Colorectal cancer remains a common disease in the United States. The projected incidence for 2007 is 153,760 cases, and 52,180 deaths are expected. Advances were made in the systemic therapy of metastatic colorectal cancer after the introduction of the novel cytotoxics irinotecan (Camptosar) and oxaliplatin (Eloxatin), extending median survival for metastatic disease from 9 months with fluorouracil (5-FU) and leucovorin, to longer than 17 months with first-line use of oxaliplatin together with 5-FU, and longer than 20 months for patients who are well enough to receive, and who have access to, all three drugs at some time in their treatment course.[2-4]
Novel targets are also being explored. A clear survival advantage has been demonstrated for the addition of bevacizumab (Avastin), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF).* Also active, but less well-studied in front-line therapy, are agents that target the epidermal growth factor receptor (EGFR). Such drugs are the focus of this review.
Epidermal Growth Factor Receptor
The epidermal growth factor receptor (EGFR or HER1) is a 170-kd polypeptide tyrosine kinase growth factor receptor. Along with HER2, HER3, and HER4, it is a member of the HER receptor family and an important mediator of cell proliferation, differentiation, and survival. The extracellular region of the EGFR contains both a ligand-binding domain and a dimerization loop; the tyrosine kinase domain is located in the molecule's cytoplasmic region. A putative nuclear localization sequence has been identified in the juxtamembrane domain. Endogenous ligands include epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, amphiregulin, heparin-binding EGF, and betacellulin, although the two most important stimulatory ligands are EGF and TGF-alpha.[8-10]
Binding of ligand leads to dimerization of the receptor with another HER molecule, followed by autophosphorylation of intracellular tyrosine residues. Signal transduction cascades via the Ras, ERK1/2, PI3K/Akt, and STAT pathways are activated. Cellular proliferation, adhesion, differentiation, angiogenesis, and apoptosis result.[6,8,10]
Pharmacologic inhibition of EGFR signaling can be achieved through competitive inhibition of ligand-binding, or by direct tyrosine kinase inhibition. Both of these approaches have undergone extensive clinical development. Two monoclonal antibodies that interfere with ligand-binding have been approved for use in metastatic colorectal cancer—cetuximab (Erbitux) and panitumumab (Vectibix).
Cetuximab (C225, IMC-225) was developed as a human-murine chimeric antibody derived from the murine antibody M225, which binds specifically to the ligand-binding domain of EGFR. Cetuximab-bound EGFR is not available for binding by natural ligand, and ligand-dependent signaling is reduced. Antibody-bound receptor is internalized, albeit by an alternative and possibly slower process than is ligand-bound receptor. Cetuximab upregulates expression of the cell-cycle inhibitor p27(kip1), resulting in G1 arrest. Reduced proliferation, substantial antitumor effect, and enhanced apoptosis have been demonstrated in cetuximab-treated A431 vulvar carcinoma xenografts. The murine antiepidermal growth factor antibody M225, from which cetuximab was derived by chimerization, substantially enhanced the antitumor effects of doxorubicin in established xenografts of EGFR-expressing tumor cells.
Phase I testing of cetuximab established that therapy with cetuximab is well-tolerated, with acneiform rash and hypersensitivity reactions as the predominant toxicities. Subsequently, hypomagnesemia has also been recognized as an adverse effect of cetuximab. The recommended phase II doses were a loading dose of cetuximab at 400 mg/m2 in week 1, followed by a maintenance dose of 250 mg/m2 given weekly. Clearance was saturated at this dose and schedule, but an optimum biologic dose was not demonstrated, formal determination of the maximum tolerated dose was not achieved, and alternative schedules such as every-other-week dosing are only now being explored.
Cetuximab in Chemotherapy-Refractory Disease
The phase II experience with cetuximab in colon cancer began with testing in patients with irinotecan-refractory disease, at a time when oxaliplatin was not commercially available in the United States. Patients with disease progression on irinotecan-containing therapy continued the dose and schedule of irinotecan given at the time of progression, with the addition of cetuximab. Objective responses were observed in 22% of patients.
This finding was later confirmed in a large randomized phase II study by Cunningham and colleagues, in a similar population of irinotecan-refractory patients. A total of 329 such patients were randomly assigned to receive either cetuximab and irinotecan (218 patients) or cetuximab monotherapy (111 patients). Objective responses were observed in 22.9 % (confidence interval [CI] = 17.5%-29.1%) of patients treated with the combination, compared with 10.8% of those who received cetuximab alone (CI = 5.7%-18.1%, P = .007). Median time to progression was 4.1 months for patients who received the combination, compared with 1.5 months for those who received the monotherapy (P < .001). Median overall survival was 8.6 months in the combination-therapy group and 6.9 months for patients who received cetuximab alone (P = .48).
Similar objective response rates for cetuximab monotherapy were described in two additional studies: a response rate of 9% among 57 patients with irinotecan-refractory metastatic colorectal cancer treated in a multicenter study, and of 11.6% among 346 patients with irinotecan- and oxaliplatin-refractory disease.[20,21]
A randomized trial of irinotecan with or without cetuximab for patients with metastatic, fluoropyrimidine- and oxaliplatin-refractory colorectal cancer has been completed. The study randomized 1,298 patients between irinotecan and irinotecan/cetuximab. Confirmed responses are reported in 4% of irinotecan, and 16% of irinotecan/cetuximab-treated patients. Median progression-free survival was 2.6 months for irinotecan and 4.0 months for irinotecan/cetuximab (hazard ratio [HR] = 0.69, stratified log-rank P < .0001). However, these improved initial outcome measures were not matched by a comparable advance in overall survival: Median survival was 10.0 months for irinotecan-treated patients and 10.7 months for patients who received irinotecan/cetuximab (P = .7). There was no clear explanation for this discrepancy—one might hypothesize that the survival impact of cetuximab at the time of progression in the control patients was sufficient for survival to match that seen in patients assigned to early cetuximab. The possibility of postprogression acceleration of disease also cannot be excluded on the basis of these data.
Likewise, a comparison of cetuximab with best supportive care for patients with chemotherapy-refractory colon cancer has also been completed, by the National Cancer Institute of Canada (NCIC) and the Australasian Gastrointestinal Trials Group. Patients who had progressed after (or were not candidates for) treatment with a fluoropyrimidine, oxaliplatin, and irinotecan received cetuximab monotherapy or best supportive care, following random assignment. The median survival for patients receiving best supportive care was 4.6 months, compared with 6.1 months for those receiving cetuximab (HR = 0.77, P = .005).
Activity of the cetuximab/irinotecan combination has also been demonstrated when the agents are given on an every-other-week schedule. In a phase II study enrolling patients who had disease progression after treatment with fluorouracil, irinotecan, and oxaliplatin—without requiring evidence of EGFR expression—cetuximab was given as a loading dose of 400 mg/m2 in week 1, 250 mg/m2 in week 2, and then 500 mg/m2 every second week. A response rate of 23% and a median time to progression of 4.7 months were observed in 40 patients. These results are similar to the response and progression data obtained with weekly cetuximab added to irinotecan in the Cunningham study described above.
Dr. Burtness is an advisor for Sanofi-Aventis, Amgen, Genentech, ImClone Systems, and Array BioPharma; a speaker for Sanofi, Genentech, and ImClone; and has received research funding from Sanofi, Bristol-Myers Squibb, and Genentech.
1. American Cancer Society: Cancer Facts & Figures 2007. Available at www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf. Accessed June 7, 2007.
2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905-914, 2000.
3. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004.
4. 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 22:1209-1214, 2004.
5. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.
6. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 61:203-212, 1990.
7. Hsu SC, Hung MC: Characterization of a novel tripartite nuclear localization sequence in the EGFR family. J Biol Chem 282:10432-10440, 2007.
8. Gibson S, Tu S, Oyer R, et al: Epidermal growth factor receptor protects epithelial cells against Fas-induced apoptosis. J Biol Chem 272:17612-17618, 1999.
9. Mattoon D, Klein P, Lemmon MA, et al: The tethered configuration of the EGF receptor extracellular domain exerts only a limited control of receptor function. Proc Natl Acad Sci USA 101:923-928, 2004.
10. Lemmon MA, Bu Z, Ladbury JE, et al: Two EGF molecules contribute additively to stabilization of the EGFR dimer. Embo J 16:281-294, 1997.
11. Fan Z, Maui H, Altas I, et al: Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 53:4322-4328, 1993.
12. Jaramillo ML, Leon Z, Grothe S, et al: Effect of the anti-receptor ligand-blocking 225 monoclonal antibody on EGF receptor endocytosis and sorting. Exp Cell Res 312:2778-2790, 2006.
13. Wu X, Rubin M, Fan Z, et al: Involvement of p27kip1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene 12:1397-1403, 1996.
14. Fan Z, Lu Y, Wu X, et al: Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. J Biol Chem 269:27595-27602, 1994.
15. 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 53:4637-4642, 1993.
16. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of anti-epidermal growth factor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904-914, 2000.
17. Burtness B, Goldwasser MA, Flood W, et al: Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 23:8646-8654, 2005.
18. Saltz LB, Rubin M, Hochster H, et al: Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that express epidermal growth factor receptor (EGFR) (abstract 7). Proc Am Soc Clin Oncol 20:3a, 2001.
19. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004.
20. 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 22:1201-1208, 2004.
21. 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 24:4914-4921, 2006.
22. Sobrero AF, Fehrenbacher L, Rivera F, et al: Randomized phase III trial of cetuximab plus irinotecan versus irinotecan alone for metastatic colorectal cancer in 1298 patients who have failed prior oxaliplatin-based therapy. The EPIC trial (abstract LB-2). Proceedings of the American Association for Cancer Research, Los Angeles, April 14-18, 2007.
23. Jonker D, Karapetis CS, Moore M, et al: Randomized phase III trial of cetuximab montherapy plus best supportive care (BSC) versus BSC alone in patients with pretreated metastatic epidermal growth factor receptor (EGFR)-positive colorectal cancer: A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIG CTG) and The Australasian Gastrointestinal Trials Group (AGITG) (abstract LB-1). Proceedings of the American Association for Cancer Research, Los Angeles, April 14-18, 2007.
24. Pfeiffer P, Bjerregaard JK, Qvortrup C: Biweekly cetuximab (Cet) and irinotecan (Iri) as third-line therapy in patients with advanced colorectal cancer (ACRC) (abstract 305). Presented at the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 19-21, 2007. Available at www.asco.org. Accessed June 7, 2007.
25. Andre T, Tabernero J, Van Cutsem E, et al: Phase II study with cetuximab plus FOLFOX-4 in first-line setting for epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC): Final results (abstract 334). Presented at the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 19-21, 2007. Available at www.asco.org. Accessed June 7, 2007.
26. Heinemann V, Moosmann N, Vehling-Kaiser U, et al: XELIRI plus cetuximab versus XELOX plus cetuximab for first-line therapy of metastatic colorectal cancer (CRC): A randomized trial of the AIO CRC Study Group (abstract 278). Presented at the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 19-21, 2007. Available at www.asco.org. Accessed June 7, 2007.
27. Venook A, Niedzwiecki D, Hollis D, et al: Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) +/- cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum: CALGB 80203 preliminary results (abstract 3509). J Clin Oncol 24(18S):148s, 2006.
28. 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 23:1803-1810, 2005.
29. 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 6:279-286, 2005.
30. Shia J, Klimstra DS, Li AR, et al: Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: An immunohistochemical and chromogenic in situ hybridization study. Mod Pathol 18:1350-1356, 2005.
31. Segaert S, Van Cutsem E: Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16:1425-1433, 2005.
32. Moss JE, Burtness B: Images in clinical medicine. Cetuximab-associated acneiform eruption. N Engl J Med 353:e17, 2005.
33. 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): Preliminary PK and efficacy data of a randomized study (abstract 237). Presented at the 2007 Gastrointestinal Cancers Symposium; Orlando, Fla; Jan 19-21, 2007. Available at www.asco.org. Accessed June 7, 2007.
34. Foon KA, Yang X-D, Weiner LM, et al: Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys 58: 984-990, 2004.
35. Hecht J, Mitchell E, Baranda J, et al: Panitumumab antitumor activity in patients (PTS) with metastatic colorectal cancer (mCRC) expression low (1-9%) or negative (< 1%) levels of epidermal growth factor receptor (EGFr) (abstract 3547). J Clin Oncol 24(18S):157s, 2006.
36. Berlin J, Neubauer P, Swanson WG, et al: Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing ≥ 10% epidermal growth factor receptor (EGFr) (abstract 3548). J Clin Oncol 24(18S):158s, 2006.
37. Peeters M, Van Cutsem E, Siena S, et al: A phase III, multicenter randomized controlled trial (RCT) of panitumumab plus best supportive care (BSC) versus BSC alone in patients (pts) with metastatic colrectal cancer (mCRC). Presented at the 97th Annual Meeting of the American Association for Cancer Research; Washington, DC; April 1-5, 2006.
38. Hecht J, Posey J, Tchekmedyian S, et al: Panitumumab with 5-fluorouracil, leucovorin, and irinotecan or FOLFIRI for first-line treatment of metastatic colorectal cancer (abstract 237). Presented at the 2006 Gastrointestinal Cancers Symposium; San Francisco; Jan 26-28, 2006. Available at www.asco.org. Accessed June 7, 2007.
39. Adams GP, Schier R, McCall AM, et al: High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res 61:4750-4755, 2001.