1993R cells, while EGFR protein expression is upregulated and leads to co-dependency between both pathways. Enhanced expression and phosphorylation of EGFR, as well as AKT, MEK and ERK activation were commonly observed in H1993R cells. Taken together, our data support the potential of AZD6094 as a novel combination therapy for MET-driven NSCLC in the context of EGFRm TKI resistance, and highlight the clinical relevance of EGFR and MET signaling in the context of emerging TKI resistance mechanisms and coordinated pathways. 1. Mok et al. N Engl J Med 2009;361:947-957. 2. Rosell et al. Lancet Oncol 2012;13:239-246. 3. Engelman et al. Science 2007;316:1039-1043. 4. Models from Precos Ltd Citation Format: Celina D'Cruz, Evan Barry, Ryan Henry, Lillian Castriotta, Alwin Schuller, Garry Beran, Susan Ashton, Cath Eberlein, Corinne Reimer, Melanie Frigault, Michael Zinda, Darren Cross, Stephen Fawell. Changing the paradigm for treating drug resistance in NSCLC: Novel combinations of AZD6094, a selective MET inhibitor, and an irreversible, selective (EGFRm/T790M) EGFRTKI, AZD9291. [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 761. doi:10.1158/1538-7445.AM2015-761