Current targeted therapies in the treatment of advanced colorectal cancer: a review:

Andrew Moriarity; Jacintha O’Sullivan; John Kennedy; Brian Mehigan; Paul McCormick

doi:10.1177/1758834016646734

Current targeted therapies in the treatment of advanced colorectal cancer: a review:

Moriarity, Andrew; O’Sullivan, Jacintha; Kennedy, John; Mehigan, Brian; McCormick, Paul 2016-05-29 00:00:00 646734 TAM0010.1177/1758834016646734Therapeutic Advances in Medical OncologyA Moriarity, J O’Sullivan research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Current targeted therapies in the treatment 2016, Vol. 8(4) 276 –293 DOI: 10.1177/ of advanced colorectal cancer: a review © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ Andrew Moriarity, Jacintha O’Sullivan, John Kennedy, Brian Mehigan and Paul McCormick journalsPermissions.nav Abstract: Treatment strategies for metastatic colorectal cancer (mCRC) patients have undergone dramatic changes in the past decade and despite improved patient outcomes, there still exist areas for continued development. The introduction of targeted agents has provided clinicians with additional treatment options in mCRC, however, results have been mixed at best. These novel therapies were designed to interfere with specific molecules involved in the cellular carcinogenesis pathway and ultimately deliver a more focused treatment. Currently, their use in mCRC has been limited primarily as an adjunct to conventional chemotherapy regimens. This review explores the relevant cell-signaling networks in colorectal cancer, provides focus on the current targeted agent armamentarium approved for use in mCRC and explores the usefulness of predictive mCRC biomarkers. Keywords: biomarkers, colorectal cancer, signaling, targeted therapy Correspondence to: Introduction a palliative, rather than curative, approach. In Andrew Moriarity, MD Colorectal cancer (CRC) represents a significant such a setting, the treatment objectives are to St James’s Hospital, Surgical Oncology, St health issue as it is the most common gastrointes- delay disease progression, prolong survival and James’s St, Dublin 8, tinal (GI) tract cancer worldwide with over 1.2 maintain quality of life. Ireland andrewmoriarity@gmail. million new diagnoses each year [Ferlay et al. com 2010]. It is the third most common cancer diag- Despite decades of research and some promising Jacintha O’Sullivan, PhD nosis in both men and women [Siegel et al. 2012]. discoveries, the mainstay of metastatic colorectal John Kennedy, MD Brian Mehigan, MD Each year, there are over 520,000 people newly cancer (mCRC) treatment remains based on Paul McCormick, MD diagnosed with colorectal cancer in the western cytotoxic chemotherapy agents such as irinotecan St James’s Hospital, Dublin, Ireland world [Ferlay et al. 2010]. Between 35–50% of or oxaliplatin combined with a fluoropyrimidine those diagnosed will die from colorectal cancer, and leucovorin (FOLFIRI or FOLFOX regi- making it the second leading cause of cancer mens) that have both shown modest outcomes deaths affecting both sexes [US Cancer Statistics when used as first-line therapy [Goldberg et al. Working Group, 2009; Ferlay et al. 2010; Siegel 2004; Meyerhardt and Mayer, 2005; Tournigand et al. 2012]. Curative approaches are limited in a et al. 2004]. When 5-fluorouracil (5-FU) and leu- large proportion of patients as nearly 25% will covorin were the only therapeutic options, the present with metastatic disease and 40–50% of survival for patients with mCRC was between 10 those diagnosed initially with early-stage disease to 12 months [Erlichman et al. 1992; Piedbois, will eventually develop metastatic disease [Ferlay 1998]. The addition of irinotecan or oxaliplatin et al. 2007; Siegel et al. 2012]. increased overall survival (OS) to 18 months [Goldberg et al. 2004]. The addition of targeted The American Joint Committee on Cancer therapies over the past 10 years has improved OS (AJCC) reports the overall 5-year survival for in mCRC to between 20 to 24 months [Fuchs colorectal cancer at 65.2% [O’Connell et al. et al. 2008; Saltz et al. 2008; Tabernero et al. 2004]. Early-stage disease has a more favorable 2007; Van-Cutsem et al. 2008]. Due the hetero- prognosis and patients are frequently cured with geneous nature of cancer, a number of patients surgical resection alone. Unfortunately most receive targeted treatments with little or no ben- patients with advanced or metastatic disease are efit to them [Simon, 2008]. Further analysis of not suitable for resection and treatment is part of patient nonresponders has led to the discovery of 276 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Figure 1. Schematic of an endothelial cell depicting VEGFR-1, VEGFR-2, and VEGFR-3 and the mechanisms of action of the antiangiogenic agents bevacizumab, aflibercept, ramucirumab and regorafenib. Bevacizumab and aflibercept bind to VEGF and interrupt the interaction with VEGF receptors. Regorafenib is a small-molecule multi-kinase inhibitor of which targets include VEGFR-1 and VEGFR-3. TAS-102 consists of trifluridine that is incorporated into DNA, inducing DNA dysfunction, including DNA strand breakage. Cetuximab and panitumumab are anti-EGFR treatments that result in disruption of the MAP kinase pathway. EGFR, endothelial growth-factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth- factor receptor; DNA, deoxyribonucleic acid; MAP, a protein kinase signaling pathway. some common genetic alterations in the cancer emerged as key candidates for molecular-targeted genome that highlights the need for a more per- therapies [Tan et al. 2009]. sonalized approach [Stuart and Sellers, 2009]. Increased toxicity and treatment costs associated There are seven Food and Drug Administration with targeted therapies have further necessitated (FDA)-approved targeted therapies in mCRC the identification of diagnostic tools to select for (Figure 1): the large-molecule monoclonal anti- patients who will benefit from such treatments. bodies (mAbs) (bevacizumab, cetuximab, panitu- Currently, our available biomarkers are limited to mumab and ramucirumab), a recombinant fusion identifying the patients for whom treatment is not protein (ziv-aflibercept), a small molecule inhibi- suited, instead of those who would benefit from tor (regorafenib) and a nucleoside analog (trifluri- treatment [Schrag, 2004; Strimpakos et al. 2009; dine/tipiracil) [Grothey et al. 2013; Hurwitz et al. Workman et al. 2006]. 2004; Van-Cutsem et al. 2010a, 2010b, 2012]. This article reviews the recent advances and evi- Multiple critical protein-encoding genes and dence related to the employment of the FDA- pathways are believed to be responsible for tum- approved targeted therapies in mCRC and origenesis [Cancer and Atlas, 2012]. Colorectal explores the available biomarkers [NCI, 2015]. tumors contain a median 76 mutations, with, on average, 15 of these affecting candidate cancer genes [Vecchione et al. 2011; Wood et al. 2007]. Targeting receptors in colorectal cancer Increased understanding of the genetic and genomic changes in CRC has helped direct ther- Vascular endothelial growth factor apies and predict response, as evident in patients Angiogenesis is essential for the normal physio- with KRAS and BRAF mutations [Sclafani et al. logical functions of tissues, however, it also rep- 2013; Vaughn et al. 2011]. Genetic and epige- resents a critical process for tumor growth, netic errors in signal-transduction pathways lead survival and metastasis [Risau, 1997]. Tumor to malignant transformations and have thus cells require an extensive supply of new blood http://tam.sagepub.com 277 Therapeutic Advances in Medical Oncology 8(4) vessels to sustain their rapid growth and spread VEGFR-3) [Matthews et al. 1991; Shibuya et al. [Tanigawa et al. 1997]. Tumor vascularization 1990]. VEGF has been identified as the most occurs through the formation of new vessels from important regulator of blood vessel formation the preexisting vasculature or by insertion of [Ferrara, 1997; Hicklin and Ellis, 2005]. It is a interstitial tissue columns into the lumen of pre- multifunctional cytokine commonly expressed by existing vessels [Hubbard and Grothey, 2010]. tumor cells [Dvorak, 2002]. VEGF binds to both Numerous signaling molecules have been identi- VEGFR-1 and VEGFR-2, inducing endothelial- fied in promoting angiogenesis, including vascu- cell migration and proliferation, in addition to lar endothelial growth factor (VEGF), ephrin, increasing microvascular dilatation, permeability angiopoietin, platelet-derived growth factor and neovascularization in cancer and other disease (PDGF) and fibroblast growth factor (FGF) processes [Dvorak, 2002; Ferrara et al. 2003]. [Folkman and Klagsbrun, 1987; Takahashi et al. VEGFR-1 and VEGFR-2 are cell-surface- 1996; Yancopoulos et al. 2000]. Among these receptor tyrosine kinases (RTKs) expressed pre- molecules, VEGF is the most important regula- dominantly by vascular endothelial cells that tor of the angiogenic process identified to date activate downstream intracellular kinase-mediated and has shown markedly increased expression in signaling sequences after ligand binding [Hicklin advanced colorectal tumors [Ferrara et al. 2003; and Ellis, 2005]. Both of these receptors act as Shibuya, 2011; Takahashi et al. 1995]. Rapidly signaling molecules during vascular development dividing tumor cells outgrow their blood supply, and have important roles in physiological and creating a hypoxic and nutrient-deficient micro- pathological angiogenesis in contrast to VEGFR- environment, leading to activation of the hypoxia- 3, which mainly functions as a regulator of lym- inducible factor (HIF) system [Pugh and phangiogenesis through which it has been linked Ratcliffe, 2003; Tonini et al. 2003]. HIF is a to promoting metastases [Alitalo and Carmeliet, critical regulatory factor in the upregulation of 2002; Mustonen and Alitalo, 1995; Nathanson, VEGF and numerous other proangiogenic medi- 2003; Roberts et al. 2006]. ators (FGF, PIGF and PDGF) from the preex- isting vasculature [Eichholz et al. 2010; Hoeben The important role of VEGF-A and its receptor et al. 2004; Wek and Staschke, 2010]. There are VEGFR-2 in tumor angiogenesis has led to a multiple ligands and receptors in the VEGF/ large amount of research and drug development VEGF-receptor (VEGFR) axis required for spe- in mCRC and other malignancies. Therapeutic cific binding and the resultant activation of mul- agents such as bevacizumab and regorafenib have tiple signaling networks [Shibuya, 2001]. VEGF been developed with activity against the VEGF binding initiates a cascade of signaling processes system, either by targeting its ligands, cell-surface that promote endothelial cell proliferation and receptors or receptor kinases. migration, remodeling of the extracellular matrix, and increased vascular permeability and dilata- tion [Ferrara et al. 2003]. In addition to this, Epidermal growth-factor receptor VEGF has been linked to endothelial progenitor The epidermal growth-factor receptor (EGFR) cells involved in neovasculogenesis [George et al. has emerged as a captivating therapeutic target 2011]. VEGF is therefore an attractive target due to its key roles in both the regulation of impor- when designing and developing drugs to restrict tant normal cellular processes and in cancer tumor angiogenesis. Numerous anti-VEGF/ pathophysiology. EGFR was one of the first VEGFR-targeted therapies have demonstrated growth-factor receptors to be identified and exten- their potential to inhibit angiogenesis and tumor sively studied [Cohen, 1975]. It is a ubiquitous growth in the preclinical setting [Hicklin and transmembrane glycoprotein belonging to the Ellis, 2005]. ErbB/HER family of receptors, of which it is one of four structurally related receptor tyrosine VEGF (also known as VEGF-A) and its glycopro- kinases (RTKs) [Robinson et al. 2000]. These tein homologues (VEGF-B, VEGF-C, VEGF-D include EGFR (or ErbB-1/HER-1), ErbB-2 and PIGF) form a subfamily within the PDGF (HER-2), ErbB-3 (HER-3) and ErbB-4 (HER-4) family of growth factors [Meyer et al. 1999; [Casalini et al. 2004]. Neufeld et al. 1999; Shibuya, 2011]. VEGF and its family members mediate their angiogenic Ligand binding to the EGFR’s extracellular effects through differential binding to the three domain triggers receptor homo- or heterodi- VEGF receptors (VEGFR-1, VEGFR-2, and merization and subsequent autophosphorylation 278 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. within its cytoplasmic domain [Scagliotti et al. Tyrosine kinase activation occurs following ligand 2004]. Phosphorylation occurs on specific tyros- binding to the extracellular domain that drives ine residues and creates binding sites for proteins receptor homo- or heterodimerization and that serve as adaptors of downstream proteins autophosphorylation of the receptor complex involved in signal transduction [Cohen et al. [Casalini et al. 2004]. The phosphorylated recep- 1981]. Activated signal pathways include RAS/ tor complex acts as a site for signaling proteins to RAF/MAPK, PI3K/AKT, phospholipase C and assemble, leading to activation of signaling path- JAK2/STAT3 [Fiske et al. 2009; Hynes and Lane, ways such as RAS/RAF/MAPK, PI3/AKT, 2005; Yarden and Sliwkowski, 2001]. Stimulation STAT3, and protein kinase C [Bogdan and of these pathways promotes processes responsible Klämbt, 2001; Schlessinger, 2000]. Intracellular for tumor cell growth, proliferation, migration, mediators in these pathways transduce signals survival and invasion [Citri and Yarden, 2006; into the nucleus, affecting DNA synthesis and cell Fischer et al. 2003]. There are over 10 ligands division as well as a variety of cellular processes identified that bind to EGFR, ErbB-3 and ErbB- [Blume-Jensen and Hunter, 2001]. Growth fac- 4. These include epidermal growth factor (EGF), tors or somatic mutations can effect inappropriate transforming growth-factor alpha (TGF-α), hep- RTK activation, consequently promoting tumor- arin-binding EGF, amphiregulin, betacellulin, cell proliferation and growth [Arora and Scholar, epiregulin, and neuregulin [Hynes and Lane, 2005]. Tyrosine kinases have been the target of 2005; Salomon et al. 1995; Yarden and biological agents such as mAbs that can interfere Sliwkowski, 2001]. Of these ligands, EGF and with RTK activation or by small-molecule inhibi- TGF-α are thought to be the most important as tors that target the intracellular adenosine triphos- they selectively bind to EGFR [Jones et al. 1999]. phate (ATP)-binding site domain. EGFR expression is associated with solid tumor growth and is a common component of various Targeted therapies malignancies including colorectal, lung, breast, and Over the past 10 years, the number of targeted head and neck [Bonner et al. 2010; Nicholson et al. agents used in various malignancies has increased 2001; Pirker et al. 2009; Spaulding and Spaulding, dramatically. Currently there are seven FDA 2002]. Inappropriate activation of EGFR can occur approved targeted agents in mCRC with many from receptor or ligand overexpression, gene muta- more in development and in clinical trials [Chu, tion or amplification and loss of regulatory mecha- 2012]. These targeted agents fall under the broad nisms [Kuan et al. 2001; Moscatello et al. 1996; classification of mAbs, fusion proteins and small Pedersen et al. 2005]. Abnormal EGFR activity molecule inhibitors. initiates and promotes processes responsible for tumor growth and progression, including cell pro- liferation and maturation, angiogenesis, invasion, Monoclonal antibodies metastasis, and inhibition of apoptosis [Nicholson MAbs were the first class of targeted agents et al. 2001; Rocha-Lima et al. 2007; Yarden and proven to provide further benefit to patients with Sliwkowski, 2001]. mCRC. Currently there are three FDA-approved monoclonal-antibody agents and they act by either binding to the ligand (e.g. bevacizumab) or Receptor tyrosine kinase the extracellular domain of a receptor (e.g. cetux- RTKs are primary mediators of the signal trans- imab and panitumumab) which inhibits tyrosine duction pathways mediating critical cellular pro- kinase signal-transduction pathways necessary for cesses, such as survival, differentiation and cancer development [Cohen et al. 2005]. proliferation [Blume-Jensen and Hunter, 2001; ElShamy, 2005]. There are 58 identified RTKs Angiogenesis inhibition through molecular-tar- with approximately 20 different classes including geted therapy has been researched for decades the VEGFR, EGFR, Her2/neu (c-erbB2), and with the rationale that disruption of the VEGF– c-Kit (stem-cell-factor receptor) [Lemmon and VEGFR axis might prove beneficial in cancer Schlessinger, 2010; Robinson et al. 2000]. RTKs therapy [Folkman et al. 1971]. Antibody block- are cell-surface allosteric enzymes consisting of a ade of VEGF-A was first demonstrated in the single transmembrane domain that separates an early 1990s to suppress human-tumor growth in intracellular kinase domain from an extracellular nude mice [Kim et al. 1993]. The antibody treat- ligand-binding domain [Cadena and Gill, 1992]. ment selectively suppressed VEGF-A originating http://tam.sagepub.com 279 Therapeutic Advances in Medical Oncology 8(4) from the tumor and impressively showed signifi- oxaliplatin-based chemotherapy in mCRC cant inhibition of tumor growth without chemo- patients whose disease had progressed while on a therapy [Kim et al. 1993]. Clinical trials with first-line bevacizumab-containing regimen. This anti-VEGF agents have not been as successful as decision was based on a large randomized inter- demonstrated in the murine model, however, national clinical trial (ML18147), which had 820 they have proven beneficial when in combination patients randomly assigned chemotherapy alone with standard chemotherapy regimens. or chemotherapy in combination with beva- cizumab. The bevacizumab plus chemotherapy Bevacizumab. Bevacizumab (Avastin, Genentech/ group had a significant improvement in OS com- Roche, CA, US) is a recombinant, humanized pared with chemotherapy alone (11.2 versus 9.8 monoclonal antibody that binds directly to all months; Table 1) [Bennouna et al. 2013]. There major isoforms of VEGF-A, forming a protein was also a significant improvement in median complex that prevents further binding to VEGF PFS which increased from 4.0 to 5.7 months with receptors [Ferrara et al. 2004]. This neutralizes bevacizumab (Table 1) [Bennouna et al. 2013]. VEGF signal transduction through both VEGFR-1 and VEGFR-2 and inhibits endothelial cell prolif- Treatment with bevacizumab is relatively safe but eration and angiogenesis [Ellis, 2006]. Combining there are some risks. Early clinical trials suggested an anti-VEGF agent with standard cytotoxic che- that treatment with bevacizumab alone or with motherapy regimens enhances the suppressive chemotherapy resulted in an increased incidence effect on tumor-cell growth and the induction of of thrombosis, bleeding, proteinuria, and hyper- apoptosis in an additive manner [Ellis, 2006]. It tension [Gordon et al. 2001; Kabbinavar and also stabilizes tumor vasculature and decreases its Hurwitz, 2003; Yang et al. 2003]. Hurwitz and hydrostatic pressure, which improves systemic colleagues found similar adverse effects in mCRC delivery of the chemotherapy agents [Ellis, 2006]. patients receiving bevacizumab therapy but also noted there was a large incidence of patients devel- In 2004, the FDA approved bevacizumab as a oping grade 3 hypertension (requiring treatment) first-line agent for patients with mCRC based on [Hurwitz et al. 2004]. A recent meta-analysis on the results of a randomized, double-blind clinical the safety of bevacizumab therapy in patients with trial of 813 patients. Bevacizumab, when admin- advanced cancer concluded that there was a istered intravenously in conjunction with the IFL slightly higher risk for any severe (grade 3 or 4) regimen (irinotecan, 5-FU bolus, and leucov- adverse event compared with chemotherapy alone orin), had a significantly longer median OS than [Geiger-Gritsch et al. 2010]. the IFL plus placebo (20.3 versus 15.6 months; Table 1). Bevacizumab plus IFL was associated Cetuximab and panitumumab. Cetuximab with increased median progression-free survival (Erbitux, ImClone, NJ, US) and panitumumab (PFS) (10.6 versus 6.2 months), increased (Vectibix, Amgen, CA, US) are mAbs with FDA response rate (RR) (44.8% versus 34.8%), and approval for use in mCRC. They differ from beva- longer duration of response (10.4 versus 7.1 cizumab in their mechanism of action by targeting months) [Hurwitz et al. 2004]. In 2006, results EGFR, which is associated with tumor progres- from the Eastern Cooperative Oncology Group sion and a worse prognosis in mCRC and other Study (E3200) led to its approval as a second-line GI tract malignancies [Kaklamanis and Gatter, treatment in patients with previously treated 1992; Yasui et al. 1988]. Cetuximab is a chimeric mCRC. Following the failure of a prior irinote- human-murine immunoglobulin (IgG1), whereas can-containing regimen, patients who then panitumumab (IgG2) is fully humanized and received bevacizumab and FOLFOX had therefore believed to have less cellular cytotoxicity increased OS (from 10.8 to 12.9 months; Table [Kimura et al. 2007; Saltz et al. 2006]. Cetuximab 1) and PFS (from 4.7 to 7.3 months; Table 1) and panitumumab bind specifically to EGFR on [Giantonio et al. 2007]. Subsequent studies have both normal and tumor cells, and competitively validated the addition of bevacizumab to inhibit the binding of EGF, TGF-α and other FOLFOX or FOLFIRI regimens in untreated ligands [Baselga, 2001]. Both mAbs block down- mCRC patients due to their improved RR and stream signaling by binding to the EGFR’s extra- PFS [Fuchs et al. 2008; Saltz et al. 2008]. The cellular domain, which prevents further ligand most recent FDA approval for bevacizumab was binding, sterically hinders dimerization with other in 2013 for use in combination with a fluoropy- RTKs and induces EGFR degradation [Cohen rimidine and either irinotecan- or et al. 2005; Li et al. 2005; Saltz et al. 2006]. 280 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Table 1. FDA-approved therapeutic monoclonal antibodies used in metastatic colorectal cancer. Drug Class Target Study (year) 1st or 2nd line Regimen Marker Improvement (months) Bevacizumab mAb VEGF-A (2004) Hurwitz et al. 1st IFL None OS (15.6–20.3) [2004] Bevacizumab mAb VEGF-A E3200 (2006) Giantonio 2nd (failure of FOLFOX None OS (10.8–12.9) et al. [2007] irinotecan regimen) PFS (4.7–7.3) Bevacizumab mAb VEGF-A ML18147 (2013) 2nd (progressed FOLFOX KRAS WT OS (9.8–11.2) Bennouna et al. [2013] with bevacizumab or PFS (4.0–5.7) regimen) FOLFIRI Cetuximab mAb EGFR BOND (2004) 2nd (failure of FOLFIRI None TSR (22.9%) Cunningham et al. [2004] irinotecan regimen) TGD (4.1) Cetuximab mAb EGFR BOND (2004) 2nd (intolerant of Mono tx None TSR (10.8%) Cunningham et al. [2004] irinotecan) TGD (1.5) Cetuximab mAb EGFR CRYSTAL (2012) 1st line (KRAS WT) FOLFIRI KRAS WT PFS (8.4–9.9) Van-Cutsem et al. [2007] Panitumumab mAb EGFR (2006) Giusti et al. [2007] 2nd (failure of BSC None PFS (7.3–8.0 FOLFOX/ FOLFIRI) weeks) OS (0–10%) Panitumumab mAb EGFR PRIME (2010) Douillard FOLFOX4 KRAS WT PFS (8.0–9.6) et al. [2010] Ramucirumab mAb VEGF-R2 RAISE Tabernero et al. 2nd (progressed FOLFIRI None OS (11.7–13.3) [2015] with bevacizumab, PFS (4.5–5.7) oxaliplatin and a fluoropyrimidine) EGFR, endothelial growth-factor receptor; VEGFR, vascular endothelial growth factor receptor; FOLFIR, chemotherapy regimen that includes FOL – Folinic acid (leucovorin, calcium folinate or FA), F – Fluorouracil (5FU), IRI – Irinotecan hydrochloride; FOLFOX4, chemotherapy regimen that includes FOL – Folinic acid (leucovorin, calcium folinate or FA), F – Fluorouracil (5FU), OX (Oxaliplatin); IFL, chemotherapy regimen that includes I (Irinotecan), F (Fluorouracil (5FU)), L (Leucovorin); mAb, monoclonal antibody; KRAS Kirsten ras proto-oncogene; WT wild type. Blocking EGFR activation and subsequent which lead to tumor development [Fernández- impairment of downstream signaling (RAS-RAF- Medarde and Santos, 2011]. KRAS is a critical MAP kinase pathway) results in inhibition of cell mediator of EGFR-induced signaling. Activation growth, induction of apoptosis, decreased matrix of EGFR recruits proteins to the cell membrane metalloproteinase (MMPs) and VEGF produc- and causes KRAS to become activated, which tion [Vincenzi et al. 2010]. results in signaling through the PI3-K/AKT and MAPK (also known as ERK) pathways [Schubbert There are numerous oncogenic mutations pre- et al. 2007]. KRAS mutants are unable to hydro- sent in CRC which have contributed to the lack of lyze RAS-GTP to RAS-GDP and thus cannot be clinical success with targeted therapies in some restrained, leading to EGFR-independent activa- patient cohorts. Intrinsic or acquired resistances tion [Schubbert et al. 2007]. from mutations can lead to a significant variabil- ity in clinical response. Identification of the KRAS KRAS mutations have been detected in 40–45% gene mutation as a marker of impending failure of of CRC samples with a high grade of concordance EGFR-targeted therapy was the first large step in between primary and metastatic sites [Loupakis tailoring treatment of individuals [Amado et al. et al. 2009; Vaughn et al. 2011]. NRAS and HRAS 2008; Khambata-Ford et al. 2007; Lievre et al. mutations are less commonly found in CRC (1– 2008; Normanno et al. 2009]. The RAS family 3% of samples) [Irahara et al. 2010; Vaughn et al. comprises some small GTPases (hydrolase 2011]. Most KRAS mutations are missense and enzymes that bind and hydrolyze guanosine affect codons 12 and 13 of exon 2 [Amado et al. triphosphate) that are integral constituents of 2008; Hayashi et al. 1995]. The mutation at codon signaling networks contributing to a multitude of 12 is the most prevalent (80% versus 20%) and vital cellular processes [Bos, 1989]. Frequent oncogenic of the two [Guerrero et al. 2000]. More oncogenic mutations are found in members of the recently, KRAS mutations on codons 61 and 146, RAS subfamily (KRAS, NRAS, and HRAS), and exons 3 and 4 have also been reported to http://tam.sagepub.com 281 Therapeutic Advances in Medical Oncology 8(4) decrease anti-EFGR therapy [Douillard et al. been shown to upregulate angiogenic factors and 2013; Heinemann et al. 2014; Loupakis et al. recently, a study demonstrated KRAS mutant 2009]. In addition to KRAS, there is strong evi- cells to express higher levels of VEGF-A dence to support BRAF and NRAS mutations [Downward, 2003; Figueras et al. 2013; Zhang inhibiting the effect of anti-EGFR therapy [De et al. 2001]. Retrospective analysis of clinical ben- Roock et al. 2010]. The BRAF mutation has been efit from bevacizumab in patients with wild- or shown to be a strong negative prognostic factor in mutant-type KRAS tumors has found compara- CRC [Eklof et al. 2013]. The BRAF gene encodes ble benefits in PFS and OS [Hurwitz et al. 2009]. a serine threonine protein kinase which is directly activated by KRAS and leads to stimulation of the Both anti-EGFR treatments appear to be well tol- MAPK pathway [Di Fiore et al. 2010; Wan et al. erated, with a low incidence of grade 3 or 4 2004]. The average prevalence of BRAF muta- adverse events. The most common adverse event tions in colorectal cancer is an estimated 9.6%, with cetuximab was an acneiform rash. Other with the valine-to-glutamic-acid-amino-acid adverse events normally associated with cetuxi- (V600E) substitution being the most common mab therapy include infusion reactions, cardiac [Davies et al. 2002; Safaee Ardekani et al. 2012]. events, and hypomagnesemia, as observed in the BRAF mutations are considered mutually exclu- wild-type KRAS populations of the CRYSTAL, sive with KRAS mutations, as concomitant tumor OPUSS and CA225025 trials [Hubbard and mutations are extremely rare [Sahin et al. 2013]. Alberts, 2013]. The most common adverse events In a pooled analysis of the CRYSTAL and OPUS with panitumumab use were skin rash, randomized clinical trials, BRAF mutations were hypomagnesemia, paronychia, fatigue, abdomi- found to be a marker of poor prognosis but not an nal pain, nausea, and diarrhea [Giusti et al. 2007]. effective biomarker predictor in patients treated with anti-EGFR mAbs [Bokemeyer et al. 2012]. In 2004, cetuximab became the first anti-EGFR NRAS is a proto-oncogene from the RAS family mAb approved by the FDA for use in mCRC. It and its mutations on exon 2, 3, and 4 have been was approved as a second-line therapy for use in shown to be effective predictors of anti-EGFR irinotecan-refractory or intolerant patients with resistance [Douillard et al. 2013; Heinemann et al. EGFR-expressing tumors. Approval was based on 2014]. PIK3CA mutations on exon 9 and 20 often a randomized, two-arm phase II clinical trial coexist with KRAS mutations and are associated (BOND study) of 329 patients. Cetuximab com- with poor survival in patients treated with anti- bined with irinotecan significantly improved RRs EGFR therapy [Perrone et al. 2009; Wu et al. (22.9% versus 10.8%; Table 1) and time to pro- 2013]. gression (TTP) (4.1 versus 1.5 months; Table 1) compared with cetuximab alone [Cunningham Anti-EGFR mAbs therefore have minimal if not et al. 2004]. The results demonstrated that interfer- harmful results in patients with KRAS mutations ing with EGFR signaling can resensitize tumors due to their EGFR-independent activation of that are refractory to irinotecan. In 2012, the FDA oncogenic signaling cascades [Benvenuti et al. expanded its approval of cetuximab for use as a 2007]. The CRYSTAL study, along with the sup- first-line treatment in patients with KRAS wild type portive cetuximab studies, have clearly demon- (mutation negative), EGFR-expressing mCRC. strated that the presence of KRAS mutations The decision was based on retrospective analyses negatively affects the anti-EGFR therapies [Chau according to KRAS mutation status of tumor sam- and Cunningham, 2009; Dahabreh et al. 2011]. ples from patients enrolled in the CRYSTAL trial This finding led to National Comprehensive and two supportive studies (CA225025 and Cancer Network (NCCN) Clinical Practice OPUS). The addition of cetuximab to chemother- Guidelines in Oncology and the American Society apy or best supportive care (BSC) resulted in for Clinical Oncology (ASCO) guidelines to rec- improved OS, PFS and objective response rate ommend restricting anti-EGFR agents to mCRC (ORR) in patients with KRAS wild-type tumors patients with a wild-type KRAS allele [Allegra [Bokemeyer et al. 2012]. The use of cetuximab in et al. 2009; Jimeno et al. 2009]. patients with KRAS mutant tumors provided no benefit, and even potential harm. The prognostic potential of KRAS mutations in mCRC and its impact on the effectiveness of The CRYSTAL (cetuximab combined with chemotherapy or anti-VEGF inhibition remains irinotecan in first-line therapy for mCRC) trial undefined. The KRAS pathway has previously was a phase III open-label, randomized, 282 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. multicenter study that included 1217 patients decreased ORR (34% versus 53%) and PFS (5.5 (irrespective of KRAS status) who had not versus 8.6 months) compared with those receiving received prior chemotherapy for mCRC. A sig- FOLFOX-4 alone [Bokemeyer et al. 2011]. nificant improvement in median PFS was observed for the cetuximab plus FOLFIRI arm A recent comprehensive meta-analysis examined compared with the FOLFIRI only arm (8.9 ver- the effect of anti-EGFR mAbs in mCRC patients sus. 8.1 months) [Van-Cutsem et al. 2007]. There expressing wild-type KRAS compared with were minor but not significant differences in the mutant KRAS [Vale et al. 2012]. A total of 10 out median OS (19.6 versus 18.5 months) and the of 14 RCTs identified had available KRAS status. ORR (46% versus 38%) in both trial arms [Van- As expected, there was a positive effect on PFS Cutsem et al. 2007]. However, following retro- when anti-EGFR mAbs were used in patients spective analyses of patient subsets for KRAS with wild-type KRAS-expressing tumors but not status, the results were more favorable in the in the mutant KRAS patients. The PFS benefits KRAS wild-type patients given cetuximab. An were confined to trials combining mAbs along- updated survival analysis in 2011 further sup- side 5FU-based chemotherapy. There was also ported the addition of cetuximab to FOLFIRI as no evidence of a PFS benefit when anti-EGFR first-line therapy in patients with KRAS wild-type mAbs were given with bevacizumab. as these patients had increased median PFS (9.9 versus 8.4 months; Table 1), median OS (23.5 In 2006, the FDA provided accelerated approval versus 20.0 months) and ORR (57.3% versus to panitumumab (Vectibix) for the treatment of 39.7%) compared with FOLFIRI alone [Van- patients with EGFR-expressing, mCRC with dis- Cutsem et al. 2011]. The patients with KRAS ease progression on or following a FOLFOX/ mutations did not benefit from the addition of FOLFIRI-containing regimen. The approval was cetuximab as they had no improvement in median based on the findings of a single, open-label, mul- PFS (8.1 versus 7.5 months), OS (15.3 versus tinational phase III study that randomized 463 15.8 months) and ORR (31.0% versus 45.0 %) patients to receive panitumumab plus BSC or compared with FOLFIRI alone [Van-Cutsem BSC alone. The median PFS was significantly et al. 2011]. greater in patients receiving panitumumab com- pared with BSC alone (8.0 versus 7.3 weeks; CA225025 was an open-label randomized trial Table 1) [Giusti et al. 2007]. The ORR also that compared cetuximab plus BSC with BSC favored panitumumab (10.0% versus 0%; Table alone in 572 patients with previously treated 1). There were 19 partial responses (8%) with a EGFR-expressing mCRC. Among patients with median duration of 17 weeks among the panitu- wild-type KRAS, cetuximab significantly mumab group. Retrospective analysis of the study increased median OS (8.6 versus 5.0 months) and provided further evidence to the importance of PFS (3.8 versus 1.9 months). No benefits were KRAS status as clinical benefit was specific to observed in the mutant KRAS patients treated patients with wild-type KRAS tumors given pani- with cetuximab. tumumab monotherapy. The median PFS in the wild-type KRAS group treated with panitu- OPUS (oxaliplatin and cetuximab in first-line mumab was 12.3 weeks compared with 7.3 weeks treatment of mCRC) was a phase II open-label, for BSC [Amado et al. 2008]. Panitumumab RRs randomized study that compared FOLFOX-4 were also improved in the wild-type KRAS group (fluorouracil, leucovorin, and oxaliplatin) plus (17% versus 0%). There was no difference in OS cetuximab versus FOLFOX-4 alone in 337 between the two study arms, likely due to the untreated EGFR-expressing mCRC patients crossover design. [Bokemeyer et al. 2009]. KRAS wild-type patients who received cetuximab plus FOLFOX-4 had The PRIME (panitumumab randomized trial in increased ORR (57% versus 34%) and PFS (8.3 combination with chemotherapy for metastatic versus 7.2 months) compared with those receiving colorectal cancer to determine efficacy) study only FOLFOX-4 [Bokemeyer et al. 2011]. examined the efficacy and safety of panitumumab Median survival time was improved with cetuxi- in combination with FOLFOX-4. This was a mul- mab plus FOLFOX-4 but it was not statistically ticenter phase III trial that enrolled 1183 patients significant (22.8 versus 18.5 months) [Bokemeyer with no prior chemotherapy for mCRC. In the et al. 2011]. Patients with KRAS mutations who wild-type KRAS group, panitumumab plus received cetuximab plus FOLFOX-4 had a FOLFOX-4 significantly improved PFS compared http://tam.sagepub.com 283 Therapeutic Advances in Medical Oncology 8(4) with FOLFOX-4 (9.6 versus 8.0 months; Table 1) ramucirumab (n = 536 per arm) as an intrave- and nonsignificantly improved the median OS nous infusion every two weeks. The primary effi- (23.9 versus 19.7 months) [Douillard et al. 2010]. cacy endpoint of the study was OS. A statistically In the mutant KRAS group, panitumumab plus significant OS improvement was observed in FOLFOX-4 had a negative effect on both PFS and patients receiving FOLFIRI plus ramucirumab median OS compared with FOLFOX-4 (15.5 ver- compared with those receiving FOLFIRI plus sus 19.3 months). placebo (13.3 versus 11.7 months; Table 1). PFS was also significantly improved in patients who A meta-analysis in 2011 of four randomized clini- received ramucirumab in combination with FOL- cal studies found significant clinical benefit for FIRI (5.7 versus 4.5 months; Table 1). The infu- panitumumab-based therapy in wild-type KRAS sion was generally well tolerated, however, thyroid mCRC patients following prior chemotherapy dysfunction was noted in 2.6% of patients. exposure [Ibrahim and Abouelkhair, 2011]. There was an associated 42% improvement in PFS when panitumumab was used as a second- Fusion proteins line therapy but no benefit in the first-line setting Ziv-aflibercept. In 2012, the FDA approved ziv- [Ibrahim and Abouelkhair, 2011]. aflibercept (Zaltrap; Sanofi and Regeneron Phar- maceuticals, Inc., Tarrytown, NY, US) for the Both cetuximab and panitumumab are indicated treatment of mCRC that has progressed following for the treatment of EGFR-expressing, mCRC. an oxaliplatin-containing regimen. Ziv-aflibercept Panitumumab approval is for patients with dis- (previously known as aflibercept) is a recombi- ease progression while on, or following a nant fusion protein consisting of VEGF-binding FOLFOX/FOLFIRI-containing regimen, sections from the extracellular domains of human whereas cetuximab is for use with FOLFIRI as a VEGFR-1 and VEGFR-2 attached to the Fc por- first-line treatment and also in patients who are tion of human IgG1 immunoglobulin [Wang and irinotecan intolerant or refractory. Panitumumab Lockhart, 2012]. Ziv-aflibercept binds to and approval was based on its improvement of PFS, inactivates circulating VEGF, VEGF-B and PlGF while cetuximab approval was based on ORR. ligands, preventing their interaction with VEGF Neither anti-EGFR agent demonstrated a statisti- receptors [Holash et al. 2002]. FDA approval was cally significant benefit in OS, representing a based on the VELOUR trial, an international change in the accepted endpoints of a treatment, randomized double-blind study in which 1226 as previous new agents required an improvement patients received FOLFIRI with either ziv- in OS to gain FDA approval [Berlin et al. 2006; aflibercept or placebo [Van-Cutsem et al. 2012]. Tabernero et al. 2007]. These patients all had disease progression during or within 6 months of receiving oxaliplatin-based Ramucirumab. Ramucirumab (Cyramza; Eli Lilly chemotherapy with or without bevacizumab. A and Co., Indianapolis, IN, US) became the latest significant improvement in OS (13.5 versus 12.1 FDA-approved mAb on 24 April 2015 [Goel and months; Table 2), PFS (6.9 versus 4.7 months; Sun, 2015]. It is now indicated in combination Table 2) and RR (20% versus 11%; Table 2) was with FOLFIRI for the treatment of patients with observed in patients receiving the FOLFIRI plus mCRC whose disease has progressed on a first- zib-aflibercept regimen compared with the pla- line bevacizumab-, oxaliplatin- and fluoropyrimi- cebo cohort [Van-Cutsem et al. 2012]. Further dine-containing regimen [Tabernero et al. 2015]. subgroup analysis found the addition of ziv- Ramucirumab is a recombinant human monoclo- aflibercept to FOLFIRI had a trend of increased nal IgG1 antibody that binds and blocks further OS and PFS, regardless of prior bevacizumab use activity of the human VEGF-R2 with its ligands. [Allegra et al. 2012]. Approval was based on the RAISE trial which was a randomized, double-blind, multinational trial enrolling patients with mCRC that progressed Small-molecule inhibitors during or within 6 months of discontinuation of mAbs target circulating growth factors or recep- bevacizumab-, oxaliplatin- and fluoropyrimidine- tors on the cell exterior whereas small-molecule based combination chemotherapy [Tabernero inhibitors block cell signaling pathways from et al. 2015]. The clinical trial consisted of 1072 within. These inhibitors primarily compete with patients who were randomly allocated (1:1) to ATP for the ATP-binding site in the hinge region receive FOLFIRI plus placebo or FOLFIRI plus of the kinase receptor by mimicking the hydrogen 284 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Table 2. US Food and Drug Administration (FDA)-approved therapeutic targeted inhibitors used in metastatic colorectal cancer. Drug Class Target Study (year) 1st or 2nd line Regimen Marker Improvement Aflibercept Fusion Ab VEGF VELOUR (2012) 2nd (failure of FOLFIRI None OS (12.1–13.5) ligand Van-Cutsem oxaliplatin) PFS (4.7–6.9) et al. [2012] RR (11–22%) Regorafenib Multikinase VEGF CORRECT (2012) 3rd (failure of BSC None OS (5–6.4) TIE2 Grothey et al. standard therapies) PFS (1.7–2.0) [2013] RR (15–44%) Trifluridine/ Nucleoside DNA RECOURSE 3rd (failure of None OS (5.3–7.1) tipiracil analog (2015) Mayer standard therapies PFS (1.7–2.0] et al. [2015] + biological DNA, deoxyribonucleic acid; VEGF, vascular endothelial growth factor; BSC, best supportive care; FOLFIRI, irinotecan or oxaliplatin combined with a fluoropyrimidine and leucovorin; OS, overall survival; PFS, progression-free survival; RR, response rate. bonds formed by the adenine ring of ATP [Liu 2), PFS (2.0 versus 1.7 months; Table 2) and RR and Gray, 2006]. Other compounds allosterically (44% versus 15%; Table 2) [Grothey et al. 2013]. inhibit the catalytic activity by binding outside the The 1.4 month increase in OS equates a 23% active site [Zhang et al. 2009]. Small-molecule reduction in risk of death in a patient population inhibitors can either target a single receptor only, with a very poor prognosis and few options. such as gefitinib (targets EGFR only), or they can target multiple receptors, as in the use of sorafenib (which targets VEGFR, PDGFR, c-kit, Raf, flt-3 Nucleoside analog and RET) [Ranson et al. 2002; Yau et al. 2009]. TAS-102 is a combination of trifluridine and The most successful use of tyrosine kinase inhibi- tipiracil (LONSURF; Taiho Oncology, Inc., tors in clinical practice has been with gastrointes- Princeton, NJ, US), the most recent targeted tinal stromal tumors (GISTs) and the inhibition agent to gain FDA approval on 22 September of c-Kit. Most solid tumors have multiple genetic 2015. It is indicated in the treatment of patients alterations in specific proteins affecting a number with mCRC who have previously been treated of signaling networks making it difficult to target with fluoropyrimidine-, oxaliplatin-, and irinote- with single inhibitors. can-based chemotherapy, an anti-VEGF bio- logic product, and an anti-EGFR mAb, if RAS is Regorafenib. Regorafenib (BAY 73-4506; Bayer wild type [Mayer et al. 2015]. The drug is an Pharma AG, Berlin, Germany) is an oral multiki- oral combination therapy consisting of trifluri- nase small-molecule inhibitor that blocks several dine (a thymidine-based nucleoside analog), protein kinases involved in tumor growth and plus tipiracil hydrochloride (a novel thymidine angiogenesis which include VEGFR-1, VEGFR- phosphorylase inhibitor) [Lenz et al. 2015]. 2, VEGFR-3, TIE2, RET, KIT, PDGFR and TAS-102 is a dual-targeting formulation, with FGFR [Bhargava and Robinson, 2011; Wilhelm its major mechanism of action through trifluri- et al. 2011]. Additionally, it disrupts the down- dine being incorporated into DNA during DNA stream tumor-signaling cascades by binding to synthesis, thereby causing DNA dysfunction and the serine/threonine-specific protein kinase BRAF damage [Peters, 2015]. The thymidine phos- in the MAPK pathway responsible for stimulating phorylase inhibitor (tipiracil) prevents the degra- cell growth [Wilhelm et al. 2011]. In 2012, rego- dation of trifluridine. rafenib became the first FDA-approved small- molecule inhibitor for use in mCRC when Approval was based on a multicenter, double- combined with FOLFIRI. This was based on the blind, placebo-controlled trial (RECOURSE results of a pivotal phase III, multinational trial study) involving 800 patients with previously called CORRECT, which randomized 760 treated mCRC [Mayer et al. 2015]. The two arms patients to receive BSC plus either regorafenib or of the study had patients receiving trifluridine/tip- placebo. All the patients had already progressed iracil (n = 534) plus BSC or matching placebo during or within 3 months of their last standard (n = 266) plus BSC. The inclusion criteria approved therapies. Regorafenib displayed an included an Eastern Cooperative Oncology Group increased median OS (6.4 versus 5 months; Table (ECOG) status of 0 or 1, absence of brain http://tam.sagepub.com 285 Therapeutic Advances in Medical Oncology 8(4) metastasis, and absence of ascites requiring drain- clinical trial conducted in the Netherlands, had age in the 4 weeks leading to treatment. 755 patients with previously untreated mCRC randomly assigned to receive bevacizumab plus A statistically significant improvement in OS was CAPOX (capecitabine and oxaliplatin), or the demonstrated in the trifluridine/tipiracil com- same regimen accompanied by cetuximab [Tol pared with the placebo arm (7.1 versus 5.3 et al. 2009]. Surprisingly, the addition of cetuxi- months; Table 2). PFS was also improved in mab worsened median PFS (10.7 versus 9.4 patients randomly allocated to receive trifluri- months) and subset analysis demonstrated no dine/tipiracil (2.0 versus 1.7 months; Table 2). improved outcome in patients with wild-type KRAS [Tol et al. 2009]. There was even a signifi- The most common adverse drug reactions or lab- cant detrimental effect in PFS (8.1 versus 10.5 oratory abnormalities were neutropenia (38%), months) to patients with mutated KRAS receiv- anemia (18%), and thrombocytopenia (5%) ing bevacizumab and cetuximab [Tol et al. 2009]. [Mayer et al. 2015]. The incidence of adverse events was similar in both treatment groups after the exclusion of cetuximab-related adverse cutaneous effects. Combination therapies Anti-VEGF anti-EGFR. Paul Ehrlich’s magic bullet A similar negative outcome was reported in the theory has been realized to some extent with selec- Panitumumab Advanced Colorectal Cancer tive-binding agents but the effects are not as over- Evaluation (PACCE) trial in which previously whelming as anticipated [Winau et al. 2004]. The untreated mCRC patients were randomly assigned vision of targeted cancer therapies have not reached to receive chemotherapy (FOLFOX or FOLFIRI) their full potential; in part due to the complexity of and bevacizumab, either alone or accompanied by multiple and often redundant molecular pathways panitumumab. The addition of panitumumab to that promote oncogenic cellular processes [Tortora the FOLFOX group reduced both the median et al. 2008]. Therefore, it is rationalized that multi- PFS (10.0 versus 11.4 months) and the median ple-targeted agents may be required to selectively OS (19.4 versus 24.5 months) [Hecht et al. 2009]. inhibit the numerous tumor pathways [Johnson A similar pattern was observed in the smaller and Dippold, 1989]. Preclinical studies had sug- FOLFIRI cohort, although the differences were gested that combined blockade of both VEGF and not statistically significant. The PACCE trial was EGFR may be beneficial [Jung et al. 2002; Sha- prematurely discontinued due to the negative heen et al. 2001]. Dual targeting of VEGF and results and increased adverse events (skin toxicity, EGFR, two functionally linked and closely related diarrhea, infections and pulmonary embolism) in targets could interfere with the molecular feedback the panitumumab group. There is no obvious rea- loops responsible for acquired resistance and son for the negative effect observed by the combi- potentially increase the antitumor effects of the nation of an anti-VEGF and anti-EGFR mAbs individual agents [Saltz et al. 2007]. with standard chemotherapy regimens. This theory was supported with the results of The encouraging results observed in anti-VEGF/ BOND-2 (bevacizumab and irinotecan compared EGFR preclinical studies were not validated when with cetuximab and bevacizumab alone in irinote- examined in randomized trials. The failure of com- can-refractory colorectal cancer), a randomized, bined targeted therapies illustrates the difficulties phase II feasibility study of 83 irinotecan-refrac- and level of understanding we have of molecular tory mCRC patients. It demonstrated that the tri- oncology. It is possible that there is some interac- ple combination of irinotecan, cetuximab, and tion between the two antibodies and cytotoxic bevacizumab achieved better results in irinotecan- chemotherapy which negatively affected outcomes refractory mCRC compared with only cetuximab in PACCE and CAIRO-2 [Blanke, 2009]. and bevacizumab. The triple-therapy arm had increased time to tumor progression (7.3 versus 4.9 months), objective RR (37% versus 20%) and Conclusion OS (14.5 versus 11.4 months) [Saltz et al. 2007]. Treatment options for mCRC continue to emerge, however, there remains a number of Further studies would not support the good challenges to overcome. The complicated signal- anti-VEGF/EGFR results seen in BOND-2. ing pathways and network cross-talk involved in The CAIRO-2 study, a large multi-institutional tumorigenesis must be more effectively targeted. 286 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Benvenuti, S., Sartore-Bianchi, A., Di Nicolantonio, There is also the dynamic tumor microenviron- F., Zanon, C., Moroni, M., Veronese, S. et al. (2007) ment, genetic instabilities and host immune Oncogenic activation of the RAS/RAF signaling responses to be better understood. Further devel- pathway impairs the response of metastatic colorectal opment of therapies aimed at membrane recep- cancers to anti-epidermal growth factor receptor tors, intracellular signaling molecules and other antibody therapies. Cancer Res 67: 2643–2648. protein kinase targets is ongoing. All of these Berlin, J., Neubauer, M. and Swanson, P. (2006) potential targets demonstrate the complexity of Panitumumab antitumor activity in patients (pts) cancer and showcase the unlikelihood of finding a with metastatic colorectal cancer (mCRC) expressing ‘magical bullet’ therapy that will work for all ⩾10% epidermal growth factor receptor (EGFr). J patients. Some promising breakthroughs have Clin Oncol 24: 3548. been made researching the role of HER2 amplifi- cation and microsatellite instability in mCRC Bhargava, P. and Robinson, M. (2011) Development of second-generation VEGFR tyrosine kinase patients. As we move forward, further progress in inhibitors: current status. Curr Oncol Rep 13: 103–111. identifying new targeted therapies with associated predictive biomarkers is essential. Blanke, C. (2009) Dual-antibody therapy in advanced colorectal cancer: gather ye rosebuds while ye may. J Funding Clin Oncol 27: 655–658. The author(s) received no financial support for Blume-Jensen, P. and Hunter, T. (2001) Oncogenic the research, authorship, and/or publication of kinase signalling. Nature 411: 355–365. this article. Bogdan, S. and Klämbt, C. (2001) Epidermal growth factor receptor signaling. Curr Biol 11: R292–R295. 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Abstract

646734 TAM0010.1177/1758834016646734Therapeutic Advances in Medical OncologyA Moriarity, J O’Sullivan research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Current targeted therapies in the treatment 2016, Vol. 8(4) 276 –293 DOI: 10.1177/ of advanced colorectal cancer: a review © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ Andrew Moriarity, Jacintha O’Sullivan, John Kennedy, Brian Mehigan and Paul McCormick journalsPermissions.nav Abstract: Treatment strategies for metastatic colorectal cancer (mCRC) patients have undergone dramatic changes in the past decade and despite improved patient outcomes, there still exist areas for continued development. The introduction of targeted agents has provided clinicians with additional treatment options in mCRC, however, results have been mixed at best. These novel therapies were designed to interfere with specific molecules involved in the cellular carcinogenesis pathway and ultimately deliver a more focused treatment. Currently, their use in mCRC has been limited primarily as an adjunct to conventional chemotherapy regimens. This review explores the relevant cell-signaling networks in colorectal cancer, provides focus on the current targeted agent armamentarium approved for use in mCRC and explores the usefulness of predictive mCRC biomarkers. Keywords: biomarkers, colorectal cancer, signaling, targeted therapy Correspondence to: Introduction a palliative, rather than curative, approach. In Andrew Moriarity, MD Colorectal cancer (CRC) represents a significant such a setting, the treatment objectives are to St James’s Hospital, Surgical Oncology, St health issue as it is the most common gastrointes- delay disease progression, prolong survival and James’s St, Dublin 8, tinal (GI) tract cancer worldwide with over 1.2 maintain quality of life. Ireland andrewmoriarity@gmail. million new diagnoses each year [Ferlay et al. com 2010]. It is the third most common cancer diag- Despite decades of research and some promising Jacintha O’Sullivan, PhD nosis in both men and women [Siegel et al. 2012]. discoveries, the mainstay of metastatic colorectal John Kennedy, MD Brian Mehigan, MD Each year, there are over 520,000 people newly cancer (mCRC) treatment remains based on Paul McCormick, MD diagnosed with colorectal cancer in the western cytotoxic chemotherapy agents such as irinotecan St James’s Hospital, Dublin, Ireland world [Ferlay et al. 2010]. Between 35–50% of or oxaliplatin combined with a fluoropyrimidine those diagnosed will die from colorectal cancer, and leucovorin (FOLFIRI or FOLFOX regi- making it the second leading cause of cancer mens) that have both shown modest outcomes deaths affecting both sexes [US Cancer Statistics when used as first-line therapy [Goldberg et al. Working Group, 2009; Ferlay et al. 2010; Siegel 2004; Meyerhardt and Mayer, 2005; Tournigand et al. 2012]. Curative approaches are limited in a et al. 2004]. When 5-fluorouracil (5-FU) and leu- large proportion of patients as nearly 25% will covorin were the only therapeutic options, the present with metastatic disease and 40–50% of survival for patients with mCRC was between 10 those diagnosed initially with early-stage disease to 12 months [Erlichman et al. 1992; Piedbois, will eventually develop metastatic disease [Ferlay 1998]. The addition of irinotecan or oxaliplatin et al. 2007; Siegel et al. 2012]. increased overall survival (OS) to 18 months [Goldberg et al. 2004]. The addition of targeted The American Joint Committee on Cancer therapies over the past 10 years has improved OS (AJCC) reports the overall 5-year survival for in mCRC to between 20 to 24 months [Fuchs colorectal cancer at 65.2% [O’Connell et al. et al. 2008; Saltz et al. 2008; Tabernero et al. 2004]. Early-stage disease has a more favorable 2007; Van-Cutsem et al. 2008]. Due the hetero- prognosis and patients are frequently cured with geneous nature of cancer, a number of patients surgical resection alone. Unfortunately most receive targeted treatments with little or no ben- patients with advanced or metastatic disease are efit to them [Simon, 2008]. Further analysis of not suitable for resection and treatment is part of patient nonresponders has led to the discovery of 276 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Figure 1. Schematic of an endothelial cell depicting VEGFR-1, VEGFR-2, and VEGFR-3 and the mechanisms of action of the antiangiogenic agents bevacizumab, aflibercept, ramucirumab and regorafenib. Bevacizumab and aflibercept bind to VEGF and interrupt the interaction with VEGF receptors. Regorafenib is a small-molecule multi-kinase inhibitor of which targets include VEGFR-1 and VEGFR-3. TAS-102 consists of trifluridine that is incorporated into DNA, inducing DNA dysfunction, including DNA strand breakage. Cetuximab and panitumumab are anti-EGFR treatments that result in disruption of the MAP kinase pathway. EGFR, endothelial growth-factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth- factor receptor; DNA, deoxyribonucleic acid; MAP, a protein kinase signaling pathway. some common genetic alterations in the cancer emerged as key candidates for molecular-targeted genome that highlights the need for a more per- therapies [Tan et al. 2009]. sonalized approach [Stuart and Sellers, 2009]. Increased toxicity and treatment costs associated There are seven Food and Drug Administration with targeted therapies have further necessitated (FDA)-approved targeted therapies in mCRC the identification of diagnostic tools to select for (Figure 1): the large-molecule monoclonal anti- patients who will benefit from such treatments. bodies (mAbs) (bevacizumab, cetuximab, panitu- Currently, our available biomarkers are limited to mumab and ramucirumab), a recombinant fusion identifying the patients for whom treatment is not protein (ziv-aflibercept), a small molecule inhibi- suited, instead of those who would benefit from tor (regorafenib) and a nucleoside analog (trifluri- treatment [Schrag, 2004; Strimpakos et al. 2009; dine/tipiracil) [Grothey et al. 2013; Hurwitz et al. Workman et al. 2006]. 2004; Van-Cutsem et al. 2010a, 2010b, 2012]. This article reviews the recent advances and evi- Multiple critical protein-encoding genes and dence related to the employment of the FDA- pathways are believed to be responsible for tum- approved targeted therapies in mCRC and origenesis [Cancer and Atlas, 2012]. Colorectal explores the available biomarkers [NCI, 2015]. tumors contain a median 76 mutations, with, on average, 15 of these affecting candidate cancer genes [Vecchione et al. 2011; Wood et al. 2007]. Targeting receptors in colorectal cancer Increased understanding of the genetic and genomic changes in CRC has helped direct ther- Vascular endothelial growth factor apies and predict response, as evident in patients Angiogenesis is essential for the normal physio- with KRAS and BRAF mutations [Sclafani et al. logical functions of tissues, however, it also rep- 2013; Vaughn et al. 2011]. Genetic and epige- resents a critical process for tumor growth, netic errors in signal-transduction pathways lead survival and metastasis [Risau, 1997]. Tumor to malignant transformations and have thus cells require an extensive supply of new blood http://tam.sagepub.com 277 Therapeutic Advances in Medical Oncology 8(4) vessels to sustain their rapid growth and spread VEGFR-3) [Matthews et al. 1991; Shibuya et al. [Tanigawa et al. 1997]. Tumor vascularization 1990]. VEGF has been identified as the most occurs through the formation of new vessels from important regulator of blood vessel formation the preexisting vasculature or by insertion of [Ferrara, 1997; Hicklin and Ellis, 2005]. It is a interstitial tissue columns into the lumen of pre- multifunctional cytokine commonly expressed by existing vessels [Hubbard and Grothey, 2010]. tumor cells [Dvorak, 2002]. VEGF binds to both Numerous signaling molecules have been identi- VEGFR-1 and VEGFR-2, inducing endothelial- fied in promoting angiogenesis, including vascu- cell migration and proliferation, in addition to lar endothelial growth factor (VEGF), ephrin, increasing microvascular dilatation, permeability angiopoietin, platelet-derived growth factor and neovascularization in cancer and other disease (PDGF) and fibroblast growth factor (FGF) processes [Dvorak, 2002; Ferrara et al. 2003]. [Folkman and Klagsbrun, 1987; Takahashi et al. VEGFR-1 and VEGFR-2 are cell-surface- 1996; Yancopoulos et al. 2000]. Among these receptor tyrosine kinases (RTKs) expressed pre- molecules, VEGF is the most important regula- dominantly by vascular endothelial cells that tor of the angiogenic process identified to date activate downstream intracellular kinase-mediated and has shown markedly increased expression in signaling sequences after ligand binding [Hicklin advanced colorectal tumors [Ferrara et al. 2003; and Ellis, 2005]. Both of these receptors act as Shibuya, 2011; Takahashi et al. 1995]. Rapidly signaling molecules during vascular development dividing tumor cells outgrow their blood supply, and have important roles in physiological and creating a hypoxic and nutrient-deficient micro- pathological angiogenesis in contrast to VEGFR- environment, leading to activation of the hypoxia- 3, which mainly functions as a regulator of lym- inducible factor (HIF) system [Pugh and phangiogenesis through which it has been linked Ratcliffe, 2003; Tonini et al. 2003]. HIF is a to promoting metastases [Alitalo and Carmeliet, critical regulatory factor in the upregulation of 2002; Mustonen and Alitalo, 1995; Nathanson, VEGF and numerous other proangiogenic medi- 2003; Roberts et al. 2006]. ators (FGF, PIGF and PDGF) from the preex- isting vasculature [Eichholz et al. 2010; Hoeben The important role of VEGF-A and its receptor et al. 2004; Wek and Staschke, 2010]. There are VEGFR-2 in tumor angiogenesis has led to a multiple ligands and receptors in the VEGF/ large amount of research and drug development VEGF-receptor (VEGFR) axis required for spe- in mCRC and other malignancies. Therapeutic cific binding and the resultant activation of mul- agents such as bevacizumab and regorafenib have tiple signaling networks [Shibuya, 2001]. VEGF been developed with activity against the VEGF binding initiates a cascade of signaling processes system, either by targeting its ligands, cell-surface that promote endothelial cell proliferation and receptors or receptor kinases. migration, remodeling of the extracellular matrix, and increased vascular permeability and dilata- tion [Ferrara et al. 2003]. In addition to this, Epidermal growth-factor receptor VEGF has been linked to endothelial progenitor The epidermal growth-factor receptor (EGFR) cells involved in neovasculogenesis [George et al. has emerged as a captivating therapeutic target 2011]. VEGF is therefore an attractive target due to its key roles in both the regulation of impor- when designing and developing drugs to restrict tant normal cellular processes and in cancer tumor angiogenesis. Numerous anti-VEGF/ pathophysiology. EGFR was one of the first VEGFR-targeted therapies have demonstrated growth-factor receptors to be identified and exten- their potential to inhibit angiogenesis and tumor sively studied [Cohen, 1975]. It is a ubiquitous growth in the preclinical setting [Hicklin and transmembrane glycoprotein belonging to the Ellis, 2005]. ErbB/HER family of receptors, of which it is one of four structurally related receptor tyrosine VEGF (also known as VEGF-A) and its glycopro- kinases (RTKs) [Robinson et al. 2000]. These tein homologues (VEGF-B, VEGF-C, VEGF-D include EGFR (or ErbB-1/HER-1), ErbB-2 and PIGF) form a subfamily within the PDGF (HER-2), ErbB-3 (HER-3) and ErbB-4 (HER-4) family of growth factors [Meyer et al. 1999; [Casalini et al. 2004]. Neufeld et al. 1999; Shibuya, 2011]. VEGF and its family members mediate their angiogenic Ligand binding to the EGFR’s extracellular effects through differential binding to the three domain triggers receptor homo- or heterodi- VEGF receptors (VEGFR-1, VEGFR-2, and merization and subsequent autophosphorylation 278 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. within its cytoplasmic domain [Scagliotti et al. Tyrosine kinase activation occurs following ligand 2004]. Phosphorylation occurs on specific tyros- binding to the extracellular domain that drives ine residues and creates binding sites for proteins receptor homo- or heterodimerization and that serve as adaptors of downstream proteins autophosphorylation of the receptor complex involved in signal transduction [Cohen et al. [Casalini et al. 2004]. The phosphorylated recep- 1981]. Activated signal pathways include RAS/ tor complex acts as a site for signaling proteins to RAF/MAPK, PI3K/AKT, phospholipase C and assemble, leading to activation of signaling path- JAK2/STAT3 [Fiske et al. 2009; Hynes and Lane, ways such as RAS/RAF/MAPK, PI3/AKT, 2005; Yarden and Sliwkowski, 2001]. Stimulation STAT3, and protein kinase C [Bogdan and of these pathways promotes processes responsible Klämbt, 2001; Schlessinger, 2000]. Intracellular for tumor cell growth, proliferation, migration, mediators in these pathways transduce signals survival and invasion [Citri and Yarden, 2006; into the nucleus, affecting DNA synthesis and cell Fischer et al. 2003]. There are over 10 ligands division as well as a variety of cellular processes identified that bind to EGFR, ErbB-3 and ErbB- [Blume-Jensen and Hunter, 2001]. Growth fac- 4. These include epidermal growth factor (EGF), tors or somatic mutations can effect inappropriate transforming growth-factor alpha (TGF-α), hep- RTK activation, consequently promoting tumor- arin-binding EGF, amphiregulin, betacellulin, cell proliferation and growth [Arora and Scholar, epiregulin, and neuregulin [Hynes and Lane, 2005]. Tyrosine kinases have been the target of 2005; Salomon et al. 1995; Yarden and biological agents such as mAbs that can interfere Sliwkowski, 2001]. Of these ligands, EGF and with RTK activation or by small-molecule inhibi- TGF-α are thought to be the most important as tors that target the intracellular adenosine triphos- they selectively bind to EGFR [Jones et al. 1999]. phate (ATP)-binding site domain. EGFR expression is associated with solid tumor growth and is a common component of various Targeted therapies malignancies including colorectal, lung, breast, and Over the past 10 years, the number of targeted head and neck [Bonner et al. 2010; Nicholson et al. agents used in various malignancies has increased 2001; Pirker et al. 2009; Spaulding and Spaulding, dramatically. Currently there are seven FDA 2002]. Inappropriate activation of EGFR can occur approved targeted agents in mCRC with many from receptor or ligand overexpression, gene muta- more in development and in clinical trials [Chu, tion or amplification and loss of regulatory mecha- 2012]. These targeted agents fall under the broad nisms [Kuan et al. 2001; Moscatello et al. 1996; classification of mAbs, fusion proteins and small Pedersen et al. 2005]. Abnormal EGFR activity molecule inhibitors. initiates and promotes processes responsible for tumor growth and progression, including cell pro- liferation and maturation, angiogenesis, invasion, Monoclonal antibodies metastasis, and inhibition of apoptosis [Nicholson MAbs were the first class of targeted agents et al. 2001; Rocha-Lima et al. 2007; Yarden and proven to provide further benefit to patients with Sliwkowski, 2001]. mCRC. Currently there are three FDA-approved monoclonal-antibody agents and they act by either binding to the ligand (e.g. bevacizumab) or Receptor tyrosine kinase the extracellular domain of a receptor (e.g. cetux- RTKs are primary mediators of the signal trans- imab and panitumumab) which inhibits tyrosine duction pathways mediating critical cellular pro- kinase signal-transduction pathways necessary for cesses, such as survival, differentiation and cancer development [Cohen et al. 2005]. proliferation [Blume-Jensen and Hunter, 2001; ElShamy, 2005]. There are 58 identified RTKs Angiogenesis inhibition through molecular-tar- with approximately 20 different classes including geted therapy has been researched for decades the VEGFR, EGFR, Her2/neu (c-erbB2), and with the rationale that disruption of the VEGF– c-Kit (stem-cell-factor receptor) [Lemmon and VEGFR axis might prove beneficial in cancer Schlessinger, 2010; Robinson et al. 2000]. RTKs therapy [Folkman et al. 1971]. Antibody block- are cell-surface allosteric enzymes consisting of a ade of VEGF-A was first demonstrated in the single transmembrane domain that separates an early 1990s to suppress human-tumor growth in intracellular kinase domain from an extracellular nude mice [Kim et al. 1993]. The antibody treat- ligand-binding domain [Cadena and Gill, 1992]. ment selectively suppressed VEGF-A originating http://tam.sagepub.com 279 Therapeutic Advances in Medical Oncology 8(4) from the tumor and impressively showed signifi- oxaliplatin-based chemotherapy in mCRC cant inhibition of tumor growth without chemo- patients whose disease had progressed while on a therapy [Kim et al. 1993]. Clinical trials with first-line bevacizumab-containing regimen. This anti-VEGF agents have not been as successful as decision was based on a large randomized inter- demonstrated in the murine model, however, national clinical trial (ML18147), which had 820 they have proven beneficial when in combination patients randomly assigned chemotherapy alone with standard chemotherapy regimens. or chemotherapy in combination with beva- cizumab. The bevacizumab plus chemotherapy Bevacizumab. Bevacizumab (Avastin, Genentech/ group had a significant improvement in OS com- Roche, CA, US) is a recombinant, humanized pared with chemotherapy alone (11.2 versus 9.8 monoclonal antibody that binds directly to all months; Table 1) [Bennouna et al. 2013]. There major isoforms of VEGF-A, forming a protein was also a significant improvement in median complex that prevents further binding to VEGF PFS which increased from 4.0 to 5.7 months with receptors [Ferrara et al. 2004]. This neutralizes bevacizumab (Table 1) [Bennouna et al. 2013]. VEGF signal transduction through both VEGFR-1 and VEGFR-2 and inhibits endothelial cell prolif- Treatment with bevacizumab is relatively safe but eration and angiogenesis [Ellis, 2006]. Combining there are some risks. Early clinical trials suggested an anti-VEGF agent with standard cytotoxic che- that treatment with bevacizumab alone or with motherapy regimens enhances the suppressive chemotherapy resulted in an increased incidence effect on tumor-cell growth and the induction of of thrombosis, bleeding, proteinuria, and hyper- apoptosis in an additive manner [Ellis, 2006]. It tension [Gordon et al. 2001; Kabbinavar and also stabilizes tumor vasculature and decreases its Hurwitz, 2003; Yang et al. 2003]. Hurwitz and hydrostatic pressure, which improves systemic colleagues found similar adverse effects in mCRC delivery of the chemotherapy agents [Ellis, 2006]. patients receiving bevacizumab therapy but also noted there was a large incidence of patients devel- In 2004, the FDA approved bevacizumab as a oping grade 3 hypertension (requiring treatment) first-line agent for patients with mCRC based on [Hurwitz et al. 2004]. A recent meta-analysis on the results of a randomized, double-blind clinical the safety of bevacizumab therapy in patients with trial of 813 patients. Bevacizumab, when admin- advanced cancer concluded that there was a istered intravenously in conjunction with the IFL slightly higher risk for any severe (grade 3 or 4) regimen (irinotecan, 5-FU bolus, and leucov- adverse event compared with chemotherapy alone orin), had a significantly longer median OS than [Geiger-Gritsch et al. 2010]. the IFL plus placebo (20.3 versus 15.6 months; Table 1). Bevacizumab plus IFL was associated Cetuximab and panitumumab. Cetuximab with increased median progression-free survival (Erbitux, ImClone, NJ, US) and panitumumab (PFS) (10.6 versus 6.2 months), increased (Vectibix, Amgen, CA, US) are mAbs with FDA response rate (RR) (44.8% versus 34.8%), and approval for use in mCRC. They differ from beva- longer duration of response (10.4 versus 7.1 cizumab in their mechanism of action by targeting months) [Hurwitz et al. 2004]. In 2006, results EGFR, which is associated with tumor progres- from the Eastern Cooperative Oncology Group sion and a worse prognosis in mCRC and other Study (E3200) led to its approval as a second-line GI tract malignancies [Kaklamanis and Gatter, treatment in patients with previously treated 1992; Yasui et al. 1988]. Cetuximab is a chimeric mCRC. Following the failure of a prior irinote- human-murine immunoglobulin (IgG1), whereas can-containing regimen, patients who then panitumumab (IgG2) is fully humanized and received bevacizumab and FOLFOX had therefore believed to have less cellular cytotoxicity increased OS (from 10.8 to 12.9 months; Table [Kimura et al. 2007; Saltz et al. 2006]. Cetuximab 1) and PFS (from 4.7 to 7.3 months; Table 1) and panitumumab bind specifically to EGFR on [Giantonio et al. 2007]. Subsequent studies have both normal and tumor cells, and competitively validated the addition of bevacizumab to inhibit the binding of EGF, TGF-α and other FOLFOX or FOLFIRI regimens in untreated ligands [Baselga, 2001]. Both mAbs block down- mCRC patients due to their improved RR and stream signaling by binding to the EGFR’s extra- PFS [Fuchs et al. 2008; Saltz et al. 2008]. The cellular domain, which prevents further ligand most recent FDA approval for bevacizumab was binding, sterically hinders dimerization with other in 2013 for use in combination with a fluoropy- RTKs and induces EGFR degradation [Cohen rimidine and either irinotecan- or et al. 2005; Li et al. 2005; Saltz et al. 2006]. 280 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Table 1. FDA-approved therapeutic monoclonal antibodies used in metastatic colorectal cancer. Drug Class Target Study (year) 1st or 2nd line Regimen Marker Improvement (months) Bevacizumab mAb VEGF-A (2004) Hurwitz et al. 1st IFL None OS (15.6–20.3) [2004] Bevacizumab mAb VEGF-A E3200 (2006) Giantonio 2nd (failure of FOLFOX None OS (10.8–12.9) et al. [2007] irinotecan regimen) PFS (4.7–7.3) Bevacizumab mAb VEGF-A ML18147 (2013) 2nd (progressed FOLFOX KRAS WT OS (9.8–11.2) Bennouna et al. [2013] with bevacizumab or PFS (4.0–5.7) regimen) FOLFIRI Cetuximab mAb EGFR BOND (2004) 2nd (failure of FOLFIRI None TSR (22.9%) Cunningham et al. [2004] irinotecan regimen) TGD (4.1) Cetuximab mAb EGFR BOND (2004) 2nd (intolerant of Mono tx None TSR (10.8%) Cunningham et al. [2004] irinotecan) TGD (1.5) Cetuximab mAb EGFR CRYSTAL (2012) 1st line (KRAS WT) FOLFIRI KRAS WT PFS (8.4–9.9) Van-Cutsem et al. [2007] Panitumumab mAb EGFR (2006) Giusti et al. [2007] 2nd (failure of BSC None PFS (7.3–8.0 FOLFOX/ FOLFIRI) weeks) OS (0–10%) Panitumumab mAb EGFR PRIME (2010) Douillard FOLFOX4 KRAS WT PFS (8.0–9.6) et al. [2010] Ramucirumab mAb VEGF-R2 RAISE Tabernero et al. 2nd (progressed FOLFIRI None OS (11.7–13.3) [2015] with bevacizumab, PFS (4.5–5.7) oxaliplatin and a fluoropyrimidine) EGFR, endothelial growth-factor receptor; VEGFR, vascular endothelial growth factor receptor; FOLFIR, chemotherapy regimen that includes FOL – Folinic acid (leucovorin, calcium folinate or FA), F – Fluorouracil (5FU), IRI – Irinotecan hydrochloride; FOLFOX4, chemotherapy regimen that includes FOL – Folinic acid (leucovorin, calcium folinate or FA), F – Fluorouracil (5FU), OX (Oxaliplatin); IFL, chemotherapy regimen that includes I (Irinotecan), F (Fluorouracil (5FU)), L (Leucovorin); mAb, monoclonal antibody; KRAS Kirsten ras proto-oncogene; WT wild type. Blocking EGFR activation and subsequent which lead to tumor development [Fernández- impairment of downstream signaling (RAS-RAF- Medarde and Santos, 2011]. KRAS is a critical MAP kinase pathway) results in inhibition of cell mediator of EGFR-induced signaling. Activation growth, induction of apoptosis, decreased matrix of EGFR recruits proteins to the cell membrane metalloproteinase (MMPs) and VEGF produc- and causes KRAS to become activated, which tion [Vincenzi et al. 2010]. results in signaling through the PI3-K/AKT and MAPK (also known as ERK) pathways [Schubbert There are numerous oncogenic mutations pre- et al. 2007]. KRAS mutants are unable to hydro- sent in CRC which have contributed to the lack of lyze RAS-GTP to RAS-GDP and thus cannot be clinical success with targeted therapies in some restrained, leading to EGFR-independent activa- patient cohorts. Intrinsic or acquired resistances tion [Schubbert et al. 2007]. from mutations can lead to a significant variabil- ity in clinical response. Identification of the KRAS KRAS mutations have been detected in 40–45% gene mutation as a marker of impending failure of of CRC samples with a high grade of concordance EGFR-targeted therapy was the first large step in between primary and metastatic sites [Loupakis tailoring treatment of individuals [Amado et al. et al. 2009; Vaughn et al. 2011]. NRAS and HRAS 2008; Khambata-Ford et al. 2007; Lievre et al. mutations are less commonly found in CRC (1– 2008; Normanno et al. 2009]. The RAS family 3% of samples) [Irahara et al. 2010; Vaughn et al. comprises some small GTPases (hydrolase 2011]. Most KRAS mutations are missense and enzymes that bind and hydrolyze guanosine affect codons 12 and 13 of exon 2 [Amado et al. triphosphate) that are integral constituents of 2008; Hayashi et al. 1995]. The mutation at codon signaling networks contributing to a multitude of 12 is the most prevalent (80% versus 20%) and vital cellular processes [Bos, 1989]. Frequent oncogenic of the two [Guerrero et al. 2000]. More oncogenic mutations are found in members of the recently, KRAS mutations on codons 61 and 146, RAS subfamily (KRAS, NRAS, and HRAS), and exons 3 and 4 have also been reported to http://tam.sagepub.com 281 Therapeutic Advances in Medical Oncology 8(4) decrease anti-EFGR therapy [Douillard et al. been shown to upregulate angiogenic factors and 2013; Heinemann et al. 2014; Loupakis et al. recently, a study demonstrated KRAS mutant 2009]. In addition to KRAS, there is strong evi- cells to express higher levels of VEGF-A dence to support BRAF and NRAS mutations [Downward, 2003; Figueras et al. 2013; Zhang inhibiting the effect of anti-EGFR therapy [De et al. 2001]. Retrospective analysis of clinical ben- Roock et al. 2010]. The BRAF mutation has been efit from bevacizumab in patients with wild- or shown to be a strong negative prognostic factor in mutant-type KRAS tumors has found compara- CRC [Eklof et al. 2013]. The BRAF gene encodes ble benefits in PFS and OS [Hurwitz et al. 2009]. a serine threonine protein kinase which is directly activated by KRAS and leads to stimulation of the Both anti-EGFR treatments appear to be well tol- MAPK pathway [Di Fiore et al. 2010; Wan et al. erated, with a low incidence of grade 3 or 4 2004]. The average prevalence of BRAF muta- adverse events. The most common adverse event tions in colorectal cancer is an estimated 9.6%, with cetuximab was an acneiform rash. Other with the valine-to-glutamic-acid-amino-acid adverse events normally associated with cetuxi- (V600E) substitution being the most common mab therapy include infusion reactions, cardiac [Davies et al. 2002; Safaee Ardekani et al. 2012]. events, and hypomagnesemia, as observed in the BRAF mutations are considered mutually exclu- wild-type KRAS populations of the CRYSTAL, sive with KRAS mutations, as concomitant tumor OPUSS and CA225025 trials [Hubbard and mutations are extremely rare [Sahin et al. 2013]. Alberts, 2013]. The most common adverse events In a pooled analysis of the CRYSTAL and OPUS with panitumumab use were skin rash, randomized clinical trials, BRAF mutations were hypomagnesemia, paronychia, fatigue, abdomi- found to be a marker of poor prognosis but not an nal pain, nausea, and diarrhea [Giusti et al. 2007]. effective biomarker predictor in patients treated with anti-EGFR mAbs [Bokemeyer et al. 2012]. In 2004, cetuximab became the first anti-EGFR NRAS is a proto-oncogene from the RAS family mAb approved by the FDA for use in mCRC. It and its mutations on exon 2, 3, and 4 have been was approved as a second-line therapy for use in shown to be effective predictors of anti-EGFR irinotecan-refractory or intolerant patients with resistance [Douillard et al. 2013; Heinemann et al. EGFR-expressing tumors. Approval was based on 2014]. PIK3CA mutations on exon 9 and 20 often a randomized, two-arm phase II clinical trial coexist with KRAS mutations and are associated (BOND study) of 329 patients. Cetuximab com- with poor survival in patients treated with anti- bined with irinotecan significantly improved RRs EGFR therapy [Perrone et al. 2009; Wu et al. (22.9% versus 10.8%; Table 1) and time to pro- 2013]. gression (TTP) (4.1 versus 1.5 months; Table 1) compared with cetuximab alone [Cunningham Anti-EGFR mAbs therefore have minimal if not et al. 2004]. The results demonstrated that interfer- harmful results in patients with KRAS mutations ing with EGFR signaling can resensitize tumors due to their EGFR-independent activation of that are refractory to irinotecan. In 2012, the FDA oncogenic signaling cascades [Benvenuti et al. expanded its approval of cetuximab for use as a 2007]. The CRYSTAL study, along with the sup- first-line treatment in patients with KRAS wild type portive cetuximab studies, have clearly demon- (mutation negative), EGFR-expressing mCRC. strated that the presence of KRAS mutations The decision was based on retrospective analyses negatively affects the anti-EGFR therapies [Chau according to KRAS mutation status of tumor sam- and Cunningham, 2009; Dahabreh et al. 2011]. ples from patients enrolled in the CRYSTAL trial This finding led to National Comprehensive and two supportive studies (CA225025 and Cancer Network (NCCN) Clinical Practice OPUS). The addition of cetuximab to chemother- Guidelines in Oncology and the American Society apy or best supportive care (BSC) resulted in for Clinical Oncology (ASCO) guidelines to rec- improved OS, PFS and objective response rate ommend restricting anti-EGFR agents to mCRC (ORR) in patients with KRAS wild-type tumors patients with a wild-type KRAS allele [Allegra [Bokemeyer et al. 2012]. The use of cetuximab in et al. 2009; Jimeno et al. 2009]. patients with KRAS mutant tumors provided no benefit, and even potential harm. The prognostic potential of KRAS mutations in mCRC and its impact on the effectiveness of The CRYSTAL (cetuximab combined with chemotherapy or anti-VEGF inhibition remains irinotecan in first-line therapy for mCRC) trial undefined. The KRAS pathway has previously was a phase III open-label, randomized, 282 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. multicenter study that included 1217 patients decreased ORR (34% versus 53%) and PFS (5.5 (irrespective of KRAS status) who had not versus 8.6 months) compared with those receiving received prior chemotherapy for mCRC. A sig- FOLFOX-4 alone [Bokemeyer et al. 2011]. nificant improvement in median PFS was observed for the cetuximab plus FOLFIRI arm A recent comprehensive meta-analysis examined compared with the FOLFIRI only arm (8.9 ver- the effect of anti-EGFR mAbs in mCRC patients sus. 8.1 months) [Van-Cutsem et al. 2007]. There expressing wild-type KRAS compared with were minor but not significant differences in the mutant KRAS [Vale et al. 2012]. A total of 10 out median OS (19.6 versus 18.5 months) and the of 14 RCTs identified had available KRAS status. ORR (46% versus 38%) in both trial arms [Van- As expected, there was a positive effect on PFS Cutsem et al. 2007]. However, following retro- when anti-EGFR mAbs were used in patients spective analyses of patient subsets for KRAS with wild-type KRAS-expressing tumors but not status, the results were more favorable in the in the mutant KRAS patients. The PFS benefits KRAS wild-type patients given cetuximab. An were confined to trials combining mAbs along- updated survival analysis in 2011 further sup- side 5FU-based chemotherapy. There was also ported the addition of cetuximab to FOLFIRI as no evidence of a PFS benefit when anti-EGFR first-line therapy in patients with KRAS wild-type mAbs were given with bevacizumab. as these patients had increased median PFS (9.9 versus 8.4 months; Table 1), median OS (23.5 In 2006, the FDA provided accelerated approval versus 20.0 months) and ORR (57.3% versus to panitumumab (Vectibix) for the treatment of 39.7%) compared with FOLFIRI alone [Van- patients with EGFR-expressing, mCRC with dis- Cutsem et al. 2011]. The patients with KRAS ease progression on or following a FOLFOX/ mutations did not benefit from the addition of FOLFIRI-containing regimen. The approval was cetuximab as they had no improvement in median based on the findings of a single, open-label, mul- PFS (8.1 versus 7.5 months), OS (15.3 versus tinational phase III study that randomized 463 15.8 months) and ORR (31.0% versus 45.0 %) patients to receive panitumumab plus BSC or compared with FOLFIRI alone [Van-Cutsem BSC alone. The median PFS was significantly et al. 2011]. greater in patients receiving panitumumab com- pared with BSC alone (8.0 versus 7.3 weeks; CA225025 was an open-label randomized trial Table 1) [Giusti et al. 2007]. The ORR also that compared cetuximab plus BSC with BSC favored panitumumab (10.0% versus 0%; Table alone in 572 patients with previously treated 1). There were 19 partial responses (8%) with a EGFR-expressing mCRC. Among patients with median duration of 17 weeks among the panitu- wild-type KRAS, cetuximab significantly mumab group. Retrospective analysis of the study increased median OS (8.6 versus 5.0 months) and provided further evidence to the importance of PFS (3.8 versus 1.9 months). No benefits were KRAS status as clinical benefit was specific to observed in the mutant KRAS patients treated patients with wild-type KRAS tumors given pani- with cetuximab. tumumab monotherapy. The median PFS in the wild-type KRAS group treated with panitu- OPUS (oxaliplatin and cetuximab in first-line mumab was 12.3 weeks compared with 7.3 weeks treatment of mCRC) was a phase II open-label, for BSC [Amado et al. 2008]. Panitumumab RRs randomized study that compared FOLFOX-4 were also improved in the wild-type KRAS group (fluorouracil, leucovorin, and oxaliplatin) plus (17% versus 0%). There was no difference in OS cetuximab versus FOLFOX-4 alone in 337 between the two study arms, likely due to the untreated EGFR-expressing mCRC patients crossover design. [Bokemeyer et al. 2009]. KRAS wild-type patients who received cetuximab plus FOLFOX-4 had The PRIME (panitumumab randomized trial in increased ORR (57% versus 34%) and PFS (8.3 combination with chemotherapy for metastatic versus 7.2 months) compared with those receiving colorectal cancer to determine efficacy) study only FOLFOX-4 [Bokemeyer et al. 2011]. examined the efficacy and safety of panitumumab Median survival time was improved with cetuxi- in combination with FOLFOX-4. This was a mul- mab plus FOLFOX-4 but it was not statistically ticenter phase III trial that enrolled 1183 patients significant (22.8 versus 18.5 months) [Bokemeyer with no prior chemotherapy for mCRC. In the et al. 2011]. Patients with KRAS mutations who wild-type KRAS group, panitumumab plus received cetuximab plus FOLFOX-4 had a FOLFOX-4 significantly improved PFS compared http://tam.sagepub.com 283 Therapeutic Advances in Medical Oncology 8(4) with FOLFOX-4 (9.6 versus 8.0 months; Table 1) ramucirumab (n = 536 per arm) as an intrave- and nonsignificantly improved the median OS nous infusion every two weeks. The primary effi- (23.9 versus 19.7 months) [Douillard et al. 2010]. cacy endpoint of the study was OS. A statistically In the mutant KRAS group, panitumumab plus significant OS improvement was observed in FOLFOX-4 had a negative effect on both PFS and patients receiving FOLFIRI plus ramucirumab median OS compared with FOLFOX-4 (15.5 ver- compared with those receiving FOLFIRI plus sus 19.3 months). placebo (13.3 versus 11.7 months; Table 1). PFS was also significantly improved in patients who A meta-analysis in 2011 of four randomized clini- received ramucirumab in combination with FOL- cal studies found significant clinical benefit for FIRI (5.7 versus 4.5 months; Table 1). The infu- panitumumab-based therapy in wild-type KRAS sion was generally well tolerated, however, thyroid mCRC patients following prior chemotherapy dysfunction was noted in 2.6% of patients. exposure [Ibrahim and Abouelkhair, 2011]. There was an associated 42% improvement in PFS when panitumumab was used as a second- Fusion proteins line therapy but no benefit in the first-line setting Ziv-aflibercept. In 2012, the FDA approved ziv- [Ibrahim and Abouelkhair, 2011]. aflibercept (Zaltrap; Sanofi and Regeneron Phar- maceuticals, Inc., Tarrytown, NY, US) for the Both cetuximab and panitumumab are indicated treatment of mCRC that has progressed following for the treatment of EGFR-expressing, mCRC. an oxaliplatin-containing regimen. Ziv-aflibercept Panitumumab approval is for patients with dis- (previously known as aflibercept) is a recombi- ease progression while on, or following a nant fusion protein consisting of VEGF-binding FOLFOX/FOLFIRI-containing regimen, sections from the extracellular domains of human whereas cetuximab is for use with FOLFIRI as a VEGFR-1 and VEGFR-2 attached to the Fc por- first-line treatment and also in patients who are tion of human IgG1 immunoglobulin [Wang and irinotecan intolerant or refractory. Panitumumab Lockhart, 2012]. Ziv-aflibercept binds to and approval was based on its improvement of PFS, inactivates circulating VEGF, VEGF-B and PlGF while cetuximab approval was based on ORR. ligands, preventing their interaction with VEGF Neither anti-EGFR agent demonstrated a statisti- receptors [Holash et al. 2002]. FDA approval was cally significant benefit in OS, representing a based on the VELOUR trial, an international change in the accepted endpoints of a treatment, randomized double-blind study in which 1226 as previous new agents required an improvement patients received FOLFIRI with either ziv- in OS to gain FDA approval [Berlin et al. 2006; aflibercept or placebo [Van-Cutsem et al. 2012]. Tabernero et al. 2007]. These patients all had disease progression during or within 6 months of receiving oxaliplatin-based Ramucirumab. Ramucirumab (Cyramza; Eli Lilly chemotherapy with or without bevacizumab. A and Co., Indianapolis, IN, US) became the latest significant improvement in OS (13.5 versus 12.1 FDA-approved mAb on 24 April 2015 [Goel and months; Table 2), PFS (6.9 versus 4.7 months; Sun, 2015]. It is now indicated in combination Table 2) and RR (20% versus 11%; Table 2) was with FOLFIRI for the treatment of patients with observed in patients receiving the FOLFIRI plus mCRC whose disease has progressed on a first- zib-aflibercept regimen compared with the pla- line bevacizumab-, oxaliplatin- and fluoropyrimi- cebo cohort [Van-Cutsem et al. 2012]. Further dine-containing regimen [Tabernero et al. 2015]. subgroup analysis found the addition of ziv- Ramucirumab is a recombinant human monoclo- aflibercept to FOLFIRI had a trend of increased nal IgG1 antibody that binds and blocks further OS and PFS, regardless of prior bevacizumab use activity of the human VEGF-R2 with its ligands. [Allegra et al. 2012]. Approval was based on the RAISE trial which was a randomized, double-blind, multinational trial enrolling patients with mCRC that progressed Small-molecule inhibitors during or within 6 months of discontinuation of mAbs target circulating growth factors or recep- bevacizumab-, oxaliplatin- and fluoropyrimidine- tors on the cell exterior whereas small-molecule based combination chemotherapy [Tabernero inhibitors block cell signaling pathways from et al. 2015]. The clinical trial consisted of 1072 within. These inhibitors primarily compete with patients who were randomly allocated (1:1) to ATP for the ATP-binding site in the hinge region receive FOLFIRI plus placebo or FOLFIRI plus of the kinase receptor by mimicking the hydrogen 284 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Table 2. US Food and Drug Administration (FDA)-approved therapeutic targeted inhibitors used in metastatic colorectal cancer. Drug Class Target Study (year) 1st or 2nd line Regimen Marker Improvement Aflibercept Fusion Ab VEGF VELOUR (2012) 2nd (failure of FOLFIRI None OS (12.1–13.5) ligand Van-Cutsem oxaliplatin) PFS (4.7–6.9) et al. [2012] RR (11–22%) Regorafenib Multikinase VEGF CORRECT (2012) 3rd (failure of BSC None OS (5–6.4) TIE2 Grothey et al. standard therapies) PFS (1.7–2.0) [2013] RR (15–44%) Trifluridine/ Nucleoside DNA RECOURSE 3rd (failure of None OS (5.3–7.1) tipiracil analog (2015) Mayer standard therapies PFS (1.7–2.0] et al. [2015] + biological DNA, deoxyribonucleic acid; VEGF, vascular endothelial growth factor; BSC, best supportive care; FOLFIRI, irinotecan or oxaliplatin combined with a fluoropyrimidine and leucovorin; OS, overall survival; PFS, progression-free survival; RR, response rate. bonds formed by the adenine ring of ATP [Liu 2), PFS (2.0 versus 1.7 months; Table 2) and RR and Gray, 2006]. Other compounds allosterically (44% versus 15%; Table 2) [Grothey et al. 2013]. inhibit the catalytic activity by binding outside the The 1.4 month increase in OS equates a 23% active site [Zhang et al. 2009]. Small-molecule reduction in risk of death in a patient population inhibitors can either target a single receptor only, with a very poor prognosis and few options. such as gefitinib (targets EGFR only), or they can target multiple receptors, as in the use of sorafenib (which targets VEGFR, PDGFR, c-kit, Raf, flt-3 Nucleoside analog and RET) [Ranson et al. 2002; Yau et al. 2009]. TAS-102 is a combination of trifluridine and The most successful use of tyrosine kinase inhibi- tipiracil (LONSURF; Taiho Oncology, Inc., tors in clinical practice has been with gastrointes- Princeton, NJ, US), the most recent targeted tinal stromal tumors (GISTs) and the inhibition agent to gain FDA approval on 22 September of c-Kit. Most solid tumors have multiple genetic 2015. It is indicated in the treatment of patients alterations in specific proteins affecting a number with mCRC who have previously been treated of signaling networks making it difficult to target with fluoropyrimidine-, oxaliplatin-, and irinote- with single inhibitors. can-based chemotherapy, an anti-VEGF bio- logic product, and an anti-EGFR mAb, if RAS is Regorafenib. Regorafenib (BAY 73-4506; Bayer wild type [Mayer et al. 2015]. The drug is an Pharma AG, Berlin, Germany) is an oral multiki- oral combination therapy consisting of trifluri- nase small-molecule inhibitor that blocks several dine (a thymidine-based nucleoside analog), protein kinases involved in tumor growth and plus tipiracil hydrochloride (a novel thymidine angiogenesis which include VEGFR-1, VEGFR- phosphorylase inhibitor) [Lenz et al. 2015]. 2, VEGFR-3, TIE2, RET, KIT, PDGFR and TAS-102 is a dual-targeting formulation, with FGFR [Bhargava and Robinson, 2011; Wilhelm its major mechanism of action through trifluri- et al. 2011]. Additionally, it disrupts the down- dine being incorporated into DNA during DNA stream tumor-signaling cascades by binding to synthesis, thereby causing DNA dysfunction and the serine/threonine-specific protein kinase BRAF damage [Peters, 2015]. The thymidine phos- in the MAPK pathway responsible for stimulating phorylase inhibitor (tipiracil) prevents the degra- cell growth [Wilhelm et al. 2011]. In 2012, rego- dation of trifluridine. rafenib became the first FDA-approved small- molecule inhibitor for use in mCRC when Approval was based on a multicenter, double- combined with FOLFIRI. This was based on the blind, placebo-controlled trial (RECOURSE results of a pivotal phase III, multinational trial study) involving 800 patients with previously called CORRECT, which randomized 760 treated mCRC [Mayer et al. 2015]. The two arms patients to receive BSC plus either regorafenib or of the study had patients receiving trifluridine/tip- placebo. All the patients had already progressed iracil (n = 534) plus BSC or matching placebo during or within 3 months of their last standard (n = 266) plus BSC. The inclusion criteria approved therapies. Regorafenib displayed an included an Eastern Cooperative Oncology Group increased median OS (6.4 versus 5 months; Table (ECOG) status of 0 or 1, absence of brain http://tam.sagepub.com 285 Therapeutic Advances in Medical Oncology 8(4) metastasis, and absence of ascites requiring drain- clinical trial conducted in the Netherlands, had age in the 4 weeks leading to treatment. 755 patients with previously untreated mCRC randomly assigned to receive bevacizumab plus A statistically significant improvement in OS was CAPOX (capecitabine and oxaliplatin), or the demonstrated in the trifluridine/tipiracil com- same regimen accompanied by cetuximab [Tol pared with the placebo arm (7.1 versus 5.3 et al. 2009]. Surprisingly, the addition of cetuxi- months; Table 2). PFS was also improved in mab worsened median PFS (10.7 versus 9.4 patients randomly allocated to receive trifluri- months) and subset analysis demonstrated no dine/tipiracil (2.0 versus 1.7 months; Table 2). improved outcome in patients with wild-type KRAS [Tol et al. 2009]. There was even a signifi- The most common adverse drug reactions or lab- cant detrimental effect in PFS (8.1 versus 10.5 oratory abnormalities were neutropenia (38%), months) to patients with mutated KRAS receiv- anemia (18%), and thrombocytopenia (5%) ing bevacizumab and cetuximab [Tol et al. 2009]. [Mayer et al. 2015]. The incidence of adverse events was similar in both treatment groups after the exclusion of cetuximab-related adverse cutaneous effects. Combination therapies Anti-VEGF anti-EGFR. Paul Ehrlich’s magic bullet A similar negative outcome was reported in the theory has been realized to some extent with selec- Panitumumab Advanced Colorectal Cancer tive-binding agents but the effects are not as over- Evaluation (PACCE) trial in which previously whelming as anticipated [Winau et al. 2004]. The untreated mCRC patients were randomly assigned vision of targeted cancer therapies have not reached to receive chemotherapy (FOLFOX or FOLFIRI) their full potential; in part due to the complexity of and bevacizumab, either alone or accompanied by multiple and often redundant molecular pathways panitumumab. The addition of panitumumab to that promote oncogenic cellular processes [Tortora the FOLFOX group reduced both the median et al. 2008]. Therefore, it is rationalized that multi- PFS (10.0 versus 11.4 months) and the median ple-targeted agents may be required to selectively OS (19.4 versus 24.5 months) [Hecht et al. 2009]. inhibit the numerous tumor pathways [Johnson A similar pattern was observed in the smaller and Dippold, 1989]. Preclinical studies had sug- FOLFIRI cohort, although the differences were gested that combined blockade of both VEGF and not statistically significant. The PACCE trial was EGFR may be beneficial [Jung et al. 2002; Sha- prematurely discontinued due to the negative heen et al. 2001]. Dual targeting of VEGF and results and increased adverse events (skin toxicity, EGFR, two functionally linked and closely related diarrhea, infections and pulmonary embolism) in targets could interfere with the molecular feedback the panitumumab group. There is no obvious rea- loops responsible for acquired resistance and son for the negative effect observed by the combi- potentially increase the antitumor effects of the nation of an anti-VEGF and anti-EGFR mAbs individual agents [Saltz et al. 2007]. with standard chemotherapy regimens. This theory was supported with the results of The encouraging results observed in anti-VEGF/ BOND-2 (bevacizumab and irinotecan compared EGFR preclinical studies were not validated when with cetuximab and bevacizumab alone in irinote- examined in randomized trials. The failure of com- can-refractory colorectal cancer), a randomized, bined targeted therapies illustrates the difficulties phase II feasibility study of 83 irinotecan-refrac- and level of understanding we have of molecular tory mCRC patients. It demonstrated that the tri- oncology. It is possible that there is some interac- ple combination of irinotecan, cetuximab, and tion between the two antibodies and cytotoxic bevacizumab achieved better results in irinotecan- chemotherapy which negatively affected outcomes refractory mCRC compared with only cetuximab in PACCE and CAIRO-2 [Blanke, 2009]. and bevacizumab. The triple-therapy arm had increased time to tumor progression (7.3 versus 4.9 months), objective RR (37% versus 20%) and Conclusion OS (14.5 versus 11.4 months) [Saltz et al. 2007]. Treatment options for mCRC continue to emerge, however, there remains a number of Further studies would not support the good challenges to overcome. The complicated signal- anti-VEGF/EGFR results seen in BOND-2. ing pathways and network cross-talk involved in The CAIRO-2 study, a large multi-institutional tumorigenesis must be more effectively targeted. 286 http://tam.sagepub.com A Moriarity, J O’Sullivan et al. Benvenuti, S., Sartore-Bianchi, A., Di Nicolantonio, There is also the dynamic tumor microenviron- F., Zanon, C., Moroni, M., Veronese, S. et al. (2007) ment, genetic instabilities and host immune Oncogenic activation of the RAS/RAF signaling responses to be better understood. Further devel- pathway impairs the response of metastatic colorectal opment of therapies aimed at membrane recep- cancers to anti-epidermal growth factor receptor tors, intracellular signaling molecules and other antibody therapies. Cancer Res 67: 2643–2648. protein kinase targets is ongoing. All of these Berlin, J., Neubauer, M. and Swanson, P. (2006) potential targets demonstrate the complexity of Panitumumab antitumor activity in patients (pts) cancer and showcase the unlikelihood of finding a with metastatic colorectal cancer (mCRC) expressing ‘magical bullet’ therapy that will work for all ⩾10% epidermal growth factor receptor (EGFr). J patients. Some promising breakthroughs have Clin Oncol 24: 3548. been made researching the role of HER2 amplifi- cation and microsatellite instability in mCRC Bhargava, P. and Robinson, M. (2011) Development of second-generation VEGFR tyrosine kinase patients. As we move forward, further progress in inhibitors: current status. Curr Oncol Rep 13: 103–111. identifying new targeted therapies with associated predictive biomarkers is essential. Blanke, C. (2009) Dual-antibody therapy in advanced colorectal cancer: gather ye rosebuds while ye may. J Funding Clin Oncol 27: 655–658. The author(s) received no financial support for Blume-Jensen, P. and Hunter, T. (2001) Oncogenic the research, authorship, and/or publication of kinase signalling. Nature 411: 355–365. this article. Bogdan, S. and Klämbt, C. (2001) Epidermal growth factor receptor signaling. Curr Biol 11: R292–R295. 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Therapeutic Advances in Medical Oncology – SAGE

Published: May 29, 2016

Keywords: biomarkers; colorectal cancer; signaling; targeted therapy

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Current targeted therapies in the treatment of advanced colorectal cancer: a review:

Current targeted therapies in the treatment of advanced colorectal cancer: a review:

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Current targeted therapies in the treatment of advanced colorectal cancer: a review:

Current targeted therapies in the treatment of advanced colorectal cancer: a review:

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