Key Words. Bevacizumab Cetuximab Colorectal cancer Irinotecan Panitumumab

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1 The Oncologist Gastrointestinal Cancer Chemotherapy with Targeted Agents for the Treatment of Metastatic Colorectal Cancer CLAUS-HENNING KÖHNE, a HEINZ-JOSEF LENZ b a Klinik für Onkologie/Hämatologie, Klinikum Oldenburg, Oldenburg, Germany; b Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, USA Key Words. Bevacizumab Cetuximab Colorectal cancer Irinotecan Panitumumab Disclosures: Claus-Henning Köhne: None; Heinz-Josef Lenz: Consultant/advisory role: Pfizer Inc., Genentech, Sanofi-Aventis Group, ImClone, Bristol-Myers Squibb, Merck KG, ResponseGenetics, Inc., Amgen; Honoraria: Pfizer Inc., Genentech, Sanofi- Aventis, ImClone, Bristol-Myers Squibb, Merck KG, Amgen; Ownership interest: ResponseGenetics. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. ABSTRACT The introduction of novel agents targeted to specific molecular features of cancer cells promises more options and marked improvements in efficacy for treatment of colon cancer. This overview of clinical studies describes the effects of administering the targeted agents bevacizumab, cetuximab, and panitumumab, also known as monoclonal antibodies, to treat metastatic colorectal cancer (mcrc) patients. All three targeted agents have been approved for use by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. Bevacizumab has been shown to extend survival when used in combination with irinotecan and 5-fluorouracil based chemotherapy, and the addition of cetuximab to irinotecan and 5-fluorouracil based chemotherapy overcomes irinotecan resistance. Cetuximab and panitumumab are both efficacious among refractory mcrc patients with wildtype KRAS tumors. Other targeted agents, for example, the tyrosine kinase inhibitors erlotinib, gefitinib, sunitinib, and vatalanib (PTK787/ZK ), are currently in various stages of clinical development. The Oncologist 2009;14: INTRODUCTION Colorectal cancer is the fourth most common cancer in men and women [1]. Nearly 1.2 million cases were expected to have occurred in 2007 [2]. When detected early, while still localized (stage I), the 5-year survival rate can reach 90%. At this stage, surgical removal may be curative. However, only 39% of colorectal cancers are diagnosed so early [2]. Untreated, patients with metastatic colorectal cancer (mcrc) have a median survival duration of 5 6 months [3]. Treatment for patients with mcrc was limited to 5-fluorouracil (5-FU) based therapy until 1996, when irinotecan was approved for use in the U.S. 5-FU is converted by the enzyme thymidine phosphorylase into fluorodeoxyuridine monophosphate, which, in the presence of reduced folate, forms a complex with thymidylate synthase, thus Correspondence: Claus-Henning Köhne, M.D., Klinik für Onkologie/Hämatologie, Klinikum Oldenburg, Dr.-Eden-Str. 10, Oldenburg, Germany. Telephone: ; Fax: ; onkologie@klinikum-oldenburg.de Received September 9, 2008; accepted for publication March 25, 2009; first published online in The Oncologist Express on May 1, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 Köhne, Lenz 479 interfering with DNA synthesis and causing apoptosis in the tumor. Leucovorin (LV; folinic acid), an agent that enhances the binding of fluorodeoxyuridine monophosphate to thymidylate synthase, is frequently added to 5-FU to enhance its efficacy [4]. The bolus administration of these two agents was widely adopted as the first-line treatment of choice in the U.S., resulting in a median survival duration of approximately 1 year [4, 5]. In Europe, where 5-FU was administered as an i.v. infusion, chemotherapy regimens for mcrc were optimized, leading to higher response rates (RRs) [6] and producing modest survival benefits when compared with bolus 5-FU administration alone [7]. Infusional 5-FU has been shown to be safer than bolus administration [8] and is now the preferred delivery method for this treatment [9]. The number of treatment options for mcrc patients has grown rapidly, producing significant improvements in the median overall survival (OS) time. The two most important of the new options are the topoisomerase inhibitor irinotecan, introduced in 1996, and the platinum compound oxaliplatin, introduced in Both have emerged as critical partners with 5-FU in improving the treatment of patients with mcrc. An analysis of several large, phase III trials demonstrated that exposure to all three agents irinotecan, oxaliplatin, and 5-FU plus LV at some time during treatment significantly improves the OS time of mcrc patients, reaching an average of 20 months [10]. Several of the possible current lines of intensive and less intensive treatment for mcrc are outlined in Figure 1 [11]. In an attempt to further improve first- and second-line chemotherapy regimens, investigators are now combining novel biologic agents that target molecular pathways of mcrc tumorigenesis with irinotecan or oxaliplatin and 5-FU plus LV-based chemotherapy or using them alone as monotherapy. These new agents, called monoclonal antibodies, are labeled fully human, humanized, or chimeric, depending on the proportion of the antibody that is humanderived, as opposed to murine-derived [12]. Three such agents that have shown particular promise are bevacizumab (Avastin ; Genentech Inc, South San Francisco, CA), which targets the vascular endothelial growth factor (VEGF)-mediated angiogenesis pathway, cetuximab (Erbitux ; ImClone Systems Inc, Branchburg, NJ), which targets the epidermal growth factor (EGF)- mediated cell growth regulatory pathway, and panitumumab (Vectibix ; Amgen, Inc, Thousand Oaks, CA), which also targets the EGF pathway. In this review, we examine efficacy and safety data from clinical trials of bevacizumab, cetuximab, and panitumumab, briefly discuss other targeted agents, and provide recommendations for clinical application of these therapies. Figure 1. Intensive and less intensive treatment lines for mcrc. *Cetuximab may be administered alone for patients intolerant to irinotecan. Abbreviations: FOLFIRI, infusional 5-fluorouracil with irinotecan; FOLFOX, 5-fluorouracil and leucovorin plus oxaliplatin. From Goldberg RM, Rothenberg ML, Van Cutsem E et al. The continuum of care: A paradigm for the management of metastatic colorectal cancer. The Oncologist 2007;12: Reprinted with permission AlphaMed Press. All rights reserved. THE TARGETS: VEGF AND EGFR The VEGF family consists of several angiogenic and lymphangiogenic growth factors and their receptors, which are expressed by endothelial cells as well as on tumor cells [13, 14]. VEGF is a diffusible glycoprotein with several different isoforms termed VEGF-A, VEGF-B, VEGF-C, and VEGF-D. VEGF-A binds to two related tyrosine kinase receptors, termed VEGF receptor (VEGFR)-1 and VEGFR-2 [13, 14]. Binding of the VEGF isoforms to one or both of these receptors then results in activation of a cell type dependent signaling cascade, leading to neovascularization, mitogenesis, and suppression of apoptosis [14]. Consequently, VEGF expression is related to metastatic potential in mcrc through the promotion of angiogenesis [15]. Bevacizumab, which has a high binding affinity to VEGF, interferes with binding of VEGF-A to VEGFR-1 and VEGFR-2, thus inhibiting VEGF-mediated intracellular signaling. Through inactivation of the VEGF VEGFR

3 480 Targeted Agents in Metastatic Colorectal Cancer pathway, this targeted agent can help prevent the formation of new blood vessels and tumor growth [14]. EGF and the structurally related peptide transforming growth factor (TGF)- are ligands for the EGF receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases. Following binding of EGF or TGF- to EGFR, a cascade of intracellular signaling stimulates cell-cycle progression and neoplastic growth [16, 17]. Elevated expression of EGFR has been found in 60% 80% of patients with mcrc [16, 18]. Cetuximab, a chimeric monoclonal antibody that binds to EGFR with high selectivity [16], inhibits EGFR-mediated intracellular signaling [19]. Panitumumab, a fully human monoclonal antibody, also targets the EGFR [20]. Because of their effects on EGFR and downstream signaling, anti-egfr targeted agents are active against tumors by promoting cell-cycle arrest and apoptosis, and by inhibiting angiogenesis and metastasis [21]. BEVACIZUMAB Bevacizumab, a humanized monoclonal antibody that targets VEGF, has shown great promise as a component in the treatment of mcrc. In early experimental work on colon cancer specimens, investigators noted a correlation between increased VEGF expression and metastatic and proliferative activity in tumors [15]. When tested in vivo, murine antihuman monoclonal antibodies targeted against VEGF inhibited the growth of human tumor xenografts [22]. Based on these preclinical findings, Kabbinavar and colleagues conducted a randomized phase II trial comparing bevacizumab and 5-FU plus LV with 5-FU plus LV alone in chemotherapy-naïve mcrc patients [23]. Those receiving bevacizumab experienced a higher RR, longer median time to disease progression, and longer median survival time [23]. A subsequent randomized, phase II trial involving 209 patients confirmed the clinical efficacy of firstline bevacizumab in mcrc [24]. Patients received bolus 5-FU plus LV with either bevacizumab or placebo. The bevacizumab arm showed a significantly longer progressionfree survival (PFS) time (9.2 months versus 5.5 months; p.0002) but not OS time. The median age of patients (71 years) was approximately 10 years above the usual median age of trial cohorts. Patients selected for this trial were not considered optimal candidates for treatment with irinotecan in the first line. However, one third of them received irinotecan as second-line therapy [24]. Kabbinavar and colleagues [25] also performed a meta-analysis of three independent studies of first-line mcrc therapy, which included 249 patients receiving bevacizumab and 5-FU plus LV and 241 patients in a combined control group receiving either 5-FU plus LV alone or irinotecan and 5-FU plus LV Figure 2. Kaplan Meier estimates of survival. The median duration of survival (indicated by the dotted lines) was 20.3 months in the group given irinotecan, 5-fluorouracil, and leucovorin (IFL) plus bevacizumab, compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (p.001). From Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: Reprinted with permission Massachusetts Medical Society. All rights reserved. bolus (IFL). That study demonstrated that bevacizumab produced significant improvements over placebo in terms of the PFS time (8.8 months versus 5.6 months; p.0001), OS time (17.9 months versus 14.6 months; p.008), and RR (34.1% versus 24.5%; p.19), thus confirming its efficacy in the first-line setting [25]. In a phase III study of bevacizumab, irinotecan, and 5-FU plus LV conducted by Hurwitz and colleagues that led to the clinical approval of bevacizumab for the treatment of mcrc [26, 27], 813 patients with untreated mcrc were randomly assigned to receive IFL plus bevacizumab (n 402) or IFL plus placebo (n 411) [26]. Hurwitz and colleagues found that adding bevacizumab to IFL improved survival and produced consistent results across all patient subgroups, including those based on age, sex, and location of the primary tumor as well as on the number of metastases, the Eastern Cooperative Oncology Group performance status score, and prior adjuvant therapy [26, 27]. The median OS duration was 20.3 months in the group given IFL plus bevacizumab, compared with 15.6 months in the group given IFL plus placebo (p.001) (Fig. 2) [26]. The median time to progression (TTP) was 10.6 months, versus 6.2 months (p.001) [26]. RRs were 44.8% and 34.8% (p.004) and the median durations of response were 10.4 months and 7.1 months, respectively (p.001) [26]. Results of the third arm of the trial, which analyzed the efficacy of bevacizumab in combination with 5-FU plus LV in the absence of irinotecan, showed efficacy similar to that of the IFL arm [27]. The significant improvement in terms of survival and

4 Köhne, Lenz 481 RR in that trial led to U.S. Food and Drug Administration (FDA) approval of bevacizumab in 2004 for use in combination with i.v. 5-FU plus LV as first-line treatment of mcrc. In 2005, the European Medicines Agency (EMEA) approved bevacizumab in combination with irinotecanbased chemotherapy regimens for first-line treatment of mcrc. Bevacizumab in combination with i.v. 5-FU based chemotherapy is currently approved as first- and secondline treatment for mcrc [28]. More recently, the BICC-C trial showed the superiority of adding bevacizumab to infusional 5-FU with irinotecan (FOLFIRI) rather than to modified IFL (mifl) [29]. That trial was a randomized, phase III study originally designed (period 1) to compare three regimens: FOLFIRI (arm A), an mifl regimen in which bolus irinotecan and 5-FU plus LV were administered on days 1 and 8 in 2-week cycles (arm B), and oral capecitabine in combination with irinotecan (arm C) [29]. The trial was amended in April 2004 (period 2) to assess the additional effects of bevacizumab in arms A and B, and arm C was discontinued because of inadequate safety data regarding capecitabine in combination with bevacizumab and greater toxicity when combined with irinotecan. In period 1, the median PFS times were 7.6 months with FOLFIRI (n 144), 5.9 months with mifl (n 141; p.004), and 5.8 months with capecitabine and irinotecan (CapeIRI) (n 145; p.015); the median OS times were 23.1, 17.6, and 18.9 months, respectively. Both the PFS and OS times favored infusional FOLFIRI. In period 2, at a median follow-up of 34.4 months, the median survival duration for patients who received FOLFIRI plus bevacizumab (28.0 months) was significantly higher than that for patients receiving mifl plus bevacizumab (19.2 months; p.037). OS for each of the arms in period 2 is charted in Figure 3 [30]. Although this trial did not directly compare FOLFIRI administered with and without bevacizumab, it does indicate that FOLFIRI plus bevacizumab is more efficacious than IFL plus bevacizumab, especially because the median OS time of 19.2 months for patients receiving mifl plus bevacizumab is near to the median OS time of 20.3 months for IFL plus bevacizumab in the Hurwitz et al. [26] trial. The combination of bevacizumab with oxaliplatinbased chemotherapy as first-line treatment was investigated in a randomized, double-blinded study of 1,400 patients, designated NO16966 [31]. In that study, patients received capecitabine plus oxaliplatin (XELOX) or 5-FU plus LV and oxaliplatin (FOLFOX4), then either bevacizumab or placebo. The median PFS times were 9.4 months among patients receiving bevacizumab plus chemotherapy and 8.0 months among patients receiving chemotherapy plus placebo (p.0023); neither the RR (47% versus 49%; p.31) nor the median OS time (21.3 months versus 19.9 Figure 3. Overall survival for Period 2 in the BICC-C trial [30]. Abbreviations: FOLFIRI, infusional 5-fluorouracil with irinotecan; mifl, modified irinotecan, 5-fluorouracil, and leucovorin. From Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Updated results from the BICC-C study. J Clin Oncol 2008;26: Reprinted with permission American Society of Clinical Oncology. All rights reserved. months; p.077) was significantly different between groups [31]. The investigators concluded that continuation of bevacizumab until disease progression may be necessary to achieve maximum clinical benefit, because 50% of patients in both arms stopped treatment before disease progression, contrary to study protocol [31]. In context with the results of the BICC-C and Hurwitz et al. [26] trials, however, the results of this study suggest that the benefits of bevacizumab are greater when combined with irinotecancontaining regimens than with oxaliplatin-containing schedules. Despite showing significant toxicity in the BICC-C trial [29] and in the European Organization for Research and Treatment of Cancer Study (which was closed early because of toxic deaths in the CapeIRI arm) [32], the combination of capecitabine and irinotecan is being re-evaluated in a phase III trial investigating the addition of bevacizumab to CapeIRI (n 74) or FOLFIRI (n 82). In a recent interim safety analysis, treatment discontinuation occurred in 13% versus 4.5% of patients, respectively, and there was no difference in terms of the RR, TTP, or OS time. These preliminary results suggest that CapeIRI plus bevacizumab may be safely administered, although the clinical relevance of the study is limited [33]. Analysis of information from the Bevacizumab Regimens Investigation of Treatment Effects and Safety (BRiTE) registry, in which 1,953 patients received bevacizumab as part of first-line therapy [34], provides additional support for the hypothesis that continuing bevacizumab therapy until disease progression may be necessary for maximum clinical benefit. Because of the many variables affecting the treatment of patients in the BRiTE registry,

5 482 Targeted Agents in Metastatic Colorectal Cancer prospective, randomized trials are needed to confirm this conclusion [34] and to determine if bevacizumab is useful in treating refractory mcrc. CETUXIMAB Cetuximab received FDA approval in February 2004 and EMEA approval in June 2004 for use either in combination with irinotecan for the treatment of EGFR-expressing, irinotecan-refractory mcrc (FDA and EMEA) or as a single agent in patients who cannot tolerate irinotecan (FDA). In 2007, it was also approved by the FDA as monotherapy for EGFR-expressing mcrc after failure of irinotecan- and oxaliplatin-based regimens. Early research showed cetuximab to be a potentially promising addition to irinotecan-based chemotherapy for mcrc. When used against in vivo xenografts of human colon cancer cells, cetuximab not only bound to the extracellular receptor domain and prevented ligand-mediated dimerization but also produced a synergistic increase in irinotecan antitumor activity and reversed resistance to SN-38 cytotoxicity [35]. Subsequent clinical applications of cetuximab confirmed these findings. Saltz and colleagues conducted a phase II study of cetuximab monotherapy in mcrc patients who had received irinotecan alone or in combination [36]. Patients were premedicated with 50 mg i.v. diphenhydramine and received an initial dose of 400 mg/m 2 cetuximab followed by a weekly dose of 250 mg/m 2. Of 57 evaluable patients, 10.5% achieved a partial response. The median survival time was 6.4 months [36]. The landmark Bowel Oncology with Cetuximab Antibody (BOND) randomized, open-label phase II study by Cunningham and colleagues confirmed the activity of cetuximab in combination with irinotecan for refractory mcrc [16]. In that trial, 329 patients with EGFR-expressing mcrc previously treated with irinotecan were randomly assigned to receive cetuximab alone (n 111) or in combination with irinotecan (n 218). Both arms responded to therapy, but the RR in the combination arm was significantly higher than that in the monotherapy arm (22.9% versus 10.8%; p.007) [16], confirming the earlier findings of Saltz and colleagues [36]. The median TTP was also greater in the combination arm (4.1 months versus 1.5 months; p.001) [16]. In a recent study conducted by Jonker and colleagues [37], cetuximab monotherapy was observed to improve survival and preserve quality of life for patients who had progressed after receiving fluoropyrimidine, irinotecan, and oxaliplatin treatment, compared with best supportive care (BSC) alone. All 572 patients had EGFR-expressing tumors. The median OS times were 6.1 months among cetuximab patients (n 287) and 4.6 months in the BSC group (n 285). Cetuximab monotherapy also led to a significantly better PFS result (hazard ratio [HR] for disease progression or death, 0.68; 95% confidence interval [CI], ; p.001). Although there was a higher incidence of grade 3 adverse events in patients receiving cetuximab (78.5% versus 59.1%; p.001), these patients also reported less deterioration in physical function and global health status (p.05 for both) [37]. Because no crossover was possible by trial design, only 7% of the patients receiving BSC alone subsequently received cetuximab. The Erbitux Plus Irinotecan for Metastatic Colorectal Cancer (EPIC) study was initiated to determine if adding cetuximab to irinotecan as second-line therapy would lengthen the survival of patients with EGFR-expressing mcrc who failed first-line fluoropyrimidine and oxaliplatin treatment [38]. In that phase III trial, 1,298 patients were randomly assigned to cetuximab and irinotecan (n 648) or irinotecan alone (n 650). The RR was significantly higher and the PFS time was significantly longer in the combination arm (RR, 16.4% versus 4.2%, respectively; PFS, 4.0 months versus 2.6 months, respectively). However, the OS times were comparable between the two regimens (p.71), as were the median survival times (10.7 months versus 10 months, respectively) [38]. The investigators hypothesized that the study failed to reach its endpoint because 46.9% of patients assigned to irinotecan monotherapy during the trial later received cetuximab as well, so a clear comparison between survival in the two arms was impossible [38]. Taken together, the Jonker and EPIC studies indicate that patients with EGFR-expressing tumors should receive cetuximab when other treatments have failed. The success of adding cetuximab to irinotecan for the treatment of mcrc in treatment-refractory patients led Folprecht and colleagues to investigate the combination of cetuximab, irinotecan, and infusional 5-FU plus LV as firstline treatment for EGFR-expressing mcrc [9]. This was the first study published on combination chemotherapy with cetuximab for first-line treatment. The overall RR for the 21 assessable patients was 67%, and the median TTP was 9.9 months. The most common grade 3 or 4 adverse events were acnelike rash (38%) and diarrhea (29%). Based on the promising results of this phase I/II study, the phase III Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study was initiated. In the CRYSTAL trial, 1,217 patients with EGFR-expressing mcrc were randomly assigned to receive either cetuximab plus FOLFIRI (group A; n 608) or FOLFIRI alone (group B; n 609). The RR was significantly higher

6 Köhne, Lenz 483 among patients receiving cetuximab (46.9% versus 38.7%; p.005). The median PFS time was also longer for group A than for group B (8.9 months versus 8 months, respectively). The authors calculated that cetuximab in combination with FOLFIRI as first-line treatment reduced the relative risk for progression by approximately 15% [39]. Recent, smaller trials have shown that adding cetuximab to either first-line FOLFIRI or FOLFOX6 [40] and first-line capecitabine plus irinotecan or XELOX [41] produces similar efficacy results. When administered with irinotecan, cetuximab has been demonstrated to have significant antitumor activity in approximately 20% of refractory mcrc patients [42]. A growing understanding of the EGFR pathway and retrospective investigations of patients who have received cetuximab suggest a number of tests for biomarkers or genetic characteristics to better identify mcrc patients who may benefit from cetuximab at any stage of treatment [42 46]. The most extensive research to date indicates that the mutation status of KRAS, a gene encoding a G protein that plays a key role in the downstream signaling of EGFR, may explain resistance to cetuximab [47]. KRAS mutations occur in approximately 30% 50% of CRC tumors [48]. Several retrospective studies suggest that cetuximab treatment may only benefit patients with wild-type, nonmutated KRAS, because the presence of a mutation correlates poorly with a positive effect from cetuximab treatment [47, 49 53]. The phase II Oxaliplatin and Cetuximab in First-Line Treatment of mcrc (OPUS) trial investigated FOLFOX plus cetuximab versus FOLFOX alone as first-line mcrc treatment [50]. In this retrospective analysis, no benefit was seen with the addition of cetuximab in patients with KRAS mutations. Mutations were detected in 42% of patients with tissue available for KRAS analysis (99 of 233). In that group, patients receiving FOLFOX alone (n 47) had a median PFS interval of 8.6 months (p 0.02), versus 5.5 months in patients receiving FOLFOX and cetuximab (n 52; HR, 1.83; p.02). Among patients with wild-type (no mutation) KRAS, the median PFS duration was 7.2 months for patients who received only FOLFOX, versus 7.7 months for those receiving FOLFOX plus cetuximab (HR, 0.57; p.02). A retrospective analysis of 587 patients in the CRYSTAL trial (n 1,198) analyzed for KRAS status also showed that those with mutant KRAS did not benefit from cetuximab treatment [54]. Patients with wild-type KRAS who received cetuximab plus FOLFIRI (n 172) had a median PFS time of 9.9 months, compared with 7.6 months for those with mutant-type KRAS who received the same treatment (n 105; p.007). Wild-type KRAS patients who received only FOLFIRI (n 176), on the other hand, had a median PFS interval of 8.1 months, whereas that of mutated KRAS patients reached 8.7 months (n 87; p.87) [54]. PANITUMUMAB Panitumumab, the biologic agent most recently approved for use in the U.S., is a fully human monoclonal antibody that targets the EGFR, as does cetuximab. On the basis of a phase III trial that compared panitumumab plus BSC with BSC alone [55], panitumumab was approved in 2006 as monotherapy for patients with EGFR-expressing mcrc after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. In Europe, panitumumab has received conditional approval as monotherapy for the same type of patients if they possess nonmutated, wild-type KRAS [56]. In the phase III trial, 231 patients were randomly assigned to receive panitumumab and 232 were randomly assigned to BSC. After a median follow-up of 35 weeks, the OS times were similar in the two groups, but patients receiving panitumumab demonstrated a 46% lower disease progression rate (p.0001). The median PFS times were 8 weeks for the panitumumab arm (95% CI, weeks) and 7.3 weeks (95% CI, weeks) for BSC. Toxicities were manageable in the panitumumab arm. Skin toxicities were the most common, with 90% of patients developing them [55]. A retrospective analysis of the KRAS mutation status of 427 patients in that trial showed that wild-type KRAS status was associated with panitumumab efficacy. KRAS mutations were identified in 43% of patients (n 184). Panitumumab had a significantly greater effect on PFS for patients with wild-type KRAS than with mutant KRAS (12.3 weeks versus 7.4 weeks; p.0001). The investigators concluded that the KRAS status of patients should be determined when considering panitumumab monotherapy [48]. COMBINING CETUXIMAB WITH BEVACIZUMAB OR PANITUMUMAB The benefits observed when administering bevacizumab and cetuximab separately initiated a trial by Saltz and colleagues to study the feasibility of administering them together. That trial, the phase II BOND-2 study, randomly assigned 83 patients with irinotecan-refractory mcrc who were bevacizumab-naïve to receive either cetuximab, bevacizumab, and irinotecan (n 43) or cetuximab and bevacizumab (n 40) [57]. RRs were 37% for the triple combination and 20% for the targeted agents alone. The TTP was 7.3 months versus 4.9 months, whereas the OS time was 14.5 versus 11.4 months. Toxicity profiles among patient groups were as expected, with no clear indications of synergistic toxicities, although the development of grade

7 484 Targeted Agents in Metastatic Colorectal Cancer 3 acnelike skin rash in 20% of patients in both arms was higher than might be expected from cetuximab alone. (In the trial by Cunningham and colleagues [16], 5.2% of patients developed a grade 3 or 4 acnelike rash with cetuximab monotherapy.) The favorable efficacy results from that trial, compared with previous studies of cetuximab or cetuximab plus irinotecan in refractory mcrc patients, have encouraged other studies of combinations of targeted agents in both first- and second-line treatment. The phase III, first-line Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer (CAIRO2) study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab reported results for 730 patients at a median follow-up of 14.7 months. The rates of grade 3 or 4 toxicity were similar with and without cetuximab when cetuximab-related skin toxicity was excluded (71.8% versus 74.5%; p.40). RRs were comparable (40.6% versus 43.9%; p.44), as were the OS times (20.4 months versus 20.3 months; p.21). However, the median PFS time was shorter in the arm containing cetuximab (10.7 months versus 9.8 months; p.019) [58]. Surprisingly, an analysis of KRAS status among 501 patients in the CAIRO2 study showed that the results for cetuximab were not significantly influenced by the presence of wild-type KRAS [59]. Although it is possible that dosage adjustments or different regimen combinations of cetuximab, oxaliplatin, and bevacizumab will show survival benefits in future studies, it is also possible that a negative interaction exists between cetuximab and bevacizumab and that they should not be used together. Whether panitumumab should be studied in other lines of treatment or in combination with other therapies is still unclear. In the Panitumumab Advanced Colorectal Cancer Evaluation Study, a first-line study of mcrc patients who received either irinotecan- or oxaliplatinbased chemotherapy plus bevacizumab with or without panitumumab, the administration of panitumumab was halted after the first interim analysis indicated a shorter PFS interval and greater toxicities in the oxaliplatinbased arm with panitumumab [60]. Interim results from the irinotecan half of the study have shown similar PFS times between patients who received panitumumab and those who did not (10.6 months versus 10.7 months, respectively), with, however, a higher RR for the irinotecan, bevacizumab, and panitumumab arm (55% versus 46%), as well as greater toxicities [61]. A phase III study known as study is under way to test the combination of FOLFIRI with panitumumab as second-line mcrc treatment. Preliminary safety results for 701 of 1,100 planned patients have been reported, and the study continues without protocol modification [62]. SAFETY AND TOLERABILITY The use of targeted agents has prolonged survival, but as with all agents in current use, they are associated with adverse events. It is important to consider that the risks for adverse events and side effects are cumulative and may occur anytime during treatment. Bevacizumab Safety Profile Bevacizumab is generally well tolerated when combined with other drugs, such as irinotecan [26 28]. Bevacizumab-associated complications leading to hospitalization, treatment discontinuation, or fatality in a large phase III study were not significantly different between the treatment and placebo groups [26]. However, several possible adverse events have been identified in clinical trials. These include hypertension, hemorrhage, proteinuria, wound-healing complications, arterial thromboembolism, gastrointestinal tract perforation, reversible posterior leukoencephalopathy, and nasal septum perforation [26 28, 63 65]. Hypertension, the only consistently observed bevacizumab-associated side effect that requires treatment, is manageable with standard oral antihypertensives (e.g., calcium channel blockers, acetylcholine-esterase inhibitors, and diuretics) [26 28]. The final results of the First Bevacizumab Expanded Access Trial confirmed that the safety profile of bevacizumab in combination with common mcrc chemotherapy regimens appears consistent with those observed in previous phase III randomized studies. For 1,914 evaluable patients with a median follow-up period of 21.4 months, the 60-day mortality rate was 2.5%. Grade 3 5 adverse events included hypertension (5.1%), bleeding (3.2%), gastrointestinal perforation (1.8%), arterial thromboembolism (1.3%), proteinuria (1.0%), and wound-healing complications (1.0%) [66]. Cetuximab and Panitumumab Safety Profiles Dermatologic toxicities, experienced by 45% 100% of patients, are the most frequent adverse events that occur with use of the EGFR inhibitors cetuximab and panitumumab. The most common reactions are a papulopustular rash on the face and upper trunk, hair loss and growth of eyelashes and facial hair, dry and itchy skin, and inflammation around the fingernails [67]. A positive correlation between the increasing severity of rash from anti-egfr therapy and the RR, TTP, and survival time in colon cancer patients has frequently been noted [55, 68]. Despite the potential for severe dermatologic reactions with these targeted agents, pretreated EGFR-expressing patients in the large, phase III,

8 Köhne, Lenz 485 randomized EPIC trial who received cetuximab and irinotecan reported a higher quality of life than patients who received only irinotecan [69]. This finding is remarkable because patients in the cetuximab irinotecan arm experienced higher incidences of grade 3 or 4 diarrhea (28.8% versus 16.2%) and fatigue (5.9% versus 4.9%) than patients in the irinotecan-only arm. That trial was the first to show that the addition of a targeted agent to conventional chemotherapy can provide a better quality of life than conventional chemotherapy alone [69]. Recommendations for managing dermatologic toxicities have been published that can help mitigate the effects of treatment with cetuximab or panitumumab [70]. In addition to dermatologic reactions, infusion reactions and hypomagnesemia are also associated with anti-egfr therapy. Approximately 3% of patients treated with cetuximab experience a grade 3 or 4 infusion reaction, but 1in 1,000 cases have been fatal [71]. Because of its fully human nature, a low incidence of infusion reactions has been reported following panitumumab treatment [55]. With prompt medical attention, patients can recover from these reactions without consequences [71]. A decline in blood magnesium levels can occur with both cetuximab and panitumumab treatment, but this can be remedied with magnesium supplementation [55, 71]. OTHER TARGETED AGENTS Several other biologic agents, including erlotinib, gefitinib, and sunitinib, are under investigation for the treatment of mcrc in combination with irinotecan-, oxaliplatin-, and fluoropyrimidine-based regimens. Although most of these agents are in early stages of investigation, vatalanib (PTK787/ZK , commonly called PTK/ZK) has been tested in two phase III trials. PTK/ZK The compound PTK/ZK is an oral angiogenesis inhibitor that potently inhibits all known VEGF tyrosine kinase receptors, including VEGFR-3 (unlike bevacizumab, which only interferes with tyrosine kinase signaling from VEGFR-1 and VEGFR-2) [72]. In a phase I/II study, the combination of PTK/ZK with FOLFIRI as first-line therapy for mcrc patients appeared safe and active [73], and the investigators reported no toxic reactions between PTK/ZK and FOLFIRI. The median PFS time for 17 evaluable patients was 7.1 months, and the median OS time for 19 intent-to-treat patients was 24.3 months. In the phase III Colorectal Oral Novel therapy For the Inhibition of angiogenesis and Retarding of Metastases in first-line (CONFIRM1) trial, 1,168 mcrc patients were randomly assigned to receive FOLFOX4 with either PTK/ZK or placebo. An interim analysis showed efficacy in the PTK/ZK arm compared with the placebo arm, but the difference in PFS failed to reach significance. Adverse events attributed to PTK/ZK were similar to those for bevacizumab, but there was no greater rate of bleeding or bowel perforation, both of which have been seen with bevacizumab. An exploratory analysis of the results showed that the greatest benefits in terms PFS were experienced by patients with high levels of serum lactate dehydrogenase (LDH) [74]. A similar finding was seen in the phase III CONFIRM2 trial, in which 855 mcrc patients who had received irinotecan- and fluoropyrimidine-based therapy were randomly assigned to second-line FOLFOX4 plus PTK/ZK or placebo. An interim analysis showed a significantly longer PFS duration for the PTK/ZK arm among the overall population (5.5 months versus 4.1 months; p.026), although the difference in OS in favor of the PTK/ZK arm was not significant (12.1 months versus 11.8 months; p.511). Among patients with high LDH levels who received PTK/ZK, however, there was a longer PFS time (5.6 months versus 3.8 months; p.001) and OS time (9.6 months versus 7.5 months; p.10). The investigators concluded that LDH level was associated with outcome in PTK/ZK use [32]. Recent exploratory genetic studies have attempted to explain the superior outcome among patients who received PTK/ZK in the CONFIRM trials. Four genes have been isolated that may help predict the outcome of therapy with PTK/ZK: ERCC-1, LDHA, Glut1, and VEGFR-1. Further studies are needed to validate these findings [75, 76]. CONCLUSIONS Targeted agents have expanded the treatment options available for patients with mcrc, and they have been shown to prolong survival. Currently investigations are under way to determine genetic profiles or other patient characteristics that may help identify patients who will benefit from targeted agents and how best to combine these agents with the standard cytotoxic irinotecan-, oxaliplatin-, and fluoropyrimidine-based regimens. The KRAS mutation status of a tumor seems to predict therapeutic response to an anti-egfr agent, like cetuximab or panitumumab, but so far, studies have failed to identify any clinical, biochemical, or molecular markers that can aid in the selection of patients for bevacizumab treatment. Until more trials can clarify the optimal use of targeted agents, the data support exposure at some time to the three cytotoxic agents irinotecan, oxaliplatin, and fluoropyrimidines that comprise the foundation of mcrc treatment. The data also support the use of targeted agents in certain circumstances, but the optimal use of these new biologic agents remains to be determined in further investigations.

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