Targeted therapy in advanced colon cancer: the role of new therapies

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1 Annals of Oncology 15 (Supplement 4): iv55 iv62, 2004 doi: /annonc/mdh905 Targeted therapy in advanced colon cancer: the role of new therapies J. Tabernero, R. Salazar, E. Casado, E. Martinelli, P. Gómez & J. Baselga Medical Oncology Service, Vall d Hebron University Hospital, Barcelona, Spain Introduction Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. Recent advances in the field of oncology have resulted in increased survival of patients with advanced CRC (ACRC). However, 40% of patients who undergo systemic chemotherapy for advanced cancers still do not achieve shrinkage of their tumours. Therefore, new strategies are warranted in order to improve these results. Much of the basic cancer research during the era of molecular biology has focused on the dissection of molecular pathways resulting in tumour growth and progression. The rationale for this approach is that it allows the identification of pathways that might be disrupted with new biological targeted therapies. Among all the biological agents that are being evaluated in cancer treatment, three different strategies are in advanced development in the treatment of CRC and have already shown unequivocal evidence of efficacy. Large phase II and III clinical trials are evaluating the role of epidermal growth factor receptor (EGFR) pathway inhibitors, vascular endothelial growth factor receptor (VEGFR) pathway inhibitors and cyclooxygenase-2 (COX-2) inhibitors, both in advanced disease and in the adjuvant setting. This review will focus on EGFR, VEGFR and COX-2 inhibitors. Other targeted therapies, such as the farnesyl transferase inhibitors and the matrix metalloprotein inhibitors, have failed to demonstrate any survival advantage in patients with CRC and will not be discussed in this review. Targeting the EGFR Rationale EGF was identified in 1962, and was purified and characterised by Stanley Cohen in 1980, work for which he later received the Nobel Prize in Physiology and Medicine. EGFR is a tyrosine kinase receptor that belongs to the ErbB family and is abnormally expressed and activated in cancer cells in many tumour types including CRC. Following stimulation by its natural ligands, EGFR initiates signal transduction cascades that promote cell division, migration and angiogenesis, and inhibit apoptosis (Figure 1). Therefore, there is a clear rationale for the development of agents capable of blocking the activity of EGFR. In 1983 and 1984, John Mendelsohn and colleagues created a murine monoclonal antibody (mab), q 2004 European Society for Medical Oncology M225, that could block the proliferation of tumour cells both in vitro and in xenograft models. These observations were confirmed with other anti-egfr mabs and led to the development of C225 or cetuximab (Erbitux w ), a human mouse chimeric mab, that was approved in Switzerland in December 2003 and has been recently approved by the Food and Drug Administration (FDA) in the USA for the treatment of refractory ACRC [1]. There is clear evidence that EGFR plays an important role in the pathogenesis of CRC. EGFR is widely present in ACRC, its expression ranging from 72% to 82% in the most recently published series [2 4]. Moreover, EGFR expression appears to be associated with poor survival and increased risk of invasion/metastasis [5]. There are several potential strategies to target EGFR. However, mabs and the low molecular weight tyrosine kinase inhibitors (TKIs) are the most advanced in clinical development. mabs bind to the extracellular domain of the receptor and compete with the natural ligands (transforming growth factor-alpha and EGF) binding to the receptor, thereby blocking activation of the receptor. In contrast, TKIs compete with ATP binding to the tyrosine kinase portion of the endodomain of the receptor, and thereby abrogate the receptor s catalytic activity. Both strategies appear to be equally effective at blocking the downstream receptor-dependent signalling pathways, including the MAPK, the PI3K/Akt and the Jak/Stat pathways. Clinical development of anti-egfr monoclonal antibodies Cetuximab Among all the available anti-egfr mabs (Table 1), cetuximab is the furthest ahead in clinical development. In fact, cetuximab was approved in Switzerland in December 2003, and has recently been approved by the FDA in the USA for the treatment of ACRC. Cetuximab is a human mouse chimeric immunoglobulin (Ig) G1 mab with a high affinity for the EGFR (K d = 0.39 nm) and a long half-life. Cetuximab inhibits the growth of CRC cell lines both in vitro and in vivo [6 8]. Moreover, it has been demonstrated that cetuximab enhances the antitumour effect of topotecan and irinotecan of CRC cell lines in vitro and in mice xenograft models [9, 10]. These encouraging preclinical studies prompted the evaluation of cetuximab in the clinical setting. In initial phase I studies,

2 iv56 Cell surface R R [PI3,4P 2 PI3,4,5P 3 ] [PI4P,PI4,5P 2 ] PTEN Akt PI3K K Sos Grb2 K Shc Ras Intra- Cellular Signaling mtor FKHR GSK-3 Bad NF-κβ Raf MEK1/2 Gene Transcription/ Cell Cycle Progression Cellular Responses Survival Proliferation Angiogenesis Metastasis Figure 1. Epidermal growth factor receptor (EGFR) signal transduction pathways. Table 1. Monoclonal antibodies targeting the epidermal growth factor receptor cetuximab showed promising activity and the recommended schedule was established with an initial dose of 400 mg/m 2 on week 1, followed by subsequent doses of 250 mg/m 2 weekly [11]. Cetuximab was well tolerated, lacking the haematological toxicity associated with many conventional anticancer agents, and did not exacerbate the toxicity of co-administered agents. Most patients developed an acne-like rash, and the severity of the rash has been shown to correlate with tumour response rate and survival in some studies. The activity seen in early trials of cetuximab in patients with heavily pretreated EGFR-expressing ACRC led to an extensive phase II and III programme in patients with CRC (Table 2). A phase II study in 120 patients with metastatic, irinotecan-treated tumours was presented at the ASCO 2001 meeting by Saltz et al. [3]. Cetuximab was administered at the recommended schedule for 6 weeks given in combination with <_125 mg/m 2 irinotecan weeks 1 4 or <_350 mg/m 2 once every 3 weeks. A response rate of 19% and a disease control rate of 46% were initially reported [3]. A subsequent small phase II study also presented by Saltz et al. at ASCO 2002 showed that single-agent cetuximab was active in 57 patients with irinotecan-refractory ACRC, with a response rate of 11% and a disease control rate of 46% [12]. The next step was to administer cetuximab in combination with 5-fluorouracil (5-FU), leucovorin (LV) and irinotecan in the first-line setting (Table 3). Three different p27 Antibody Pharmaceutical industry Type Origin Phase Cetuximab (C225) Merck KGaA/BMS/Imclone IgG1 Chimeric mab III ABX-EGF Amgen/Abgenix IgG2 Human mab II/III EMD72000 Merck KGaA IgG1 Humanised mab II h-r3 York Medical Bioscience, Inc. IgG1 Humanised mab I/II Ig, immunoglobulin; mab, monoclonal antibody. MAPK small phase I/II studies reported preliminary but highly encouraging results with a response rate between 48% and 74%, and a disease control rate between 90% and 95% [13 15]. Additionally, the combination of cetuximab and the oxaliplatin/5-fu/lv-based chemotherapy schedule FOLFOX4 is currently being evaluated in the first-line setting. Preclinical in vivo studies demonstrated that the combination of cetuximab and irinotecan was superior to cetuximab alone in mice xenografts bearing human CRC refractory to irinotecan [10]. The two clinical studies presented by Saltz et al. in patients refractory to irinotecan-based chemotherapy suggested a higher response rate with a similar disease control rate in patients treated with the combination of cetuximab and irinotecan when compared with cetuximab alone. In order to elucidate which was the most active treatment, Merck KgaA conducted in Europe a well-designed randomised phase II study (BOND) in patients with ACRC that had progressed on an irinotecan-based chemotherapy [4]. In the BOND trial 576 patients were screened and 470 exhibited EGFR expression (82%). A total of 329 patients were randomised 2 : 1 to receive either arm A with cetuximab (400 mg/m 2 first infusion followed by 250 mg/m 2 weekly) plus irinotecan at the same dose and schedule on which they had been progressing, or arm B with cetuximab as a single agent. In this study, >60% of the patients had previously received all available

3 iv57 Table 2. Activity of cetuximab in an irinotecan-refractory population [3, 12] Irinotecan + cetuximab Cetuximab n PR 19.2% 10.5% [95% CI] [13 27] [4 22] SD 26.7% 35.1% DC 45.9% 45.6% RD (m) OS (m) PR, partial response; CI, confidence interval; SD, stable disease; DC, disease control (complete response, partial response and disease stabilisation); RD, median response duration; OS, median overall survival. Table 3. Activity of cetuximab combined with irinotecan/5-fu/lv schedules in the first-line setting [13 15] Author n Schedule OR (%) DC (%) Rosenberg [14] 29 Cetuximab + irinotecan/ FU/LV (IFL) Lutz [13] 21 (19) Cetuximab + irinotecan/ 5-FU/LV (AIO) Van Laethem [15] 23 (21) Cetuximab + irinotecan/ 5-FU/LV (FOLFIRI) OR, overall response; DC, disease control (complete response, partial response and disease stabilisation); 5-FU, 5-fluorouracil; LV, leucovorin. standard treatments for ACRC, including oxaliplatin and 5-FU/LV. More than 80% of the patients received the investigational treatment at least as third-line treatment. The BOND trial confirmed that cetuximab did not increase the side-effects of the given chemotherapy. The results of this study have clearly demonstrated a significant superiority of the combination cetuximab/irinotecan compared with cetuximab as a single agent in terms of response rate (23% versus 11%), disease control rate (56% versus 32%) and median time to progression (4.1 versus 1.5 months) (Table 4). There was a clear trend favouring the combination arm in median overall survival (8.6 versus 6.9 months), but this difference did not reach statistical significance, probably because the study was Table 4. BOND study: efficacy [4] Cetuximab/irinotecan (n = 218) (95% CI) Cetuximab (n = 111) (95% CI) PR (%) 22.9 ( ) 10.8 ( ) DC (%) 55.5 ( ) 32.4 ( ) TTP (months) < OS (months) 8.6 ( ) 6.9 ( ) 0.48 CI, confidence interval; PR, partial response; DC, disease control (complete response, partial response and disease stabilisation); TTP, median time to progression; OS, median overall survival. P underpowered for this end point, which was a secondary objective in its design, and because cross-over was accepted. Incidentally, 54 out of 111 patients receiving the monotherapy arm were switched to receive the combined treatment when they failed to respond to treatment with cetuximab as a single agent. In this group of patients, a response rate of 2% and a disease control rate of 41% were observed. Interestingly, both response and survival were higher in patients who presented skin rash, but there was no correlation between the percentage of EGFR-expressing cells or staining intensity and outcome. All these data indicate clearly that cetuximab is able to overcome irinotecan resistance in patients with ACRC, and the survival benefit is outstanding for this heavily pre-treated population for whom life expectancy is short. The activity of cetuximab against EGFR-expressing CRC supports the development of well-designed phase III studies that might demonstrate the superiority of cetuximab when combined with standard chemotherapy in the first-line or in the adjuvant setting. Other anti-egfr monoclonal antibodies Other anti-egfr mabs that have a similar mechanism of action to cetuximab are in clinical development. EMD72000 is a humanised IgG1 mab with high affinity (K d = 0.01 nm) currently in phase I and II development. This mab has a prolonged half-life that may allow for a less frequent administration schedule. In an ongoing trial, preliminary pharmacokinetic, pharmacodynamic and efficacy data indicate that a more convenient every 2 or every 3 weeks schedule with EMD72000 is feasible [16]. The limited efficacy information from the phase I studies shows a similar efficacy to cetuximab in patients with refractory ACRC [16, 17]. ABX-EGF is a fully human IgG2 mab with high affinity for the EGFR (K d = 50 pm). In a phase I/II study of ABX-EGF in patients with ACRC, a response rate of 9% was observed [18]. Anti-EGFR TKIs There are a large number of TKIs directed to the EGFR family in clinical development (Table 5). So far, three TKIs have been specifically evaluated in ACRC: gefitinib (ZD1839, Iressa w ) and erlotinib (OSI-774, Tarceva w ), both reversible EGFR-specific TKIs, and EKB-569, an EGFR-specific and irreversible TKI. In the initial phase I studies with these compounds as single agents, no formal responses were observed, although there were some signs of activity in patients with ACRC. Gefitinib was further evaluated in patients with refractory ACRC, with two patients achieving a minor response and seven patients a disease stabilisation out of 27 patients included in the study, giving a disease control rate of 32% [19]. Erlotinib as a single agent has also been evaluated in patients with refractory ACRC, with eight out of 25 patients included in the study achieving disease stabilisation, with a disease control rate of 32% [20]. An ongoing study is evaluating the activity of the irreversible TKI EKB-569 in the same population. To summarise these studies with EGFR TKIs as

4 iv58 Table 5. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors Type of inhibition Agent IC 50 Irreversible Development stage EGFR HER2 EGFR specific and reversible ZD1839, gefitinib No Phase II and III OSI-774, erlotinib No Phase II and III PKI-166 No Phase I EGFR specific and irreversible EKB Yes Phase I and II Pan-HER reversible GW No Phase I and II Pan-HER irreversible CI Yes Phase I Pan-HER and KDR reversible AEE No Phase I single agents in ACRC, no objective responses have been observed so far, although there are clear signs of activity in this refractory population. There are a large number of preclinical studies in different tumour cell lines that have demonstrated synergistic activity when TKIs are combined with cytotoxic drugs. In view of these studies, TKIs have been evaluated in combination with standard chemotherapy schedules in patients with ACRC. In a phase I/II study, the combination of the oxaliplatin-based chemotherapy FOLFOX4 with gefitinib showed a response rate of 23% in those patients with refractory tumours and an impressive 73% in patients treated in the first-line setting [21]. Similarly, erlotinib in combination with FOLFOX4 has been evaluated in a phase I/II study in patients with refractory ACRC, with a response rate of 23% and disease control rate of 73% [22]. Finally, EKB-569 has been evaluated in combination with the irinotecan-based chemotherapy FOLFIRI in a phase I study in patients with ACRC in the first-line setting. The preliminary results of this study yielded a response rate and a disease control rate of 38% and 85%, respectively [23]. In summary, the response and disease control rates observed in these limited phase I/II combination studies, both in the first-line setting and in the refractory population, are encouraging compared with the results obtained with standard chemotherapy in the same population, although randomised phase III studies are needed in order to reach definitive conclusions. Challenges with anti-egfr therapies in CRC This area of research continues to expand, and a number of issues are of particular interest for the future development of the anti-egfr therapies in CRC. First, it is not known what level of EGFR expression is required to obtain clinical benefit. While a relationship appears to exist between the levels of the erbb-2 receptor and response to trastuzumab (Herceptin w ), no clear association has emerged between the levels of EGFR and response to cetuximab. Furthermore, we do not know at this time whether patients with tumours that do not express EGFR by immunohistochemistry have any chance of responding to cetuximab or other EGFR-directed therapies. Secondly, it remains to be established which patients will show the greatest response to these therapies. There is a clear need to identify factors that predict response (e.g. gene and proteomic profile) in order to select the patients who have a reasonable chance of responding to EGFR inhibitors. Thirdly, studies that explore longer intervals of administration of cetuximab are needed in order to deliver schedules that are more convenient in terms of quality of life and compatible with standard chemotherapy regimens used in CRC. Fourthly, as the degree of skin rash clearly correlates with efficacy and survival in most of the studies with cetuximab, there is a need to clarify whether higher doses of cetuximab could increase the incidence of moderate rash, and whether this would translate into higher efficacy. Targeting the angiogenesis process Rationale One novel approach in the treatment of solid tumours involves therapeutic agents that inhibit the neovascularisation process of growing tumours. There is strong evidence that links tumour growth and metastasis with the angiogenesis process in most human tumours, including CRC [24 26]. Moreover, a clear correlation between the microvessel density in the pathology specimens and progression-free and overall survival in patients with CRC has been demonstrated. The formation of a vascular network in the tumour growth involves different complex pathways [27] including angiogenic factors, membrane receptors and signalling transduction cascades that lead to the vessel formation and stabilisation processes. VEGF is the most potent and specific angiogenic factor, and its expression in CRC has been demonstrated to correlate with recurrence and prognosis [28]. Multiple strategies have been developed to inhibit the VEGF pathway, but two different approaches have reached advanced clinical development. The first is the generation of a humanised mab, directed to the VEGF itself. In in vivo models, the administration of anti- VEGF mabs reduces the size and the number of liver metastasis from human CRC cell lines [29] and has a synergic effect when combined with some cytotoxic drugs [30]. Bevacizumab (Avastin w ) is a recombinant humanised anti-vegf mab that is being clinically evaluated in many tumour types including CRC. The second strategy directed to the VEGF pathway comprises different small molecules with tyrosine kinase inhibition capacity that are directed to the receptors of VEGF,

5 Flt-1 and Flk-1/KDR. In this category there are several compounds, some of them specific to the VEGFRs, like PTK787/ZK and SU5416, and others that inhibit not only a VEGFR but also other tyrosine kinase receptors, like ZD6474, AEE788, SU6668 and SU Bevacizumab After initial preclinical studies had demonstrated that the murine anti-vegf mab could reduce the tumour size of wellestablished liver metastasis from CRC cell lines, a humanised version of this antibody was developed. A randomised phase II study compared the safety and efficacy of bevacizumab at two different dose levels (5 or 10 mg/kg every 2 weeks) plus 5-FU/LV according to the Roswell Park regimen versus 5-FU/LV alone as first-line treatment for ACRC [31]. Administration of bevacizumab at 5 mg/kg combined with 5-FU/LV resulted in statistically significant increases in response rate (40% versus 17%; P = 0.029) and median time to progression (9 versus 5.2 months; P = 0.005), and a trend for an increase in median overall survival (21.5 versus 13.8 months; P = 0.137) when compared with 5-FU/LV alone. These preliminary results, although limited due to the small size of the study, suggested that bevacizumab in combination with 5-FU/LV increased activity and prolonged median overall survival compared with 5-FU/LV alone in patients with ACRC. These data prompted further evaluation of the efficacy of bevacizumab when combined with a more active schedule in CRC. A phase III study compared the combination of irinotecan/5-fu/lv (IFL schedule) with either IFL/bevacizumab or 5-FU/LV/bevacizumab in the first-line setting. Once the results of other studies demonstrating the superiority of IFL over 5-FU/LV became available and the safety of IFL/bevacizumab was granted, the arm 5-FU/LV/bevacizumab was closed for recruitment. The preliminary results of this phase III study were presented by Hurwitz et al. [32] at ASCO 2003 (Table 6). The addition of bevacizumab 5 mg/kg every 2 weeks to the IFL schedule resulted in statistically significant increases in response rate (45% versus 35%; P = 0.003), median time to progression (10.6 versus 6.2 months; P < ) and median overall survival (20.3 versus 15.6 months; P = ) compared with IFL alone. In terms of safety, the combination treatment produced only more grade 3 hypertension episodes than IFL alone (11% versus 2%; P <0.01), with all other adverse events being similar in the Table 6. Avastin w study: efficacy [32] Bevacizumab/IFL (n = 403) IFL (n = 412) PR + CR (%) TTP (months) < OS (months) IFL, irinotecan, 5-fluorouracil, leucovorin; PR, partial response; CR, complete response; TTP, median time to progression; OS, median overall survival. P two arms. The results of this study have prompted the FDA to recently approve bevacizumab for the treatment of ACRC in combination with irinotecan/5-fu/lv or 5-FU/LV, the remaining arm of the study that also resulted in better outcome than IFL. To put these results into context, one must bear in mind the definitive results of the N9741 study, where the infusional oxaliplatin containing schedule FOLFOX4 was superior to IFL, thus rendering the bolus schedule to be no longer considered a standard first-line treatment in ACRC [33]. One as yet unanswered question about the efficacy of bevacizumab is whether the benefit that has been observed when it is added to the bolus IFL schedule could also be observed when administered with a continuous infusion irinotecan/5-fu/lv- or oxaliplatin/5-fu/lv-based schedule. A vast development program including phase II and III studies with other irinotecan- and oxaliplatin-based schedules is ongoing in order to establish the role of bevacizumab both in the first-line setting of patients with ACRC and in the adjuvant setting after radical surgery of locoregional colon cancer. These studies will also define the role of bevacizumab added to more standard chemotherapy schedules. Anti-VEGFR TKIs Several TKIs of the angiogenic pathways receptor have undergone or are undergoing clinical development in CRC [34]. SU5416, a TKI of Flk-1/KDR, was studied in ACRC on the basis of its activity both in in vitro models, inhibiting the proliferation of endothelial cells, and in vivo models, suppressing tumour growth of xenografts from CRC cell lines [35 37]. However, two phase III studies failed to demonstrated any survival advantage of SU5416 when added to either 5-FU/LV or irinotecan/5-fu/lv in the first-line setting. Two other TKIs with constitutive capacity to inhibit multiple receptors (Flk- 1/KDR and Flt-1), SU6668 and PTK787/ZK222584, are under clinical development. Both compounds have shown antitumoral and antiangiogenic activity in in vivo models [38]. PTK787/ZK showed signs of clinical activity in patients with ACRC in a phase I study [39]. Two phase III studies are evaluating the role of the addition of PTK787/ZK to oxaliplatin/5-fu/lv both in the firstand second-line setting of ACRC. COX-2 inhibitors iv59 There is clear evidence that the COX-2 isoform plays an important role in the pathogenesis of CRC. COX-2 is virtually undetectable in normal colon, but is upregulated in 40% of adenomas and 85% of CRC [40]. Moreover, strong COX-2 expression is a marker for poor survival in CRC [41]. COX-2 inhibitors decrease the number and size of polyps and may prevent the progression from adenomatous polyp to invasive carcinoma. This effect has been clinically studied in patients with familiar adenomatous polyposis (FAP). In a randomised study in 77 patients with FAP, the administration of 400 mg of celecoxib twice a day for 6 months significantly decreased the number and the size of polyps in this population [42].

6 iv60 On the basis of this study, celecoxib was approved by the FDA for the treatment of polyps in patients with FAP. COX-2 inhibitors inhibit the growth of CRC cell lines both in vitro and in vivo [43]. Moreover, it has been demonstrated that celecoxib enhances the antitumour effect of CPT-11 and reduces the severity of diarrhoea in in vivo models [44]. These encouraging preclinical studies have prompted the evaluation of COX-2 inhibitors in the clinical setting. A number of studies suggest that the addition of celecoxib to standard chemotherapy (irinotecan-based schedule IFL, bolus 5-FU/LV regimen or capecitabine) may decrease the severity of adverse events related to the chemotherapy treatment, especially diarrhoea and hand foot syndrome [45 47]. However, this effect has not been observed when rofecoxib has been administered in combination with 5-FU/LV [48]. Interestingly, there is a suggestion that celecoxib could increase the efficacy of capecitabine in a retrospective analysis of 67 patients with ACRC [45]. The European Organisation for Research and Treatment of Cancer has designed a study that will evaluate two different irinotecan-based schedules (combined with 5-FU or capecitabine) with the addition of either celecoxib or placebo in patients with ACRC. It is also felt that COX-2 inhibitors may have a role in the adjuvant setting. Four different phase III studies will evaluate this hypothesis in the adjuvant setting. The VICTOR study will randomise 7000 patients with stage II/III to 2 or 5 years of rofecoxib or placebo following surgery and, if indicated, standard chemotherapy. The ACTION study will randomise 1500 patients with stage III to 3 years of celecoxib or placebo following surgery and standard chemotherapy. The PETACC-5 study will randomise patients with stage III to receive 3 years of celecoxib or placebo after standard chemotherapy (either irinotecan/5-fu or 5-FU). Finally, the National Surgical Adjuvant Breast and Bowel Project group has projected a study that will randomise 1200 patients with stage I colon cancer to 3 years of celecoxib or placebo after surgery, and in this study, the primary objective is to demonstrate a lower incidence of new adenomatous polyps. These studies will determine the role of COX-2 inhibitors both in the advanced and in the adjuvant setting. Conclusions Phase II/III studies with cetuximab and bevacizumab have produced promising clinical results in ACRC, particularly when these compounds have been administered in combination with irinotecan-based schedules. Given the efficacy demonstrated by the combination of cetuximab and irinotecan in the BOND study, there is little doubt that cetuximab is one of the most active drugs in the treatment of ACRC. The next step in clinical research is to translate the approval in the irinotecan-refractory population to a more optimal, less refractory advanced setting or even in the adjuvant setting. The addition of bevacizumab to the irinotecan-based schedule IFL has provided an increase in survival over IFL alone in patients with chemo-naïve ACRC. In the light of these results, the clinical development with bevacizumab continues with a number of randomised phase II and phase III studies designed to determine whether the same benefit can be obtained or increased with the more standard infusional irinotecan- and oxaliplatin-based schedules in both the first-line advanced disease and/or the adjuvant setting. With reference to the COX-2 inhibitors, these compounds are not as active as EGFR and VEGF pathway inhibitors in the advanced disease, but are useful in preventing polyp formation in FAP patients, and there are some encouraging preclinical data that suggest that they may have a potential role in the adjuvant setting. The questions that are being addressed, or need to be, with these targeted therapies in future trials are: (i) which combined modality regimens show the largest benefits in terms of improving the outcome of patients; (ii) what timing and sequence of the combination treatments will provide the greatest therapeutic gain; and (iii) which are the patient populations that may best benefit from these compounds? As this information becomes available over the next decade, there should be a gradual introduction of cetuximab and bevacizumab therapies into routine clinical practice, with a continuous improvement in ACRC patients survival. References 1. Mendelsohn J. 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