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The Role of Epidermal Growth Factor Receptor–Targeted Antibody Therapy in Previously Treated Colorectal Cancer
The Role of Epidermal Growth Factor Receptor–Targeted Antibody Therapy in Previously Treated Colorectal Cancer David Watkins, David Cunningham Abstract In recent years, increasing amounts of trial data have become available indicating the clinical efficacy of epidermal growth factor receptor (EGFR)–targeted antibody therapy in the management of advanced colorectal cancer (CRC).These trial data have consistently demonstrated the modest single-agent activity of these agents when given in the chemorefractory setting and the potential ability for EGFR-targeted agents to reverse chemoresistance when given in combination with cytotoxic chemotherapy agents. In this article, we review the clinical development of EGFR-targeted therapies and discuss their current role in the management of patients with previously treated advanced CRC. Clinical Colorectal Cancer, Vol. 6, Suppl. 2, S47-S52, 2007 Key words: EPIC, EVEREST, Monoclonal antibodies, Oxaliplatin, Panitumumab, Refractory disease
Introduction The potential therapeutic utility of targeting the epidermal growth factor receptor (EGFR) with monoclonal antibody (MoAb) therapy was first demonstrated at the laboratory bench more than 20 years ago.1,2 Over recent years, we have seen the clinical realization of this pre-clinical promise, with EFGR-targeted antibody therapies entering routine practice in the field of colorectal cancer. Epidermal growth factor receptor and its associated downstream signaling pathways are involved in the maintenance of many of the malignant characteristics displayed by tumor cells, including tissue invasion, metastatic potential, self-sufficient growth, evasion of apoptosis, and sustained angiogenesis.3,4 Thus, the inhibition of EGFR activation has long been considered an important therapeutic target in many malignant diseases. The EGFR is expressed in approximately 70%-80% of colorectal tumors,5-7 and the degree of expression appears to correlate with a poorer prognosis8; this knowledge supported the initial evaluation of EFGR-targeted agents in colorectal cancer (CRC). Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, United Kingdom Submitted: Jul 3, 2007; Revised: Sep 17, 2007; Accepted: Oct 8, 2007 Address for correspondence: David Cunningham, MD, FRCP, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey, SM2 5PT United Kingdom Fax: 4-208-6939414; e-mail: [email protected]
The Clinical Development of Cetuximab in IrinotecanRefractory Disease Cetuximab was the first EGFR-targeted MoAb to undergo clinical evaluation in CRC. Preclinical data had indicated the potential for EGFR-targeted antibodies to potentiate the activity of chemotherapy and possibly reverse chemoresistance.9,10 In xenograft tumor models, synergistic activity for the combination irinotecan/cetuximab was demonstrated. Furthermore, in an irinotecan-refractory xenograft model, it was shown that the combination of cetuximab and irinotecan significantly inhibited tumor growth, although either agent given independently had no noticeable antitumor activity.10 Based on these preclinical observations, an initial phase II clinical trial evaluated the action of cetuximab/irinotecan in the setting of irinotecan-refractory disease. The findings of this study were presented by Saltz et al the 37th Annual Meeting of the American Society of Clinical Oncology, held May 1215, 2001, in San Francisco, CA.11 One hundred twenty-one patients with EGFR-expressing advanced CRC who were refractory to irinotecan and 5-fluorouracil (5-FU) received treatment with the combination of cetuximab together with irinotecan according to the same dose and schedule on which they had previously progressed. In this patient population with irinotecan-refractory disease, the combination treatment produced a radiologic partial response (PR) rate (RR) of 17%, with an additional 31% of patients achieving stable disease (SD).
Dr Watkins has no relevant relationships to disclose. Dr Cunningham has received research support from Roche, Merck, Amgen, and Astra-Zeneca. He has also served as a paid consultant for Roche, Amgen, Bristol-Myers Squibb, Merck, Pfizer, and Astra-Zeneca. This article includes discussion of investigational and/or unlabeled use of drugs, including the use of cetuximab in metastatic colorectal cancer.
Clinical Colorectal Cancer Supplement October 2007 • S47
EGFR-Targeted Antibody Therapy in Previously Treated CRC Further data demonstrating the activity of cetuximab was gained from a second nonrandomized phase II study using cetuximab alone.12 In this study, patients with EGFR-expressing tumors who had demonstrated resistance to irinotecanbased chemotherapy received cetuximab alone. Again, clinical activity was demonstrated with a radiologic RR of 9%, and an additional 35% of patients achieving SD that lasted ≥ 12 weeks from study entry. Within both of these studies, cetuximab was well tolerated with the main toxicity being ache-like rash and allergic reactions. No interactions or unexpected toxicities were seen with the combination cetuximab/irinotecan. Federal Drug Administration approval for cetuximab was only gained after the results of a further randomized phase II study. The BOND study enrolled 329 patients who had progressed during or within 3 months of receiving irinotecan-based chemotherapy. Patients were randomized in a 2:1 ratio to receive cetuximab/irinotecan (according to the same dose and schedule as prestudy) or cetuximab alone. For patients recruited to the monotherapy arm, the protocol allowed for crossover to receive combination treatment at the time of progression. The primary endpoint of the study was radiologic RR, with secondary endpoints including time to progression (TTP) and overall survival (OS). Of the 577 patients screened, 82.1% had EGFR-expressing tumors and were randomized within the study. All patients had progressed on or within 3 months of receiving an irinotecan-based therapy, and of note, 62.2% of randomized patients had also received previous oxaliplatin. The results demonstrated a statistically significant improvement in RR and TTP in patients receiving the combination irinotecan/cetuximab. The RRs were 22.9% and 10.8%, respectively (P = .007), and the median TTPs were 4.1 months and 1.5 months in the combination and monotherapy arms, respectively. There was no statistically significant difference in OS (8.6 months in the combination arm and 6.9 months in the monotherapy arm), but this was not intended to be demonstrated as part of the original statistical design, and not expected because of the planned crossover. Toxicities were as expected. Approximately 80% of patients developed an acnelike rash, which was grade 3/4 in 9.4% and 5.2% of the combination and monotherapy arms, respectively. Only 1.2% of patients suffered severe anaphylactic reactions necessitating the discontinuation of cetuximab.7 Cetuximab demonstrated no clear impact on the incidence of irinotecan-related toxicities. A finding that was clearly demonstrated across these early studies was the lack of correlation between EGFR expression by immunohistochemistry (IHC) and radiologic RR. Other studies assessing EGFR-targeted antibodies in patients with negative staining for EGFR expression have demonstrated benefit in this patient group.13 It is clear that the current IHC methods of EGFR testing are of little value in patient selection,14 and indeed, many ongoing studies do not stipulate EGFR expression as an entry requirement. Although EGFR expression by IHC does not correlate with RR or outcome, an intriguing finding has been the correlation between severity of rash with RR and survival. Within patients receiving combination therapy on the BOND study, the RR and median survival in patients with skin reactions were 25.8% and
S48 • Clinical Colorectal Cancer Supplement October 2007
9.1 months, respectively, compared with 6.3% and 3 months, respectively, in patients without skin reactions.7 A similar pattern was seen in the monotherapy arm. The activity of cetuximab in patients with irinotecan-refractory disease had been clearly demonstrated by these studies; based on these data, FDA approval was granted for the use of cetuximab/irinotecan or as a single agent, in the setting of irinotecan-resistant disease.
Panitumumab, a Fully Humanized Epidermal Growth Factor Receptor–Targeted Antibody Panitumumab is the second EGFR-targeted antibody that has undergone clinical evaluation in CRC. Panitumumab differs from cetuximab in that it is a fully humanized immunoglobulin (Ig)G2 antibody, whereas cetuximab is a chimeric IgG1 antibody. The humanized antibody has the advantage of being associated with a lower risk of inducing allergic reactions. Both antibodies act by binding to the extracellular domain of the EGFR, preventing ligand binding and receptor activation. There is in vitro data suggesting that, as well as inhibiting EGFR activation, cetuximab can also induce antibody-dependent cellular cytotoxicity (ADCC).15 It is feasible that cetuximab being an IgG1 antibody is more likely to induce ADCC than panitumumab (IgG2). There is currently no published data to support or refute this. However, preliminary clinical data has suggested that Fc receptor polymorphisms might play a role in determining the response to cetuximab therapy, indicating the possible role of ADCC.16 The phase I trial of panitumumab included a pharmacokinetics evaluation of various dosing schedules: weekly, every 2 weeks, and every 3 weeks. The results indicate that each of the schedules provides a similar drug exposure and tolerability profile.17
Single-Agent Studies of Epidermal Growth Factor Receptor–Targeted Antibody Agents Versus Best Supportive Care The initial clinical development of panitumumab focused on its single-agent efficacy in the setting of chemorefractory disease. After phase II trials in advanced CRC, 18 a randomized phase III study of panitumumab versus best support care (BSC) in the third-line setting was undertaken.The study recruited 430 patients with EGFR-expressing tumors who demonstrated progressive disease having previously received irinotecan- and oxaliplatin-based regimens. Patients were randomized to receive panitumumab 6 mg/kg every 2 weeks with BSC or BSC alone. The study design allowed for patients in the BSC arm to cross over to receive panitumuab at the time of disease progression, with progression-free survival (PFS) being the primary endpoint. The results demonstrated the activity of panitumumab in this patient group, with a radiologic RR of 8% in the panitumumab arm and no response in the BSC arm. Progression-free survival was improved in the panitumumab arm with a hazard ratio (HR) of 0.54 (95% CI, 0.44-0.66; P < .0001). Of patients in the BSC arm, 174 patients (75%) crossed over to receive
David Watkins, David Cunningham panitumumab at the time of disease progression; of these patients, 10% achieved a PR. No difference in OS between the treatment arms was seen. Toxicities were as expected: 81% of patients in the panitumumab arm developed a skin reaction which was grade 3/4 in 18% of patietns. Infusion reactions were less frequent than in the cetuximab studies, with no grade 3/4 infusion reactions reported. A further toxicity that was apparent in patients receiving panitumumab was hypomagnesemia; this occurred in approximately 38% of patients but was rarely severe, with grade 3 or 4 toxicity seen in only 3% of patients.19 Hypomagnesemia has also been reported in studies utilizing cetuximab.20 A similar randomized study versus BSC has been undertaken with cetuximab. The NCIC (National Cancer Institute of Canada)–CO.17 study randomized 572 patients with progressing chemorefractory EGFR-positive CRC to receive BSC alone or cetuximab and BSC. This study differs significantly from the panitumumab study in that crossover from BSC to cetuximab was not planned. In this study, a benefit in PFS was again seen with an HR of 0.68 (95% CI, 0.57-0.8) and a stratified log-rank P value < .0001. Furthermore, an OS benefit was also demonstrated with a median survival of 6.1 months in the cetuximab arm versus 4.6 months in the BSC arm (HR, 0.77 [95% CI, 0.64-0.92]) and a stratified log-rank P value equal to .0046. In the cetuximab arm, grade 3/4 toxicities were as expected: rash 11.8%; hypersensitivity reaction 4.5%; hypomagnesemia 5.8%.21 A noticeable finding seen across the phase II/III studies assessing single-agent cetuximab and panitumumab has been the consistency of the RRs reported. In contrast to traditional cytotoxic agents, the efficacy of EGFR-targeted antibody therapies does not appear to be influenced by the number of previous therapies a patient has received (Table 1).
Epidermal Growth Factor Receptor– Targeted Antibody Therapy in Combination with Oxaliplatin The early clinical data for cetuximab clearly demonstrated its potential ability to reverse irinotecan chemoresistance in patients with irinotecan-refractory disease. At the current time, there is less data to support the use of the EGFR-targeted antibodies in combination with oxaliplatin in the setting of oxaliplatinrefractory disease. However, a recently published phase II study provides evidence of similar activity in this disease setting. The study recruited 44 patients who had evidence of disease progression after previous treatment with an oxaliplatin-based regimen. Seventy-eight percent of the enrolled patients had progressed on or within 3 months of completing oxaliplatin-based therapy (refractory). The most common previous oxaliplatin regimen was XELOX (capecitabine/oxalipatin; 65%); 80% of patients had also received previous irinotecan therapy. Within the trial, all patients received the combination of cetuximab given weekly, together with oxaliplatin (85 mg/m2 on day 1) and capecitabine (2000 mg/m2 on days 1-7) given in cycles every 2 weeks. The radiologic RR achieved was 20%, with SD in a further 27.5% of patients. A subgroup analysis of patients whose disease was refractory to oxaliplatin at entry revealed an RR of 16.1% in this patient
Table 1
Efficacy of Single-Agent Epidermal Growth Factor Receptor–Targeted Antibody Agents in the Chemorefractory Setting
Study
Agent
N
Patients Who Received Previous Oxaliplatinand Irinotecan-Based Chemotherapy (%)
RR (%)
Saltz et al12
Cetuximab
57
14
8.8
Malik et
al18
Panitumumab
148
44
9
Cunningham et al7
Cetuximab
111
62.2
10.8
Jonker et al21
Cetuximab
287
95
6.6
Panitumumab
231
100
10
Van Cutsem et al19
population. The results of this study provide an indication of the ability of cetuximab to reverse oxaliplatin resistance. A further interesting observation made was that of 21 patients who received poststudy therapy with the combination irinotecan/cetuximab, an RR of 9.5% was seen. This result hints at the potential ability of EGFR-targeted therapy to continue to augment chemotherapy responses through ≥ 1 line of cytotoxic agent.22 This concept will require further validation in prospective studies.
Epidermal Growth Factor Receptor–Targeted Antibodies in Combination with Chemotherapy in the Second-Line Setting Cetuximab is currently licensed for use in irinotecan-refractory disease. Intuitively, we would wish to consider the earlier introduction of EGFR-targeted therapies before the development of chemoresistance. Thus, potentially improving the quality of early response seen. The feasibility of combining EGFR-targeted agents with traditional cytotoxic therapies has been assessed in numerous phase II studies.23-28 More recently, randomized data demonstrating the comparative safety and efficacy of the addition of cetuximab to irinotecan chemotherapy in the second-line setting have become available. The EPIC (European Prospective Investigation of Cancer) study enrolled 1300 patients with EGFR-expressing tumors which had progressed on first-line oxaliplatin-based chemotherapy. Patients were randomized to receive single-agent irinotecan therapy or the combination irinotecan/cetuximab. The toxicity profile seen in the irinotecan/cetuximab arm was largely as expected, but a higher incidence of grade 3/4 diarrhea was seen (Table 2). Efficacy data is summarized in Table 3. The addition of cetuximab to irinotecan produced a higher radiologic RR and a statistically significant improvement in PFS. However, no significant difference in OS was seen between the 2 treatment arms. It is possible that the lack of OS benefit relates to cetuximab usage after the study, with 47% of patients in the irinotecan arm subsequently receiving cetuximab therapy.29 The US-based EXPLORE study was designed to evaluate the combination of FOLFOX (oxaliplatin/leucovorin [LV]/5-FU) 4 with or without cetuximab in patients previously treated with Clinical Colorectal Cancer Supplement October 2007 • S49
EGFR-Targeted Antibody Therapy in Previously Treated CRC Table 2
Table 3
EPIC Study Toxicity Results
Grade 3/4 Toxicity
Cetuximab/Irinotecan (N = 638) N (%)
Irinotecan (N = 629) N (%)
Any Adverse Event > 5%
457 (71.6)
Diarrhea
EPIC Study Efficacy Results
Treatment Arm
Response Rate (%)
PFS (Months)
OS (Months)
357 (56.8)
Irinotecan/Cetuximab (N = 648)
16.4
4 (P a .0001)
10.71 (P = .7115)
184 (28.8)
102 (16.2)
Irinotecan (N = 650)
4.2
2.6
9.99
Acneiform Rash
52 (8.2)
3 (0.5)
Infusion Reaction
9 (1.4)
5 (0.8)
Hypomagnesemia
9 (3.3)
1 (0.4)
irinotecan-based therapy. This trial opened in March 2003 with a planned recruitment of 1100 patients. As a result of oxaliplatin receiving FDA approval as first-line therapy in 2004, standard practice in the United States changed and study recruitment slowed. The study was closed in December 2004 because of poor accrual. The outcomes of the 102 enrolled patients have been reported.30 The radiologic RR of FOLFOX4/cetuximab was 21% compared with 8.5% in the standard FOLFOX4 arm. Progression-free survival was similar in both arms. The results of this study indicate an encouraging improvement in RR with the addition of cetuximab, but because of the small sample size, no conclusions regarding efficacy can be drawn. A further study evaluating the combination irinotecan/panitumumab in the second-line setting, is the UK-based PICCOLO (Panitumumab, Irinotecan and Ciclosporin in Colorectal Cancer) trial. This study is recruiting patients with disease progression after previous 5-FU with or without oxaliplatin therapy. Patients are randomized to 1 of 3 of the following treatment arms: irinotecan alone, irinotecan/panitumumab, or irinotecan/cyclosporin.
Second-Line Epidermal Growth Factor Receptor–Targeted Therapy After First-line–Targeted Therapy There are currently no phase III studies evaluating EGFRtargeted antibody therapy in specific groups of patients having previously received treatment with EGFR or vascular endothelial growth factor (VEGF)–targeted therapy in the first-line setting. Figure 1
Some insight into to the activity of EGFR-targeted agents in this setting is likely to be gained from studies such as PICCOLO, which will include a proportion of patients having received previous cetuximab and/or bevacizumab. A randomised phase II study (SPIRITT) is specifically evaluating the use of FOLFIRI (irinotecan/LV/5-FU) with bevacizumab or panitumumab as second-line treatment in patients who had not previously exhibited a response to oxaliplatin-based chemotherapy and who had received ≥ 4 doses of bevacizumab therapy.
Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Combination Therapies in the Chemorefractory Setting Based on preclinical data suggesting potential synergistic activity with the combination of an EGFR-targeted agent and VEGF inhibitor, the BOND II trial was undertaken.This randomized phase II study enrolled patients with progressive irinotecan-refractory disease. Patients were randomized to receive cetuximab/bevacizumab/irinotecan or cetuximab/bevacizumab. The radiologic RRs were 37% and 23% in the cetuximab/ bevacizumab/irinotecan and the cetuximab/bevacizumab arms, respectively. 31 When these RRs are compared with the treatment arms in the first BOND study, it appears that the addition of bevacizumab to an EGFR-targeted antibody can improve the efficacy of therapy. However, this is a nonrandomized, cross- trial comparison and can be misleading. The recent results of the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) study, on which the combination of cytotoxic chemotherapy with bevacizumab and panitumumab was examined, have raised con-
EVEREST Study Scheme
Day 22 EGFR-Positive CRC Progression on previous irinotecan Cetuximab (400 mg/m2 then 250 mg/m2 per week) Irinotecan (180 mg/m2 every 2 weeks)
Rash grade a 1 No toxicity grade 2 Other patients Not randomized
Arm A Continue standard dose treatment Cetuximab (250 mg/m2 per week) Irinotecan (180 mg/m2 every 2 weeks) Arm B Escalating dose Cetuximab dose increases by 50 mg/m2 every 2 weeks maximum of 500 mg/m2 Irinotecan (180 mg/m2 every 2 weeks) Arm C Patients not eligible for randomization Cetuximab (250 mg/m2 per week) Irinotecan (180 mg/m2 every 2 weeks)
S50 • Clinical Colorectal Cancer Supplement October 2007
David Watkins, David Cunningham cerns as to the safety of combining EGFR- and VEGF-targeted therapy with cytotoxic chemotherapy.32
Rash and Dose Response in the EVEREST Study The intriguing relationship between rash, tumor response, and improved outcome led to the development of the EVEREST study. This was undertaken to examine the relationship between antibody dose, rash, and tumor response in a prospective fashion. This study enrolled patients with EGFR-expressing tumors who had been previously treated with irinotecan chemotherapy. All patients commenced initial treatment with irinotecan/cetuximab and, at day 22, an assessment of rash and other toxicity was made (Figure 1). Patients who had not developed grade ≥ 2 rash were randomized at day 22 to continue standard treatment (arm A) or to commence cetuximab dose escalation (arm B). Patients not meeting the criteria for randomization continued with standard therapy (arm C). After the initial 22-day run-in period, 99 patients met the criteria for randomization. Forty-five patients were randomized to arm A, 44 to arm B, and 77 patients were not randomized and continued to receive treatment in arm C. The rates of rash and radiologic RRs are shown in Table 4. These results indicate that cetuximab dose escalation in patients with no or mild rash appears to increase the severity of rash, and possibly improve radiologic tumor RR.19 The EVEREST study was exploratory, and before the adoption of dose escalation into standard practice, the concept will require further formal clinical evaluation. The EVEREST study includes translational aspects with patients undergoing skin and tumor tissue biopsies for biomarker research. The results of these aspects of the study are keenly awaited. Much effort is currently being focused on translational research aimed at exploring the molecular mechanisms involved in response and resistance to EGFR-targeted therapies. Avenues currently under evaluation include mutated K-ras, which can predict for resistance to therapy,33 EGFR copy number,34 EGFR mutational status,35 high-affinity EGFR distribution,36 and EGFR dimerization patterns37 together with other signaling pathways such as the insulin-like growth factor–1R38,39 and VEGF,40 which might also be implicated.
Conclusion The published data evaluating EGFR-targeted antibody therapy has clearly demonstrated the ability of these agents to reverse chemoresistance when given in combination with cytotoxic chemotherapy, together with modest single-agent activity in the chemorefractory disease setting. Available data from the CRYSTAL and EPIC studies have indicated the additional activity provided by the combination of cetuximab with chemotherapy in the first-line and second-line settings. However, whether this upfront combination approach provides any benefits over the sequential use of traditional cytotoxic agents and the later introduction of EGFR-targeted agents is unclear. On the basis of randomized41,42 and nonrandomized studies,43 bevacizumab is currently considered part of standard first-line
Table 4
EVEREST Study Results
Patients with Rash (%)
Arm A
Arm B
Arm C
Grade 2
22
25
43
Grade 3/4
0
5
9
30
22 (34 in patients with grade > 1 rash)
Radiologic Response Rate (%)
13
therapy, with cetuximab and panitumumab in general recommended for second-line or subsequent-line use.44 Whether this pattern of use alters over the coming years will depend on the results of ongoing first-line studies evaluating the relative benefit of each of the biologic agents in combination with cytotoxic chemotherapy. Data from the PACCE study has given an indication that the combination of traditional cytotoxic therapy with EGFR and VEGF targeting agents might carry excessive toxicities without benefiting efficacy.32 The results from studies such as CALGB (Cancer and Leukemia Group B) 80405 and CARIO 2 will provide further data as to the relevant benefit of each of the biologic agents in the first-line setting. The place of EGFR-targeted agents in the second-line treatment setting will, to an extent, be dependent on the findings of these first-line studies. After the introduction of irinotecan and oxaliplatin into clinical practice, it was seen that exposure to all 3 agents during the course of therapy provides a survival advantage.45 It will be interesting to see whether the same pattern can be demonstrated for the biologic agents that we now have available in the clinical setting. Among the questions to be asked in future trials will be the ability of EGFR-targeted antibodies to augment chemotherapy responses across multiple lines of therapy. There are a variety of molecular mechanisms involved in the development of resistance to EGFR-targeted therapies46; our current understanding of these mechanisms is limited. In this era of combination cytotoxic and EGFR-targeted therapy, it is currently not possible to evaluate the relative contribution of each agent to treatment outcome in an individual. Useful biomarkers will not only be able to predict which tumors are likely to have de novo resistance to therapy, but can also help us to identify when resistance to a therapy has developed on treatment. The potential benefit of EGFR-targeted antibody therapy was demonstrated at the laboratory bench more than 20 years ago. It is now clear that the optimal clinical benefit of these agents will only be achieved through a combination of clinical and ongoing laboratory research.
References 1. Masui H, Kawamoto T, Sato JD, et al. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984; 44:1002-7. 2. Gill G, Kawamoto T, Cochet C, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 1984; 259:7755-60. 3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70. 4. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002; 20(18 suppl):1s-13s.
Clinical Colorectal Cancer Supplement October 2007 • S51
EGFR-Targeted Antibody Therapy in Previously Treated CRC 5. Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000; 21:105-15. 6. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer 2001; 92:1331-46. 7. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337-45. 8. Mayer A, Takimoto M, Fritz E, et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer 1993; 71:2454-560. 9. Fan Z, Baselga J, Masui H, et al. Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 1993; 53:4637-42. 10. Prewett MC, Hooper AT, Bassi R, et al. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 2002; 8:994-1003. 11. Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 2001; 20:3a (Abstract 7). 12. Saltz LB, Meropol NJ, Loehrer PJ, Sr, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22:1201-8. 13. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005; 23:1803-10. 14. Saltz L. In Reply: 10.1200/JCO.2005.05.354. J Clin Oncol 2005; 23:923-4. 15. Kurai J, Chikumi H, Hashimoto K, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007; 13:1552-61. 16. Wang Y, Jatkoe T, Zhang Y, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes' B colon cancer. J Clin Oncol 2004; 22:1564-71. 17. Arends R, Yang BB, Schwab G, et al. Flexible dosing schedules of panitumumab (ABX-EGF) in cancer patients. J Clin Oncol 2005; 23(16 suppl):214s (Abstract 3089). 18. Malik I, Hecht JR, Patnaik A, et al. Safety and efficacy of panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). J Clin Oncol 2005; 23(16 suppl):251s (Abstract 3520). 19. Van Cutsem E, Humblet Y, Gelderblom H, et al. Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): pharmacokinetic and efficacy data of a randomized study. Presented at: the 2007 ASCO Gastrointestinal Cancers Symposium; January 19-21; Orlando, FL. Abstract 237. 20. Wilke H, Glynne-Jones R, Thaler J, et al. MABEL–A large multinational study of cetuximab plus irinotecan in irinotecan resistant metastatic colorectal cancer. J Clin Oncol 2006; 24(18 suppl):158s (Abstract 3549). 21. Jonker D, O’Callaghan C, et al. Randomized phase III trial of cetuximab + best supportive care (BSC) versus BSC alone in patients with pretreated metastatic EGFR-positive colorectal cancer (NCIC CTG CO.17). Presented at: the 2007 Meeting of the American Association for Cancer Research; April 14-18, 2007; Los Angeles, CA. Abstract LB1. 22. Souglakos J, Kalykaki A, Vamvakas L, et al. Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol 2007; 18:305-10. 23. Rosenberg AH, Loehrer PJ, Needle MN, et al. Erbitux (IMC-C225) plus weekly irinotecan (CPT-11), fluorouracil (5FU) and leucovorin (LV) in colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFr). Proc Am Soc Clin Oncol 2002; 21:135a (Abstract 536). 24. Folprecht G, Lutz MP, Schoffski P, et al. Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 2006; 17:450-6. 25. Rougier P, Raoul J-L, Van Laethem J-L, et al. Cetuximab+FOLFIRI as first-line treatment for metastatic colorectal CA. J Clin Oncol 2004; 22(14 suppl):248 (Abstract 3513). 26. Díaz Rubio E, Tabernero J, van Cutsem E, et al. Cetuximab in combina-
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27.
28.
29.
30. 31.
32.
33. 34.
35. 36. 37.
38. 39. 40. 41. 42.
43.
44. 45.
46.
tion with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer: an international phase II study. J Clin Oncol 2005; 23(16 suppl):254s (Abstract 3535). Dakhil S, Cosgriff T, Headley D, et al. Cetuximab + FOLFOX6 as first line therapy for metastatic colorectal cancer (an International Oncology Network study, I-03-002). J Clin Oncol 2006; 24(18 suppl):160s (Abstract 3557). Hecht J, Posey J, Tchekmedyian S, et al. Panitumumab in combination with 5-fluorouracil, leucovorin, and irinotecan (IFL) or FOLFIRI for first-line treatment of metastatic colorectal cancer (mCRC). Presented at: the 2006 ASCO Gastrointestinal Cancers Symposium; January 26-28, 2006; San Francisco, CA. Abstract 237. Sobrero AF, Fehrenbacher L, Rivera F, et al. Randomized phase III trial of cetuximab plus irinotecan vs irinotecan alone for metastatic colorectal cancer (mCRC) after failing prior oxaliplatin-based therapy: the EPIC trial. Presented at: the 2007 Meeting of the American Association for Cancer Research; April 14-18, 2007; Los Angeles, CA. Abstract LB2. Polikoff J, Mitchell EP, Badarinath S, et al. Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): preliminary efficacy analysis of a randomized phase III trial. J Clin Oncol 2005; 23(16 suppl):264s (Abstract 3574). Saltz LB, Lenz H-J, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007; 25:4557-61. Hecht JR, Chidiac T, Mitchell E, et al. An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (Bev) for metastatic colorectal cancer (mCRC). Proceedings of the 9th World Congress on Gastrointestinal Cancer. Ann Oncol 2007; 18:vii21 (Abstract 0-0033). Lievre A, Bachet J-B, Le Corre D, et al. KRAS Mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66:3992-5. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24:4914-21. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005; 6:279-86. Francoual M, Etienne-Grimaldi MC, Formento JL, et al. EGFR in colorectal cancer: more than a simple receptor. Ann Oncol 2006; 17:962-7. Yatabe Y, Mitsudomi T, Cao L, et al. Correlation of ErbB/HER receptor expression and dimerization patterns as measured by a proximity-based assay using formalin-fixed, paraffin-embedded specimens with clinical response in a cohort of non-small-cell lung cancer patients treated with gefitinib. Presented at the AACR-EORTC meeting; November 14-15, 2005; Philadelphia, PA. Abstract 123. Jones HE, Goddard L, Gee JM, et al. Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 2004; 11:793-814. Adams TE, McKern NM, Ward CW. Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor. Growth Factors 2004; 22:89-95. Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 2001; 61:5090-101. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-42. Saltz L, Clark S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). Presented at: the 2007 Gastrointestinal Cancers Symposium 2007; January 19-21, 2007; Orlando, FL. Abstract 238. Hochster HS, Welles L, Hart L, et al. Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as firstline treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 studies. J Clin Oncol 2005; 23(16 suppl):249s (Abstract 3515). National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology™ Colon Cancer. Available at: http://www.nccn.org/ professionals/physician_gls/PDF/colon.pdf. Accessed: October 18, 2007. Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22:1209-14. Camp ER, Summy J, Bauer TW, et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005; 11:397-405.
Introduction The potential therapeutic utility of targeting the epidermal growth factor receptor (EGFR) with monoclonal antibody (MoAb) therapy was first demonstrated at the laboratory bench more than 20 years ago.1,2 Over recent years, we have seen the clinical realization of this pre-clinical promise, with EFGR-targeted antibody therapies entering routine practice in the field of colorectal cancer. Epidermal growth factor receptor and its associated downstream signaling pathways are involved in the maintenance of many of the malignant characteristics displayed by tumor cells, including tissue invasion, metastatic potential, self-sufficient growth, evasion of apoptosis, and sustained angiogenesis.3,4 Thus, the inhibition of EGFR activation has long been considered an important therapeutic target in many malignant diseases. The EGFR is expressed in approximately 70%-80% of colorectal tumors,5-7 and the degree of expression appears to correlate with a poorer prognosis8; this knowledge supported the initial evaluation of EFGR-targeted agents in colorectal cancer (CRC). Department of Medicine, Royal Marsden Hospital, Sutton, Surrey, United Kingdom Submitted: Jul 3, 2007; Revised: Sep 17, 2007; Accepted: Oct 8, 2007 Address for correspondence: David Cunningham, MD, FRCP, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey, SM2 5PT United Kingdom Fax: 4-208-6939414; e-mail: [email protected]
The Clinical Development of Cetuximab in IrinotecanRefractory Disease Cetuximab was the first EGFR-targeted MoAb to undergo clinical evaluation in CRC. Preclinical data had indicated the potential for EGFR-targeted antibodies to potentiate the activity of chemotherapy and possibly reverse chemoresistance.9,10 In xenograft tumor models, synergistic activity for the combination irinotecan/cetuximab was demonstrated. Furthermore, in an irinotecan-refractory xenograft model, it was shown that the combination of cetuximab and irinotecan significantly inhibited tumor growth, although either agent given independently had no noticeable antitumor activity.10 Based on these preclinical observations, an initial phase II clinical trial evaluated the action of cetuximab/irinotecan in the setting of irinotecan-refractory disease. The findings of this study were presented by Saltz et al the 37th Annual Meeting of the American Society of Clinical Oncology, held May 1215, 2001, in San Francisco, CA.11 One hundred twenty-one patients with EGFR-expressing advanced CRC who were refractory to irinotecan and 5-fluorouracil (5-FU) received treatment with the combination of cetuximab together with irinotecan according to the same dose and schedule on which they had previously progressed. In this patient population with irinotecan-refractory disease, the combination treatment produced a radiologic partial response (PR) rate (RR) of 17%, with an additional 31% of patients achieving stable disease (SD).
Dr Watkins has no relevant relationships to disclose. Dr Cunningham has received research support from Roche, Merck, Amgen, and Astra-Zeneca. He has also served as a paid consultant for Roche, Amgen, Bristol-Myers Squibb, Merck, Pfizer, and Astra-Zeneca. This article includes discussion of investigational and/or unlabeled use of drugs, including the use of cetuximab in metastatic colorectal cancer.
Clinical Colorectal Cancer Supplement October 2007 • S47
EGFR-Targeted Antibody Therapy in Previously Treated CRC Further data demonstrating the activity of cetuximab was gained from a second nonrandomized phase II study using cetuximab alone.12 In this study, patients with EGFR-expressing tumors who had demonstrated resistance to irinotecanbased chemotherapy received cetuximab alone. Again, clinical activity was demonstrated with a radiologic RR of 9%, and an additional 35% of patients achieving SD that lasted ≥ 12 weeks from study entry. Within both of these studies, cetuximab was well tolerated with the main toxicity being ache-like rash and allergic reactions. No interactions or unexpected toxicities were seen with the combination cetuximab/irinotecan. Federal Drug Administration approval for cetuximab was only gained after the results of a further randomized phase II study. The BOND study enrolled 329 patients who had progressed during or within 3 months of receiving irinotecan-based chemotherapy. Patients were randomized in a 2:1 ratio to receive cetuximab/irinotecan (according to the same dose and schedule as prestudy) or cetuximab alone. For patients recruited to the monotherapy arm, the protocol allowed for crossover to receive combination treatment at the time of progression. The primary endpoint of the study was radiologic RR, with secondary endpoints including time to progression (TTP) and overall survival (OS). Of the 577 patients screened, 82.1% had EGFR-expressing tumors and were randomized within the study. All patients had progressed on or within 3 months of receiving an irinotecan-based therapy, and of note, 62.2% of randomized patients had also received previous oxaliplatin. The results demonstrated a statistically significant improvement in RR and TTP in patients receiving the combination irinotecan/cetuximab. The RRs were 22.9% and 10.8%, respectively (P = .007), and the median TTPs were 4.1 months and 1.5 months in the combination and monotherapy arms, respectively. There was no statistically significant difference in OS (8.6 months in the combination arm and 6.9 months in the monotherapy arm), but this was not intended to be demonstrated as part of the original statistical design, and not expected because of the planned crossover. Toxicities were as expected. Approximately 80% of patients developed an acnelike rash, which was grade 3/4 in 9.4% and 5.2% of the combination and monotherapy arms, respectively. Only 1.2% of patients suffered severe anaphylactic reactions necessitating the discontinuation of cetuximab.7 Cetuximab demonstrated no clear impact on the incidence of irinotecan-related toxicities. A finding that was clearly demonstrated across these early studies was the lack of correlation between EGFR expression by immunohistochemistry (IHC) and radiologic RR. Other studies assessing EGFR-targeted antibodies in patients with negative staining for EGFR expression have demonstrated benefit in this patient group.13 It is clear that the current IHC methods of EGFR testing are of little value in patient selection,14 and indeed, many ongoing studies do not stipulate EGFR expression as an entry requirement. Although EGFR expression by IHC does not correlate with RR or outcome, an intriguing finding has been the correlation between severity of rash with RR and survival. Within patients receiving combination therapy on the BOND study, the RR and median survival in patients with skin reactions were 25.8% and
S48 • Clinical Colorectal Cancer Supplement October 2007
9.1 months, respectively, compared with 6.3% and 3 months, respectively, in patients without skin reactions.7 A similar pattern was seen in the monotherapy arm. The activity of cetuximab in patients with irinotecan-refractory disease had been clearly demonstrated by these studies; based on these data, FDA approval was granted for the use of cetuximab/irinotecan or as a single agent, in the setting of irinotecan-resistant disease.
Panitumumab, a Fully Humanized Epidermal Growth Factor Receptor–Targeted Antibody Panitumumab is the second EGFR-targeted antibody that has undergone clinical evaluation in CRC. Panitumumab differs from cetuximab in that it is a fully humanized immunoglobulin (Ig)G2 antibody, whereas cetuximab is a chimeric IgG1 antibody. The humanized antibody has the advantage of being associated with a lower risk of inducing allergic reactions. Both antibodies act by binding to the extracellular domain of the EGFR, preventing ligand binding and receptor activation. There is in vitro data suggesting that, as well as inhibiting EGFR activation, cetuximab can also induce antibody-dependent cellular cytotoxicity (ADCC).15 It is feasible that cetuximab being an IgG1 antibody is more likely to induce ADCC than panitumumab (IgG2). There is currently no published data to support or refute this. However, preliminary clinical data has suggested that Fc receptor polymorphisms might play a role in determining the response to cetuximab therapy, indicating the possible role of ADCC.16 The phase I trial of panitumumab included a pharmacokinetics evaluation of various dosing schedules: weekly, every 2 weeks, and every 3 weeks. The results indicate that each of the schedules provides a similar drug exposure and tolerability profile.17
Single-Agent Studies of Epidermal Growth Factor Receptor–Targeted Antibody Agents Versus Best Supportive Care The initial clinical development of panitumumab focused on its single-agent efficacy in the setting of chemorefractory disease. After phase II trials in advanced CRC, 18 a randomized phase III study of panitumumab versus best support care (BSC) in the third-line setting was undertaken.The study recruited 430 patients with EGFR-expressing tumors who demonstrated progressive disease having previously received irinotecan- and oxaliplatin-based regimens. Patients were randomized to receive panitumumab 6 mg/kg every 2 weeks with BSC or BSC alone. The study design allowed for patients in the BSC arm to cross over to receive panitumuab at the time of disease progression, with progression-free survival (PFS) being the primary endpoint. The results demonstrated the activity of panitumumab in this patient group, with a radiologic RR of 8% in the panitumumab arm and no response in the BSC arm. Progression-free survival was improved in the panitumumab arm with a hazard ratio (HR) of 0.54 (95% CI, 0.44-0.66; P < .0001). Of patients in the BSC arm, 174 patients (75%) crossed over to receive
David Watkins, David Cunningham panitumumab at the time of disease progression; of these patients, 10% achieved a PR. No difference in OS between the treatment arms was seen. Toxicities were as expected: 81% of patients in the panitumumab arm developed a skin reaction which was grade 3/4 in 18% of patietns. Infusion reactions were less frequent than in the cetuximab studies, with no grade 3/4 infusion reactions reported. A further toxicity that was apparent in patients receiving panitumumab was hypomagnesemia; this occurred in approximately 38% of patients but was rarely severe, with grade 3 or 4 toxicity seen in only 3% of patients.19 Hypomagnesemia has also been reported in studies utilizing cetuximab.20 A similar randomized study versus BSC has been undertaken with cetuximab. The NCIC (National Cancer Institute of Canada)–CO.17 study randomized 572 patients with progressing chemorefractory EGFR-positive CRC to receive BSC alone or cetuximab and BSC. This study differs significantly from the panitumumab study in that crossover from BSC to cetuximab was not planned. In this study, a benefit in PFS was again seen with an HR of 0.68 (95% CI, 0.57-0.8) and a stratified log-rank P value < .0001. Furthermore, an OS benefit was also demonstrated with a median survival of 6.1 months in the cetuximab arm versus 4.6 months in the BSC arm (HR, 0.77 [95% CI, 0.64-0.92]) and a stratified log-rank P value equal to .0046. In the cetuximab arm, grade 3/4 toxicities were as expected: rash 11.8%; hypersensitivity reaction 4.5%; hypomagnesemia 5.8%.21 A noticeable finding seen across the phase II/III studies assessing single-agent cetuximab and panitumumab has been the consistency of the RRs reported. In contrast to traditional cytotoxic agents, the efficacy of EGFR-targeted antibody therapies does not appear to be influenced by the number of previous therapies a patient has received (Table 1).
Epidermal Growth Factor Receptor– Targeted Antibody Therapy in Combination with Oxaliplatin The early clinical data for cetuximab clearly demonstrated its potential ability to reverse irinotecan chemoresistance in patients with irinotecan-refractory disease. At the current time, there is less data to support the use of the EGFR-targeted antibodies in combination with oxaliplatin in the setting of oxaliplatinrefractory disease. However, a recently published phase II study provides evidence of similar activity in this disease setting. The study recruited 44 patients who had evidence of disease progression after previous treatment with an oxaliplatin-based regimen. Seventy-eight percent of the enrolled patients had progressed on or within 3 months of completing oxaliplatin-based therapy (refractory). The most common previous oxaliplatin regimen was XELOX (capecitabine/oxalipatin; 65%); 80% of patients had also received previous irinotecan therapy. Within the trial, all patients received the combination of cetuximab given weekly, together with oxaliplatin (85 mg/m2 on day 1) and capecitabine (2000 mg/m2 on days 1-7) given in cycles every 2 weeks. The radiologic RR achieved was 20%, with SD in a further 27.5% of patients. A subgroup analysis of patients whose disease was refractory to oxaliplatin at entry revealed an RR of 16.1% in this patient
Table 1
Efficacy of Single-Agent Epidermal Growth Factor Receptor–Targeted Antibody Agents in the Chemorefractory Setting
Study
Agent
N
Patients Who Received Previous Oxaliplatinand Irinotecan-Based Chemotherapy (%)
RR (%)
Saltz et al12
Cetuximab
57
14
8.8
Malik et
al18
Panitumumab
148
44
9
Cunningham et al7
Cetuximab
111
62.2
10.8
Jonker et al21
Cetuximab
287
95
6.6
Panitumumab
231
100
10
Van Cutsem et al19
population. The results of this study provide an indication of the ability of cetuximab to reverse oxaliplatin resistance. A further interesting observation made was that of 21 patients who received poststudy therapy with the combination irinotecan/cetuximab, an RR of 9.5% was seen. This result hints at the potential ability of EGFR-targeted therapy to continue to augment chemotherapy responses through ≥ 1 line of cytotoxic agent.22 This concept will require further validation in prospective studies.
Epidermal Growth Factor Receptor–Targeted Antibodies in Combination with Chemotherapy in the Second-Line Setting Cetuximab is currently licensed for use in irinotecan-refractory disease. Intuitively, we would wish to consider the earlier introduction of EGFR-targeted therapies before the development of chemoresistance. Thus, potentially improving the quality of early response seen. The feasibility of combining EGFR-targeted agents with traditional cytotoxic therapies has been assessed in numerous phase II studies.23-28 More recently, randomized data demonstrating the comparative safety and efficacy of the addition of cetuximab to irinotecan chemotherapy in the second-line setting have become available. The EPIC (European Prospective Investigation of Cancer) study enrolled 1300 patients with EGFR-expressing tumors which had progressed on first-line oxaliplatin-based chemotherapy. Patients were randomized to receive single-agent irinotecan therapy or the combination irinotecan/cetuximab. The toxicity profile seen in the irinotecan/cetuximab arm was largely as expected, but a higher incidence of grade 3/4 diarrhea was seen (Table 2). Efficacy data is summarized in Table 3. The addition of cetuximab to irinotecan produced a higher radiologic RR and a statistically significant improvement in PFS. However, no significant difference in OS was seen between the 2 treatment arms. It is possible that the lack of OS benefit relates to cetuximab usage after the study, with 47% of patients in the irinotecan arm subsequently receiving cetuximab therapy.29 The US-based EXPLORE study was designed to evaluate the combination of FOLFOX (oxaliplatin/leucovorin [LV]/5-FU) 4 with or without cetuximab in patients previously treated with Clinical Colorectal Cancer Supplement October 2007 • S49
EGFR-Targeted Antibody Therapy in Previously Treated CRC Table 2
Table 3
EPIC Study Toxicity Results
Grade 3/4 Toxicity
Cetuximab/Irinotecan (N = 638) N (%)
Irinotecan (N = 629) N (%)
Any Adverse Event > 5%
457 (71.6)
Diarrhea
EPIC Study Efficacy Results
Treatment Arm
Response Rate (%)
PFS (Months)
OS (Months)
357 (56.8)
Irinotecan/Cetuximab (N = 648)
16.4
4 (P a .0001)
10.71 (P = .7115)
184 (28.8)
102 (16.2)
Irinotecan (N = 650)
4.2
2.6
9.99
Acneiform Rash
52 (8.2)
3 (0.5)
Infusion Reaction
9 (1.4)
5 (0.8)
Hypomagnesemia
9 (3.3)
1 (0.4)
irinotecan-based therapy. This trial opened in March 2003 with a planned recruitment of 1100 patients. As a result of oxaliplatin receiving FDA approval as first-line therapy in 2004, standard practice in the United States changed and study recruitment slowed. The study was closed in December 2004 because of poor accrual. The outcomes of the 102 enrolled patients have been reported.30 The radiologic RR of FOLFOX4/cetuximab was 21% compared with 8.5% in the standard FOLFOX4 arm. Progression-free survival was similar in both arms. The results of this study indicate an encouraging improvement in RR with the addition of cetuximab, but because of the small sample size, no conclusions regarding efficacy can be drawn. A further study evaluating the combination irinotecan/panitumumab in the second-line setting, is the UK-based PICCOLO (Panitumumab, Irinotecan and Ciclosporin in Colorectal Cancer) trial. This study is recruiting patients with disease progression after previous 5-FU with or without oxaliplatin therapy. Patients are randomized to 1 of 3 of the following treatment arms: irinotecan alone, irinotecan/panitumumab, or irinotecan/cyclosporin.
Second-Line Epidermal Growth Factor Receptor–Targeted Therapy After First-line–Targeted Therapy There are currently no phase III studies evaluating EGFRtargeted antibody therapy in specific groups of patients having previously received treatment with EGFR or vascular endothelial growth factor (VEGF)–targeted therapy in the first-line setting. Figure 1
Some insight into to the activity of EGFR-targeted agents in this setting is likely to be gained from studies such as PICCOLO, which will include a proportion of patients having received previous cetuximab and/or bevacizumab. A randomised phase II study (SPIRITT) is specifically evaluating the use of FOLFIRI (irinotecan/LV/5-FU) with bevacizumab or panitumumab as second-line treatment in patients who had not previously exhibited a response to oxaliplatin-based chemotherapy and who had received ≥ 4 doses of bevacizumab therapy.
Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Combination Therapies in the Chemorefractory Setting Based on preclinical data suggesting potential synergistic activity with the combination of an EGFR-targeted agent and VEGF inhibitor, the BOND II trial was undertaken.This randomized phase II study enrolled patients with progressive irinotecan-refractory disease. Patients were randomized to receive cetuximab/bevacizumab/irinotecan or cetuximab/bevacizumab. The radiologic RRs were 37% and 23% in the cetuximab/ bevacizumab/irinotecan and the cetuximab/bevacizumab arms, respectively. 31 When these RRs are compared with the treatment arms in the first BOND study, it appears that the addition of bevacizumab to an EGFR-targeted antibody can improve the efficacy of therapy. However, this is a nonrandomized, cross- trial comparison and can be misleading. The recent results of the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) study, on which the combination of cytotoxic chemotherapy with bevacizumab and panitumumab was examined, have raised con-
EVEREST Study Scheme
Day 22 EGFR-Positive CRC Progression on previous irinotecan Cetuximab (400 mg/m2 then 250 mg/m2 per week) Irinotecan (180 mg/m2 every 2 weeks)
Rash grade a 1 No toxicity grade 2 Other patients Not randomized
Arm A Continue standard dose treatment Cetuximab (250 mg/m2 per week) Irinotecan (180 mg/m2 every 2 weeks) Arm B Escalating dose Cetuximab dose increases by 50 mg/m2 every 2 weeks maximum of 500 mg/m2 Irinotecan (180 mg/m2 every 2 weeks) Arm C Patients not eligible for randomization Cetuximab (250 mg/m2 per week) Irinotecan (180 mg/m2 every 2 weeks)
S50 • Clinical Colorectal Cancer Supplement October 2007
David Watkins, David Cunningham cerns as to the safety of combining EGFR- and VEGF-targeted therapy with cytotoxic chemotherapy.32
Rash and Dose Response in the EVEREST Study The intriguing relationship between rash, tumor response, and improved outcome led to the development of the EVEREST study. This was undertaken to examine the relationship between antibody dose, rash, and tumor response in a prospective fashion. This study enrolled patients with EGFR-expressing tumors who had been previously treated with irinotecan chemotherapy. All patients commenced initial treatment with irinotecan/cetuximab and, at day 22, an assessment of rash and other toxicity was made (Figure 1). Patients who had not developed grade ≥ 2 rash were randomized at day 22 to continue standard treatment (arm A) or to commence cetuximab dose escalation (arm B). Patients not meeting the criteria for randomization continued with standard therapy (arm C). After the initial 22-day run-in period, 99 patients met the criteria for randomization. Forty-five patients were randomized to arm A, 44 to arm B, and 77 patients were not randomized and continued to receive treatment in arm C. The rates of rash and radiologic RRs are shown in Table 4. These results indicate that cetuximab dose escalation in patients with no or mild rash appears to increase the severity of rash, and possibly improve radiologic tumor RR.19 The EVEREST study was exploratory, and before the adoption of dose escalation into standard practice, the concept will require further formal clinical evaluation. The EVEREST study includes translational aspects with patients undergoing skin and tumor tissue biopsies for biomarker research. The results of these aspects of the study are keenly awaited. Much effort is currently being focused on translational research aimed at exploring the molecular mechanisms involved in response and resistance to EGFR-targeted therapies. Avenues currently under evaluation include mutated K-ras, which can predict for resistance to therapy,33 EGFR copy number,34 EGFR mutational status,35 high-affinity EGFR distribution,36 and EGFR dimerization patterns37 together with other signaling pathways such as the insulin-like growth factor–1R38,39 and VEGF,40 which might also be implicated.
Conclusion The published data evaluating EGFR-targeted antibody therapy has clearly demonstrated the ability of these agents to reverse chemoresistance when given in combination with cytotoxic chemotherapy, together with modest single-agent activity in the chemorefractory disease setting. Available data from the CRYSTAL and EPIC studies have indicated the additional activity provided by the combination of cetuximab with chemotherapy in the first-line and second-line settings. However, whether this upfront combination approach provides any benefits over the sequential use of traditional cytotoxic agents and the later introduction of EGFR-targeted agents is unclear. On the basis of randomized41,42 and nonrandomized studies,43 bevacizumab is currently considered part of standard first-line
Table 4
EVEREST Study Results
Patients with Rash (%)
Arm A
Arm B
Arm C
Grade 2
22
25
43
Grade 3/4
0
5
9
30
22 (34 in patients with grade > 1 rash)
Radiologic Response Rate (%)
13
therapy, with cetuximab and panitumumab in general recommended for second-line or subsequent-line use.44 Whether this pattern of use alters over the coming years will depend on the results of ongoing first-line studies evaluating the relative benefit of each of the biologic agents in combination with cytotoxic chemotherapy. Data from the PACCE study has given an indication that the combination of traditional cytotoxic therapy with EGFR and VEGF targeting agents might carry excessive toxicities without benefiting efficacy.32 The results from studies such as CALGB (Cancer and Leukemia Group B) 80405 and CARIO 2 will provide further data as to the relevant benefit of each of the biologic agents in the first-line setting. The place of EGFR-targeted agents in the second-line treatment setting will, to an extent, be dependent on the findings of these first-line studies. After the introduction of irinotecan and oxaliplatin into clinical practice, it was seen that exposure to all 3 agents during the course of therapy provides a survival advantage.45 It will be interesting to see whether the same pattern can be demonstrated for the biologic agents that we now have available in the clinical setting. Among the questions to be asked in future trials will be the ability of EGFR-targeted antibodies to augment chemotherapy responses across multiple lines of therapy. There are a variety of molecular mechanisms involved in the development of resistance to EGFR-targeted therapies46; our current understanding of these mechanisms is limited. In this era of combination cytotoxic and EGFR-targeted therapy, it is currently not possible to evaluate the relative contribution of each agent to treatment outcome in an individual. Useful biomarkers will not only be able to predict which tumors are likely to have de novo resistance to therapy, but can also help us to identify when resistance to a therapy has developed on treatment. The potential benefit of EGFR-targeted antibody therapy was demonstrated at the laboratory bench more than 20 years ago. It is now clear that the optimal clinical benefit of these agents will only be achieved through a combination of clinical and ongoing laboratory research.
References 1. Masui H, Kawamoto T, Sato JD, et al. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1984; 44:1002-7. 2. Gill G, Kawamoto T, Cochet C, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 1984; 259:7755-60. 3. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70. 4. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002; 20(18 suppl):1s-13s.
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EGFR-Targeted Antibody Therapy in Previously Treated CRC 5. Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol 2000; 21:105-15. 6. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer 2001; 92:1331-46. 7. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337-45. 8. Mayer A, Takimoto M, Fritz E, et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer 1993; 71:2454-560. 9. Fan Z, Baselga J, Masui H, et al. Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 1993; 53:4637-42. 10. Prewett MC, Hooper AT, Bassi R, et al. Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 2002; 8:994-1003. 11. Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 2001; 20:3a (Abstract 7). 12. Saltz LB, Meropol NJ, Loehrer PJ, Sr, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22:1201-8. 13. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005; 23:1803-10. 14. Saltz L. In Reply: 10.1200/JCO.2005.05.354. J Clin Oncol 2005; 23:923-4. 15. Kurai J, Chikumi H, Hashimoto K, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007; 13:1552-61. 16. Wang Y, Jatkoe T, Zhang Y, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes' B colon cancer. J Clin Oncol 2004; 22:1564-71. 17. Arends R, Yang BB, Schwab G, et al. Flexible dosing schedules of panitumumab (ABX-EGF) in cancer patients. J Clin Oncol 2005; 23(16 suppl):214s (Abstract 3089). 18. Malik I, Hecht JR, Patnaik A, et al. Safety and efficacy of panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). J Clin Oncol 2005; 23(16 suppl):251s (Abstract 3520). 19. Van Cutsem E, Humblet Y, Gelderblom H, et al. Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): pharmacokinetic and efficacy data of a randomized study. Presented at: the 2007 ASCO Gastrointestinal Cancers Symposium; January 19-21; Orlando, FL. Abstract 237. 20. Wilke H, Glynne-Jones R, Thaler J, et al. MABEL–A large multinational study of cetuximab plus irinotecan in irinotecan resistant metastatic colorectal cancer. J Clin Oncol 2006; 24(18 suppl):158s (Abstract 3549). 21. Jonker D, O’Callaghan C, et al. Randomized phase III trial of cetuximab + best supportive care (BSC) versus BSC alone in patients with pretreated metastatic EGFR-positive colorectal cancer (NCIC CTG CO.17). Presented at: the 2007 Meeting of the American Association for Cancer Research; April 14-18, 2007; Los Angeles, CA. Abstract LB1. 22. Souglakos J, Kalykaki A, Vamvakas L, et al. Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol 2007; 18:305-10. 23. Rosenberg AH, Loehrer PJ, Needle MN, et al. Erbitux (IMC-C225) plus weekly irinotecan (CPT-11), fluorouracil (5FU) and leucovorin (LV) in colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFr). Proc Am Soc Clin Oncol 2002; 21:135a (Abstract 536). 24. Folprecht G, Lutz MP, Schoffski P, et al. Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol 2006; 17:450-6. 25. Rougier P, Raoul J-L, Van Laethem J-L, et al. Cetuximab+FOLFIRI as first-line treatment for metastatic colorectal CA. J Clin Oncol 2004; 22(14 suppl):248 (Abstract 3513). 26. Díaz Rubio E, Tabernero J, van Cutsem E, et al. Cetuximab in combina-
S52 • Clinical Colorectal Cancer Supplement October 2007
27.
28.
29.
30. 31.
32.
33. 34.
35. 36. 37.
38. 39. 40. 41. 42.
43.
44. 45.
46.
tion with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer: an international phase II study. J Clin Oncol 2005; 23(16 suppl):254s (Abstract 3535). Dakhil S, Cosgriff T, Headley D, et al. Cetuximab + FOLFOX6 as first line therapy for metastatic colorectal cancer (an International Oncology Network study, I-03-002). J Clin Oncol 2006; 24(18 suppl):160s (Abstract 3557). Hecht J, Posey J, Tchekmedyian S, et al. Panitumumab in combination with 5-fluorouracil, leucovorin, and irinotecan (IFL) or FOLFIRI for first-line treatment of metastatic colorectal cancer (mCRC). Presented at: the 2006 ASCO Gastrointestinal Cancers Symposium; January 26-28, 2006; San Francisco, CA. Abstract 237. Sobrero AF, Fehrenbacher L, Rivera F, et al. Randomized phase III trial of cetuximab plus irinotecan vs irinotecan alone for metastatic colorectal cancer (mCRC) after failing prior oxaliplatin-based therapy: the EPIC trial. Presented at: the 2007 Meeting of the American Association for Cancer Research; April 14-18, 2007; Los Angeles, CA. Abstract LB2. Polikoff J, Mitchell EP, Badarinath S, et al. Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): preliminary efficacy analysis of a randomized phase III trial. J Clin Oncol 2005; 23(16 suppl):264s (Abstract 3574). Saltz LB, Lenz H-J, Kindler HL, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 2007; 25:4557-61. Hecht JR, Chidiac T, Mitchell E, et al. An interim analysis of efficacy and safety from a randomized controlled trial of panitumumab with chemotherapy plus bevacizumab (Bev) for metastatic colorectal cancer (mCRC). Proceedings of the 9th World Congress on Gastrointestinal Cancer. Ann Oncol 2007; 18:vii21 (Abstract 0-0033). Lievre A, Bachet J-B, Le Corre D, et al. KRAS Mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006; 66:3992-5. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 2006; 24:4914-21. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005; 6:279-86. Francoual M, Etienne-Grimaldi MC, Formento JL, et al. EGFR in colorectal cancer: more than a simple receptor. Ann Oncol 2006; 17:962-7. Yatabe Y, Mitsudomi T, Cao L, et al. Correlation of ErbB/HER receptor expression and dimerization patterns as measured by a proximity-based assay using formalin-fixed, paraffin-embedded specimens with clinical response in a cohort of non-small-cell lung cancer patients treated with gefitinib. Presented at the AACR-EORTC meeting; November 14-15, 2005; Philadelphia, PA. Abstract 123. Jones HE, Goddard L, Gee JM, et al. Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 2004; 11:793-814. Adams TE, McKern NM, Ward CW. Signalling by the type 1 insulin-like growth factor receptor: interplay with the epidermal growth factor receptor. Growth Factors 2004; 22:89-95. Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 2001; 61:5090-101. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-42. Saltz L, Clark S, Diaz-Rubio E, et al. Bevacizumab (Bev) in combination with XELOX or FOLFOX4: efficacy results from XELOX-1/NO16966, a randomized phase III trial in the first-line treatment of metastatic colorectal cancer (MCRC). Presented at: the 2007 Gastrointestinal Cancers Symposium 2007; January 19-21, 2007; Orlando, FL. Abstract 238. Hochster HS, Welles L, Hart L, et al. Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as firstline treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 studies. J Clin Oncol 2005; 23(16 suppl):249s (Abstract 3515). National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology™ Colon Cancer. Available at: http://www.nccn.org/ professionals/physician_gls/PDF/colon.pdf. Accessed: October 18, 2007. Grothey A, Sargent D, Goldberg RM, et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22:1209-14. Camp ER, Summy J, Bauer TW, et al. Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005; 11:397-405.