Associate editor: B. TeicherTreatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures
Introduction
The epidermal growth factor receptor (EGFR) is a 486 amino-acid receptor protein of 170-kDa with a single transmembrane sequence, first identified as a binding partner of EGF and has tyrosine kinase activity (Carpenter & Cohen, 1979). The EGFR has been involved in the pathogenesis and progression of different types of tumors. Accordingly, it has been regarded as an attractive target for cancer therapy and many anti-EGFR inhibitors including monoclonal antibodies or small molecule tyrosine kinase inhibitors (TKIs) have been developed and investigated. In the early 2000s, the first two EGFR TKIs, gefitinib and erlotinib, were initially developed to inhibit the EGFR signaling pathway through blocking the intracellular tyrosine kinase (TK) domain and studied in previously treated patients with non-small cell lung cancer (NSCLC) (Shepherd et al., 2005, Thatcher et al., 2005). Following clinical trials of EGFR TKI therapy combined with chemotherapy were done in unselected treatment-naïve patient populations to improve survival time, but disappointingly, four large randomized trials of addition of EGFR TKI to standard chemotherapy did fail to show an improvement in survival outcome when compared to standard chemotherapy alone (Gatzemeier et al., 2007, Giaccone et al., 2004, Herbst et al., 2004, Herbst et al., 2005). During their clinical development, somatic mutations in this TK domain were discovered, and fortunately, they were reported to correlate with high response rates of EGFR TKI therapy (Lynch et al., 2004, Paez et al., 2004, Pao et al., 2004). This identification of “driver mutation” and “actionable alteration” was a breakthrough in molecular-targeted therapy and led to change of paradigm in cancer treatment. In addition, it has significantly impacted on molecular profiling and developing of biomarker-driven targeted therapies in NSCLC as well as many other tumors (Tan, Mok et al., 2016). These EGFR mutations are usually heterozygous and occur in exons between 18 and 21, corresponding to the intracellular TK domain (Fig. 1). Although various types of EGFR mutation are identified, approximately 90% of the mutations are exon 19 deletions or exon 21 L858R point mutations. The prevalence of the mutations across ethnicities was reported different, occurring in about 10–15% of NSCLC patients in the US but about 30–40% in East Asians (Mihda et al., 2015, Shigematsu et al., 2005, Tan et al., 2016a, Tan et al., 2016b, Yatabe et al., 2015). But, regardless of ethnicity, the mutations are more frequently found in females, never smokers and/or adenocarcinoma histology even though they can be found in other subsets, such as males, ex- or current smokers and in other histologies, which had raised the issue regarding genotypic approach and phenotypic approach for treatment decision (Mihda et al., 2015, Pao et al., 2005). A following phase III study of gefitinib conducted in Asia, known as Iressa Pan-Asia Study or the IPASS study, indicated more clearly that EGFR mutation status affects the choice of first-line therapy, ending the issue related to genotypic approach over phenotypic one (Mok et al., 2009). The IPASS study, comparing gefitinib with carboplatin-paclitaxel doublet in previously untreated never- or light ex-smoker, showed improvement of progression-free survival (PFS) in only patients who were positive for EGFR mutation, which was confirmed in following clinical trials. As a result, current guidelines recommend EGFR mutation testing in all patients with metastatic or advanced adenocarcinoma of the lung in order to identify the presence of EGFR activating mutations, and also recommend an EGFR-TKI as first-line therapy for only patients having the mutation (Master et al., 2015, National Comprehensive Cancer Network, 2016, Novello et al., 2016).
However, the initial hope to cure of EGFR mutant lung cancer did not last long since acquired resistance to the inhibitor developed inevitably after a median response duration of 9 to 13 months despite initial dramatic and rapid response to EGFR TKI therapy. We have had to face a new challenge of overcoming acquired mechanisms, including development of T790M mutation in EGFR exon 20, a secondary mutation at the gatekeeper position (Camidge et al., 2014, Kobayashi et al., 2005, Pao et al., 2005). During identifying acquired mechanisms, T790M mutation was reported the major mechanism, accounting for 50–60% of resistant cases (Camidge et al., 2014, Yu et al., 2013). As a result, second-generation EGFR TKIs, such as afatinib, were developed hoping that they could overcome the resistance through covalently binding C797 position in the EGFR at the lip of the ATP binding site and showed the potential in preclinical studies (Li et al., 2008). However, their on-target toxicity leading to severe adverse events (AEs), such as skin rash or diarrhea, limited their clinical activity because of not reaching sufficiently a high dose for overcoming T790M resistance (Miller et al., 2012). After all, the urgent need for newer agents targeting T790M mutation has led us to develop distinctive molecules, which have a different scaffold to avoid the steric hindrance of the changed methionine gate keeper residue. Newer generation inhibitors or third-generation EGFR TKIs, osimertinib (AZD9291) and rociletinib (CO1686), were developed to meet these considerations that the drugs have a different aminopyrimidine scaffold from prior first- and second-generation EGFR TKIs and overcome the steric hindrance of T790M mutation. The newer inhibitors showed promising efficacy in preclinical studies and good response rates in following early phase clinical trials for patients harboring T790M mutation (Cross et al., 2014, Janne et al., 2015, Sequist et al., 2015, Walter et al., 2013). Randomized phase III studies of the third-generation EGFR TKIs are ongoing but the development process of new generation EGFR TKIs highlighted that the knowledge of oncogenic drivers and acquired resistances and following rational designs of targeted agents can give us a very informative insight of how to implement precision cancer medicine successfully. Tertiary resistant mutations, such as C797S mutation, during third generation EGFR TKI therapy were also recently identified and might be overcome by other generation EGFR TKIs (Thress et al., 2015).
Occurrence of a secondary or tertiary mutation is one of the major acquired resistance mechanisms, but there are also reported many other resistance ones (Sequist et al., 2011). Alternative bypass pathways are often activated, including MET amplification (Sequist et al., 2011, Yu et al., 2013), HER2 amplification (Takezawa et al., 2012, Yu et al., 2013), AXL overexpression (Zhang et al., 2012), HGF overexpression (Yano et al., 2011), PTEN loss (Yamamoto et al., 2010), and so on. Histologic transformation to other types of lung cancer such as small cell lung cancer has also been described (Niederst et al., 2015a, Sequist et al., 2011, Zhang et al., 2012). However, numerous clinical trials with different strategies have addressed these resistance mechanisms, but unfortunately failed to show their efficacy so far. Therefore, as no successful therapeutic treatment to overcome the resistance is available except T790M mutation-targeting third generation EGFR TKIs as mentioned above, standard chemotherapy, to date, remains a reasonable and the most widely accepted approach (Master et al., 2015, National Comprehensive Cancer Network, 2016, Novello et al., 2016). Nevertheless, as heterogeneity of the resistance mechanisms might affect the outcome of subsequent therapies, identification of involved resistance mechanism is informative for establishing possible treatment guidelines as well as helpful for designing further prospective studies, finally to get conclusive or solid evidence to optimize the use of subsequent treatments. Recently, new agents other than EGFR TKIs or small molecules, for example, anti-immune checkpoint monoclonal antibodies, have been emerging as major cancer therapeutics for many types of tumors including NSCLC. Nivolumab and pembrolizumab, programmed death-1 (PD-1) inhibitors, and atezolizumab, programmed death-ligand 1(PD-L1) inhibitor, have received approval for previously treated NSCLC patients and pembrolizumab has recently received approval for treatment-naïve NSCLC patients whose tumor expressed PD-L1. In addition, many other PD-1 or PD-L1 inhibitors including avelumab and durvalumab are under clinical investigation. Current investigations of immune checkpoint inhibitors as a single agent or in combination with other agents including EGFR TKI therapy in patients with EGFR mutations will give us insights of the role of immune checkpoint inhibitors. Actually, there were some responses to PD-L1 inhibitors, but the subgroup analyses of the published studies of PD-1 inhibitors regarding the efficacy did not show the benefit compared to docetaxel or chemotherapy in patients with EGFR mutations (Borghaei et al., 2015, Herbst et al., 2016).
Targeting EGFR activating mutations and resistance mutations in EGFR mutant NSCLC has shown a representative example of how precision cancer medicine can be implemented and should be put forward. In this review, clinical outcomes of the efforts having been put during the last decade for EGFR mutant patients are summarized, which provides an overview of current standard treatment for EGFR mutation-positive NSCLC and uncovers important issues in the management decisions. Lessons learned from many successes and much more failures of developing and testing EGFR TKIs as a single agent or in combination are also addressed, which renders us insights for future directions of basic and translational research and clinical developments.
Section snippets
Clinical outcomes of EGFR TKI therapy for treatment-naïve patients
First-generation EGFR TKIs, gefitinib and erlotinib, were developed for competitively blocking adenosine triphosphate binding to the TK domain. In 2003, gefitinib was first approved after showing response rates of 9–12% in unselected but previously treated or recurrent NSCLC patients, even though it was conditional and later withdrawn in the US (Fukuoka et al., 2003, Kris et al., 2003, Thatcher et al., 2005). Erlotinib was subsequently approved in 2007 for a similar indication (Shepherd et al.,
Clinical implications of molecular testings for ascertaining EGFR mutation
Before touching on clinical outcomes of EGFR targeting therapies regardless of monotherapy or combination therapy, we have to know how important molecular diagnostics ascertaining EGFR mutation status is. With ever-increasing accessibility to EGFR TKIs, routine molecular testing for EGFR mutation has become the standard care for advanced or metastatic NSCLC, which, however, has raised some issues related to molecular testing itself, for example, what testing platform should be used or what kind
Primary resistance and overcoming combination strategies
Primary resistance, defined as lack of any response or objective response defined to EGFR TKIs, accounts for about 20% to 40%. As mentioned above, uncommon non-sensitive EGFR mutations, such as exon 20 insertion or duplication mutation or de novo T790M mutation, are one of primary resistance mechanisms (Wang, Narasanna, et al. 2006). In addition, signaling through alternate oncogenic kinase, including BRAF mutation, HER2 mutation, KRAS mutation, and P3K mutation, was identified as causes of
Conclusion
The discovery of EGFR mutations and the success story of EGFR TKI therapy have changed the paradigm of cancer therapy from empirical cytotoxic chemotherapy to molecular targeted cancer therapy, or launching precision medicine in NSCLC. As a result, EGFR TKI therapy has become the standard therapy for EGFR mutant patients as first-line therapy. However, as known well, a big hope of cure for lung cancer have come with good experiences of dramatic and rapid responses of first-generation EGFR TKIs,
Conflict of interest statements
I have received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CJ Healthcare, Eli Lilly, Jansen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, and Samyang Biopharm for participating in advisory boards. I have received consulting fees from Ministry of Food and Drug Safety (MFDS), Korea, and Health Insurance Review and Assessment Service (HIRA), Korea.
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