Epidermal Growth Factor Receptor Inhibitors and Colorectal Cancer

The epidermal growth factor receptor (EGFR) plays an important role in cell growth, differentiation, and survival. Targeting EGFR in patients with colorectal cancer has become an important therapeutic tool. Recently, a monoclonal antibody against the extracellular domain of the receptor (cetuximab [Erbitux]) has been approved for the treatment of patients with EGFR-positive metastatic disease refractory to irinotecan (Camptosar)-based therapy. The role of other targeted agents against EGFR, including other monoclonal antibodies as well as inhibitors of the intracellular tyrosine kinase domain, will also be discussed.

In 2004, an estimated 146,900 people will be diagnosed with colorectal cancer, and 57,100 will die from the disease.[1] Surgical resection remains the only curative treatment. Unfortunately, approximately 20% of patients present with metastatic cancer, and through the natural history of the disease, 45% of patients will eventually develop metastases.[2] Despite a decade of progress in the treatment of metastatic colorectal cancer, the median survival remains under 2 years.[3] Ultimately, meaningful improvements in advanced colorectal cancer therapy will require the development of more effective systemic therapies. Epidermal Growth Factor Receptor The epidermal growth factor receptor (EGFR) is a member of the EGF family of receptors that share the property of being transmembrane molecules with an extracellular ligandbinding domain and an intracellular domain with tyrosine kinase activity.[ 4] Alterations in the function of these receptors are associated with oncogenic transformation, and altered regulation leads to cell growth, invasion, angiogenesis, and metastases. EGFR is expressed and overexpressed in an extensive range of human cancers; in colorectal cancer, between 25% and 77% of tumors overexpress EGFR.[5-7] Overexpression has also been associated with poorer prognosis.[ 5,7] Thus, the inhibition of the EGFR to treat colorectal tumors is of great interest. Multiple strategies to target against the EGFR and subsequent signaling pathways have been developed. Approaches to blocking the pathway include monoclonal antibodies specific for the extracellular domain of EGFR that block ligand binding, antibodies against the ligands of EGFR to inhibit their binding to the receptor, smallmolecule inhibitors against the intracellular tyrosine kinase (TK) domain, antibody and ligand-toxin conjugates that target EGFR, and antisense oli- gonucleotides to reduce the expression of EGFR.[8] Of these approaches, monoclonal antibodies directed against the extracellular domain and TK inhibitors are farthest along in clinical development. Monoclonal Antibodies in Colorectal Cancer At least four antibodies against EGFR are being investigated in clinical trials: cetuximab (Erbitux), ABXEGF (panitumumab), EMD 72000, and Theracim h-R3. Trials have been reported on the activity of cetuximab and ABX-EGF in patients with colorectal cancer. Cetuximab is a chimeric humanmurine monoclonal antibody that binds selectively to EGFR. Its binding inhibits autophosphorylation of EGFR, and induces internalization and degradation of the receptor. Cetux imab has been extensively studied in colorectal cancer, with promising activity both as a single agent and in combination (Table 1). Based on the initial two trials of Saltz and colleagues[ 9,10] and the Bowel Oncology with Cetuximab ANtiboDy (BOND) trial,[11] the US Food and Drug Administration (FDA) approved cetuximab for the treatment of patients with metastatic colorectal cancer with EGFR expression detected by immunohistochemistry and whose tumor was refractory to irinotecan (Camptosar), as those were inclusion criteria for patients on those trials.

Of interest, the level of expression of EGFR has not corresponded to the likelihood of response.[11] Recently, Lenz et al demonstrated a 12% response rate for single-agent cetuximab in patients refractory to both irinotecan and oxaliplatin (Eloxatin).[12] Phase II trials of combination therapy with cetuximab as initial therapy for patients with metastatic disease have been promising.[13,14] The Cancer and Leukemia Group B (CALGB) is currently leading a trial exploring the activity of the antibody in chemonaive patients. ABX-EGF is a fully humanized monoclonal antibody specific for the human EGFR. Recently, a phase II trial of single-agent ABX-EGF demonstrated similar activity to cetuximab in patients who previously progressed on either irinotecan- or oxaliplatinbased therapy.[15] Among 148 patients with overexpression of EGFR, the response rate of single-agent ABX-EGF was 10%, with another 37% of patients having stable disease. Trials combining ABX-EGF with cytotoxic chemotherapy are currently in development. Tyrosine Kinase Inhibitors in Colorectal Cancer A second approach that has been developed to block the EGFR signaling pathway has been the competitive inhibition of the binding of adenosine triphosphate (ATP) to the TK domain of the receptor, thereby blocking autophosphorylation and the activation of downstream events. Multiple agents are currently in development using this mechanism of action, including erlotinib (Tarceva), gefitinib (Iressa), CI-1033, EKB-569, PKI-166, and GW2016. The latter two compounds are considered pan-HER inhibitors as they appear to act on both the EGFR (HER-1) and other receptors in the family. Erlotinib and gefitinib are farthest along in clinical trials for colorectal cancer and will be discussed below. Erlotinib is a quinazoline derivation that reversibly blocks the ATP binding site of the TK domain of EGFR. In a phase I trial of erlotinib with 40 patients, 9 patients with colorectal cancer were enrolled at varying dose levels.[16] Using an intermittent dosing schedule, one patient with colorectal cancer had a 30% reduction in measurable liver metastases that lasted for 11 months, and two patients experienced stable disease for at least 5 months. In a small phase II trial reported at the European Organization for Research and Treatment of Cancer/National Cancer Institute/ American Association for Cancer Research symposium in Frankfurt, Germany (November 2002), daily administration of erlotinib to patients with metastatic colorectal cancer did not lead to any responses; however, five pa- tients (33%) had stable disease.[17]

Gefitinib, an anilinoquinazoline that reversibly inhibits EGFR-TK inhibitor, was recently approved by the FDA for patients with non-small-cell lung cancer who progressed on prior chemotherapy. Despite an encouraging response rate of 11% to 20% in patients with non-small-cell lung cancer,[ 18,19] no responses have been reported among patients with colorectal cancer in two small studies.[20,21] Goss and colleagues treated 24 patients with 750 mg/d of gefitinib and demonstrated stable disease in eight patients (median duration 2.2 months). Dorligschaw et al recently reported 20% stable disease in a small phase II study among chemotherapy-refractory patients. Biologic agents may require a new paradigm in terms of evaluating efficacy, where disease stabilization and symptomatic clinical improvement, rather than response rate, will be the true marker of their potential.[8] However, to date, the TK inhibitors have shown limited success as single agents in stabilizing disease in metastatic colorectal cancer, at least in chemotherapy- refractory patients. Combination Therapy With TK Inhibitors The combination of gefitinib and irinotecan has been studied in human colon cancer cell lines. The active metabolite of irinotecan, SN-38, inhibits topoisomerase I in drug-stabilized DNA complexes. However, cells develop resistance to SN-38 when topoisomerase II compensates for loss of topoisomerase I function.[22] Braun and colleagues studied combination therapy in cell lines sensitive to irinotecan (HCT-8/wt) and fourfold- resistant to irinotecan (HCT-8/ SN-38).[23] Addition of gefitinib at noncytotoxic doses restored SN-38 sensitivity in HCT-8/SN-38 cells. The study also reported a time- and dosedependent downregulation of topoisomerase IIa protein levels. Based on these intriguing observations, Fuchs et al at the Dana-Farber Cancer Institute and Massachusetts General Hospital initiated two trials testing the combination of gefitinib with irinotecan, fluorouracil (5-FU), and leucovorin among previously untreated patients with metastatic colorectal cancer. The Cancer Treatment Evaluation Program of the National Cancer Institute sponsored the first trial. Twentyfour patients were enrolled into a phase I trial with gefitinib (250 or 500 mg daily) and irinotecan, bolus 5-FU, and leucovorin (modified Saltz regimen of two weekly treatments followed by a 1-week break). Patients with measurable locally advanced, locally recurrent, or metastatic disease not amenable to curative treatment were eligible. Patients with recurrent disease had to be at least 12 months from last adjuvant therapy. An Eastern Cooperative Oncology Group performance status of 0 or 1 was required. No prior radiation therapy to > 15% of the bone marrow was allowed and normal creatinine and bilirubin were required. The maximum tolerated dose of the combination therapy was gefitinib at 250 mg/d plus days 1 and 8 of a 21- day cycle of irinotecan at 100 mg/m², 5-FU at 500 mg/m², and leucovorin at 20 mg/m², with neutropenia and diarrhea being dose-limiting toxicities. Promising activity has been observed, and analysis of this trial is ongoing. Fuchs et al are currently accruing patients to a similar phase I trial of gefitinib (250 mg or 500 mg) with irinotecan, infusional 5-FU, and leucovorin (FOLFIRI). The two trials will determine tolerable doses of gefitinib and chemotherapy in order to move forward to comparative trials. Preliminary data from trials combining a TK inhibitor with an oxaliplatin- based regimen were recently presented. Fisher and colleagues treated 56 patients with metastatic colorectal cancer with gefitinib and oxaliplatin, infusional 5-FU, and leucovorin (FOLFOX4).[24] The group reported a 78% response rate for chemonaive patients and 36% for previously treated patients. However, gastrointestinal toxicities were higher than expected for FOLFOX4 alone, with a 49% rate of grade 3/4 diarrhea, a 28% rate of grade 3 nausea, and a 21% rate of grade 3/4 vomiting. Our group recently reported promising results with the combination of erlotinib, capecitabine (Xeloda), and oxaliplatin in patients previously treated for metastatic colorectal cancer, with 24% of the first 28 patients experiencing a partial response.[25] Conclusion The epidermal growth factor receptor pathway is an exciting and active area of research. In colorectal cancer, expression and overexpression of EGFR make targeting of the pathway of great interest. To date, monoclonal antibodies against the extracellular domain of the receptor have shown the most promise, at least as single agents, against this disease. Combination therapy with an EGFR inhibitor and standard cytotoxic chemotherapy is biologically sound and requires further research (Table 2). Though many important questions remain on how best to utilize EGFR inhibitors, these agents are clearly going to be part of the growing armamentarium in the treatment of patients with colorectal cancer.

Disclosures:

Dr. Meyerhardt has acted as a consultant for Sanofi-Synthelabo and Bristol-Myers Squibb, and has served on speaker’s bureaus for Sanofi-Synthelabo, Pfizer Oncology, and Genentech. Dr. Fuchs has received grant support from and served on speaker’s bureaus for Sanofi, Pfizer, AstraZeneca, and Genentech.

References:

1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003.
2. Guillem JG, Paty PB, Cohen AM: Surgical treatment of colorectal cancer. CA Cancer J Clin 47:113-128, 1997.
3. 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.
4. Baselga J: Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 7(suppl 4):2-8, 2002.
5. 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 71:2454-2460, 1993.
6. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995.
7. Hemming AW, Davis NL, Kluftinger A, et al: Prognostic markers of colorectal cancer: An evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol 51:147-152, 1992.
8. Grunwald V, Hidalgo M: Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 95:851-867, 2003.
9. 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.
10. 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) (abstract 7). Proc Am Soc Clin Oncol 20:3a, 2001.
11. 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.
12. Lenz HJ, Mayer RJ, Gold PJ, et al: Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin (abstract 3510). Proc Am Soc Clin Oncol 23:248, 2004.
13. Van Laethem JL, Raoul JL, Brezault C, et al: Cetuximab (C225) in combination with bi-weekly irinotecan (CPT-11), infusional 5- fluorouracil (5-FU) and folinic acid (FA) in patients with metastatic colorectal cancer (CRC) expressing the epidermal growth factor receptor (EGFR). Preliminary safety and efficacy results (abstract 1058). Proc Am Soc Clin Oncol 22:264, 2003.
14. Tabernero JM, Van Cutsem E, Sastre J, et al: An international phase II study of cetuximab in combination with oxaliplatin/5- fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR). Preliminary results (abstract 3512). Proc Am Soc Clin Oncol 23:248, 2004.
15. Hecht JR, Patnaik A, Malik I, et al: ABXEGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): An updated analysis (abstract 3511). Proc Am Soc Clin Oncol 23:248, 2004.
16. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001.
17. Hightower M, Klem J, Lee D: Epidermal growth factor receptor is not correlated with prognosis in patients with metastatic colorectal cancer treated with erlotinib (OSI- 774, Tarceva). Clin Colorectal Cancer 3:10- 11, 2003.
18. Fukuoka M, Yano S, Giaccone G, et al: A multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer (The IDEAL 1 trial). J Clin Oncol 21:2237-2246, 2003.
19. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003.
20. Goss GD, Stewart DJ, Hirte H, et al: Initial results of part 2 of a phase I/II pharmacokinetics (PK), pharmacodynamic (PD) and biological activity study of ZD1839 (Iressa) (abstract 59). NCIC CTG IND 122, 2002.
21. Dorligschaw O, Kegel T, Jordan K, et al: ZD 1839 (Iressa) -based treatment as lastline therapy in patients with advanced colorectal cancer (ACRC) (abstract 1494). Proc Am Soc Clin Oncol 22:372, 2003.
22. Douglass EC: Development of ZD1839 in colorectal cancer. Semin Oncol 30:17-22, 2003.
23. Braun AD, Dirsch O, Hilger RA, et al: Preclinical evaluation of the combination of epidermal growth factor inhibitor ZD1839 (Iressa) and irinotecan (SN-38) in human colon cancer cells (abstract 329). Proc Am Soc Clin Oncol 21:83a, 2002.
24. Fisher GA, Kuo T, Cho CD, et al: A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer (abstract 3514). Proc Am Soc Clin Oncol 23:249, 2004.
25. Meyerhardt JA, Zhu A, Enzinger PC, et al: Phase II study of capecitabine, oxaliplatin and erlotinib in previously treated patients with metastatic colorectal cancer (MCRC) (abstract 3580). Proc Am Soc Clin Oncol 23:265, 2004.
26. 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) (abstract 536). Proc Am Soc Clin Oncol 21:135a, 2002.