Abstract IA36: Treatment strategies to overcome EGFR TKI resistance.
Authors: Ahn Myung-Ju 
Published: August 2014

Abstract
With advances in understanding of lung cancer biology and in technologies, there has been a significant improvement in the treatment of non-small cell lung cancer (MSCLC) during the last decades, through the development of targeted agents for molecular subgroups harboring specific genomic alterations within driver oncogenes. Somatic mutations in epidermal growth factor receptor (EGFR) accounting for 10-30% of patients with NSCLC where exon 19 deletion and L858R point mutation as most common activating mutations, result in activation of downstream signaling pathway through RAS/RAF/MEK pathway and PI3K/AKT/mTOR pathway, leading to cell proliferation and anti-apoptotic effect. Inhibition of these signals by EGFR TKIs, gefitinib and erlotinib demonstrates high and durable response rate in patients with EGFR mutation. However, this clinical efficacy is eventually limited by the development of acquired resistance after a median approximately 10-12 months of progression free survival (PFS).
Several mechanisms of acquired resistance have been reported through extensive in vitro studies and comprehensive molecular genotyping of re-biopsy specimen and can be categorized into several groups. Secondary mutations in EGFR, where T790M confers the most common one; Activation of bypass signaling pathways including c-met amplification or hepatocyte growth factor (HGF) overexpression; Phenotype transformation including transformation to small cell lung cancer or epithelial to mesenchymal transition (EMT); Additional genomic alterations such as PIK3CA and PTEN mutation, HER2 amplification, MAPK1 amplification, BRAF mutation, activation of JAK2 or activation of insulin-like growth factor-1 receptor (IGF-1R) pathway.
Although no optimal therapy to overcome acquired resistance has been established yet, the knowledge of the underlying resistant mechanism would provide new treatment strategies.
Continuation of EGFR TKI beyond progression can be an option for patients who show slow progression especially in selected cases of T790M mutation. Along with continuation of EGFR TKI, local therapy to oligometastatic lesions (brain or bone) can be applied. ASPIRATION study to determine the role of continuation of erlotinib beyond RECIST progression is ongoing.
Given the oncogenic addicted nature of EGFR mutation and disease flare-up phenomenon after discontinuation of EGFR TKI at the time of progression, switching to chemotherapy along with continuation of EGFR TKI is considered alternative strategy. Currently, IMPRESS study which is a randomized phase III trial of cisplatin/pemetrexed/gefitinib vs cisplatin/pemetrexed/placebo in EGFR mutation NSCLC patients who develop resistance is underway.
To overcome 790M mutation, second generation of irreversible EGFR TKIs, afatinib, neratinib and dacomitinib have been developed and encouraging results were found in preclinical studies. However, the clinical results have been disappointing in terms of response rate and PFS in patients who develop resistance. Dramatic response to combination of afatinib plus cetuximab in transgenic murine and mice models in erlotinib resistant tumors has led to clinical trial of combination of two agents, demonstrating 32% of response rate and 4.6 months of PFS which is encouraging results. Based on these results, randomized phase III trial comparing afatinib vs afatinib + cetuximab is ongoing. It is of note that these combinations can be beneficial in patients with HER2 amplification, because preclinical model showed significant inhibition of HER2 phosphorylation by afatinib and cetuximab combination.
Third generation EGFR TKIs targeting activating EGFR mutations and T790M but sparing wild type EGFR, leading to less toxicity on skin or GI tract, have been developed. These include WZ-4002, CO-1686, AZ9291, and HM61713. Preliminary results of phase I study of CO-1686 demonstrated promising data with 29% of tumor shrinkage in patients with T790M resistance mutation. Results of AZD9291 and other compounds are eager to wait.
For patients who develop c-met amplification as resistance mechanism, several early clinical trials of combination of EGFR TKI with c-met inhibitors, INC280, XL184 (MET/VEGFR2/RET inhibitors), or crizotinib (ALK/MET inhibitors) are ongoing.
Although the exact mechanism of resistance for histologic transformation to small cell lung cancer has not been established, histologic examination of re-biopsy should be recommended for choice of chemotherapy in these cases. A combination of EFR TKI with E-cadherin inducing agent to reduce EMT might be another potential therapeutic strategy.
Heat shock protein (HSP90) is a molecular chaperone for several proteins including EGFR, MET, EML4-ALK and HER2, aiding in the folding and maturation of a distinct subset of proteins and inhibition of HSP90 results in proteasomal degradation of client proteins. AUY922, HSP90 inhibitor as a single agent in EGFR resistant patients demonstrated 26% of response rate. A combination of AUY922 plus erlotinib is currently being tested.
For patients with alternative genomic alterations as resistance mechanism, agents targeting each genes involved in pathway can be candidates. These include PI3K inhibitors (BKM120, MK-2206), MEK inhibitor (AZD6244), mTOR inhibitor, or JAK2 inhibitor although only few clinical trials are undergoing due to rare incidence.
Even though many different treatment strategies have been proposed and several preliminary clinical trials showed encouraging results, there is no standard treatment at the progressive disease on EGFR TKI. Also several issues and challenges should be considered. Considering continuous evolving nature of cancer cells especially, in case of resistance, tumor heterogeneity, and complexity of pathway network, determination of genomic alteration from re-biopsy at single time point cannot be representative for guiding treatment decision. Co-existence of other pathway activation may be missed from molecular analysis of small biopsy specimen, although next generation sequencing technique might solve this issue. Moreover, repeated re-biopsy at the each time of progression cannot be applied in clinical practice due to lack of available drug and biopsy-related risk. Thus, non-invasive method for monitoring resistance using plasma DNA or circulating tumor cells should be further developed. Finally, treatment strategies should be directed to individualized therapy according to underlying dynamic nature of resistance mechanism.
Citation Format: Myung-Ju Ahn. Treatment strategies to overcome EGFR TKI resistance. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA36.