- Email: [email protected]
The Role of Cetuximab in the Therapy of Previously Treated Advanced Colorectal Cancer
The Role of Cetuximab in the Therapy of Previously Treated Advanced Colorectal Cancer Geoff Chong and David Cunningham Much remains to be learned about the best ways to integrate molecular-targeted therapies into the chemotherapeutic armamentarium. The epidermal growth factor receptor inhibitor cetuximab has been extensively evaluated in patients with chemotherapy-resistant metastatic colorectal cancer. In patients with irinotecan-refractory or irinotecan/oxaliplatin-refractory disease, single-agent cetuximab has produced a partial response in 9% to 11.6% of patients and stable disease in 21.6% to 36.8%. In irinotecan-resistant disease, the combination of cetuximab and irinotecan has resulted in partial responses in 17% to 22.9% of patients and stable disease in 31% to 32.6%. The degree of epidermal growth factor receptor expression has not been predictive of treatment response; severity of a characteristic acneiform rash does appear to be predictive of response. Ongoing trials in colorectal cancer are examining the combination of cetuximab and bevacizumab with or without irinotecan in irinotecan-refractory disease, irinotecan with or without cetuximab in oxaliplatin-refractory disease, and FOLFOX4 with or without cetuximab in patients receiving first-line irinotecan treatment. Semin Oncol 32(suppl 9):S55-S58 © 2005 Elsevier Inc. All rights reserved.
O
ncologists now have access to multiple agents that have been shown to benefit patients with advanced colorectal cancer (CRC), including cytotoxic chemotherapeutics as well as agents that target specific signaling pathways within cancer cells. As a result of recent progress with these agents, the median survival of patients with advanced CRC has been extended to almost 2 years in randomized trials. Yet, much still needs to be learned about the best way to integrate targeted therapies into our current therapeutic armamentarium. This task poses significant challenges, especially because there are currently numerous ongoing trials testing diverse strategies in this patient population. Recent data have shown the efficacy of cetuximab in patients with chemotherapy-resistant advanced CRC. This article will summarize the current evidence relating to cetuximab in patients who have previously been treated for advanced CRC.
Targeting the Epidermal Growth Factor Receptor The epidermal growth factor receptor (EGFR) is a 145 to 170-kilodalton transmembrane receptor with an extracelluRoyal Marsden Hospital, London and Surrey, United Kingdom. Dr Cunningham has no significant financial relationships to disclose. Address reprint requests to David Cunningham, MD, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK; E-mail: [email protected]
0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.04.020
lar ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain.1,2 EGFR is expressed in 60% to 70% of CRCs, and it plays a key role in driving cell growth and division via tyrosine kinase-mediated signalling.3,4 The expression of EGFR has been associated with poorer survival in CRC patients.5 Two principal strategies have been used to abrogate EGFR-mediated tumor growth: (1) inhibition of receptor dimerization by monoclonal antibodies directed against the extracellular EGFR domain, and (2) inhibition of the intracellular tyrosine kinase component by competitive binding to the adenosine triphosphate binding pocket, thereby inhibiting autophosphorylation and the activation of downstream signaling pathways. The downstream effects of EGFR inhibition are mediated predominantly by three intracellular pathways.6,7 The first involves modulation of cyclin-D levels within the nucleus; the inhibition of which leads to inhibition of cell cycling. Normally, phosphorylation of the EGFR tyrosine kinase activates the oncoprotein ras that activates mitogen-activated protein (MAP) kinase via a sequence of phosphorylations. MAP kinase enters the cell nucleus and causes the accumulation of cyclin D that, in association with cyclin-dependent kinases (CDK), stimulates the cell to proceed into cycle. Inhibition of this pathway by inactivation of EGFR therefore suppresses tumor cell division. Simultaneously, EGFR inhibition causes inhibition of phosphatidylinositol 3-kinase (PI3K), and subsequently activin-like kinase (AKT). Normally, phosphorylated (activated) AKT inactivates pro-apopS55
G. Chong and D. Cunningham
S56
Table 1 Response to Cetuximab Monotherapy or Combination Therapy in Pretreated Metastatic Colorectal Cancer: Clinical Trial Data Study Monotherapy Saltz et al, 200417 Cunningham et al, 200416* Lenz et al, 200418 Combination therapy Saltz et al, 200115 Cunningham et al, 200416*
Chemotherapy Resistance
Treatment Arm
No. of Patients
Partial Responses
Stable Disease
Irinotecan Irinotecan Oxaliplatin/irinotecan
Cetuximab Cetuximab Cetuximab
57 111 346
9% 10.8% 11.6%
36.8% 21.6% 31.8%
Irinotecan Irinotecan
Cetuximab/irinotecan Cetuximab/irinotecan
121 218
17% 22.9%
31% 32.6%
*Single-treatment arm from the randomized Bowel Oncology with Cetuximab Antibody (BOND) study.
totic molecules such as bcl-xL/bcl-2–associated death promoter (BAD) and caspase-9.8,9 Therefore, inhibition of this anti-apoptotic pathway has the potential to shift the tumor cell towards apoptosis.10 The third pathway normally involves activation of the Jak/Stat/protein kinase C pathway, which leads to the transcription of genes that are responsible for cell division, survival, motility, and invasion.11 Cetuximab is a chimeric, monoclonal antibody that binds to EGFR, competes with natural ligand binding, and induced receptor dimerization and down-regulation.12 This results in cell-cycle arrest and apoptosis because of inhibition of the pathways described above. In addition, cetuximab-mediated blockade of EGFR activation results in reduced production of angiogenic factors, such as basic fibroblast growth factor and vascular endothelial growth factor (VEGF).13 Cetuximab may also inhibit tumor cell invasion and metastasis by blocking production of matrix metalloproteinases that are important tumor cell adhesion molecules.14
Clinical Trials of Cetuximab in Advanced CRC Response rates with cetuximab alone or with irinotecan in patients with pretreated metastatic CRC are summarized in Table 1.15-18 Two clinical studies showed the ability of cetuximab to restore chemosensitivity in irinotecan-refractory patients with advanced CRC.15,16 Saltz et al15 first conducted a phase II study of 121 patients with CRC who were refractory to both 5-fluorouracil and irinotecan.15 Each patient was treated with cetuximab 400 mg/m2 (loading dose), followed by 250 mg/m2 weekly (maintenance) in combination with the same irinotecan dose and schedule on which the patient had previously progressed. Overall, 17% of patients achieved a partial response (PR), with a median duration of 84 days. An additional 31% of patients achieved disease stabilization. Grade 1/2 rash occurred in 53% of patients, and 8% had a grade 3 rash. The second study was the Bowel Oncology with Cetuximab Antibody (BOND) study, a randomized phase II study of 329 patients with EGFR-expressing irinotecan-refractory advanced CRC.16 Patients were randomized in a 2-to-1 ratio to receive either irinotecan re-treatment in combination with cetuximab (n ⫽ 218); or cetuximab monotherapy (n ⫽ 111).
The cetuximab schedule was identical to the study by Saltz et al15 described above. Crossover from cetuximab monotherapy to irinotecan plus cetuximab was permitted on disease progression. The response rate in patients treated with combination therapy was higher than those randomized to monotherapy: 22.9% (95% confidence interval (CI), 17.5% to 29.1%) versus 10.8% (95% CI, 5.7% to 18.1%; P ⫽ .007). There was no evidence of improved response rate with either a greater percentage of EGFR-expressing cells based on immunohistochemistry (P ⫽ .87) or greater intensity of EGFR staining (P ⫽ .64). Essentially, patients had the same chance of response in a given arm, regardless of their degree of cellular EGFR expression. Median time to progression was significantly longer in the combination therapy group: 4.1 versus 1.5 months (P ⬍.001). However, there was no difference in median survival time, probably because of the crossover of patients in the monotherapy arm to combination therapy once tumor progression had occurred. Both treatments were well tolerated. Grade 3/4 diarrhea and neutropenia occurred more frequently in the combination arm, whereas grade 3/4 dyspnea and hypersensitivity reactions occurred more frequently in the cetuximab monotherapy arm. Acne-like rash occurred in approximately 80% of patients in each arm; however, grade 3/4 rash occurred in only 9.4% of combination therapy and 5.2% of monotherapy patients. Upon analysis and based on grades none versus 1/2 versus 3/4 toxicities; there was a trend toward improved response rate with greater rash severity (P ⫽ .001). Similar findings were obtained using the less specific toxicity of “skin reaction.” These post-hoc analyses suggest that patients who experience the characteristic skin toxicity of cetuximab may have a greater chance of tumor response, although the mechanism of this effect remains unclear. A previous analysis of four clinical trials of cetuximab in different tumor types by Saltz et al19 also found a relationship between the development of acneiform rash and survival. Saltz et al17 also conducted another phase II study that confirmed the modest single-agent activity of cetuximab in EGFR-expressing patients who were refractory to irinotecan. In this study, 57 patients received the standard cetuximab schedule. Five patients (9%; 95% CI, 3% to 19%) achieved a PR, with an additional 21 achieving minor responses or disease stabilization.
Cetuximab in advanced colorectal cancer
S57
Lenz et al18 recently presented data that showed the activity of cetuximab monotherapy in patients who were refractory to both irinotecan and oxaliplatin. A total of 346 patients who were heavily pretreated (median, four prior regimens administered) received cetuximab monotherapy until either disease progression or unacceptable toxicity. The objective response rate in these patients was 11.6% (95% CI, 8.4% to 15.4%), with an additional 31.8% having disease stabilization. The median overall survival was 6.7 months (95% CI, 5.9 to 7.8 months). Notably, nine patients who enrolled in this study had tumors that did not have detectable EGFR on bioassay. One patient had a confirmed PR, while three patients had stabilization of disease. While this cohort represented only 3% of the study population, it is interesting that the response rate to cetuximab in EGFR-negative patients appeared to be similar to that of EGFR-positive patients. The EGFR gene sequence analyses of 35 patients with a PR, stable disease, and progressive disease identified two sequence variants in patients with stable disease. Neither was of the type of mutations that were previously reported from clinical experiences with gefitinib in non–small cell lung cancer patients.20,21 None of 18 patients who achieved a PR had detectable EGFR mutations. In this study, 90% of all patients developed acneiform rash; however, only 6% had grade 3/4 rash. In the studies described, cetuximab was well tolerated, with asthenia and the characteristic acneiform rash constituting the most frequent toxicities. Restoration of irinotecan sensitivity occurred in approximately 20% of irinotecan-refractory patients who received irinotecan combined with cetuximab. Cetuximab monotherapy had a consistent response rate of approximately 10% in pretreated patients with metastatic CRC. In the BOND study, the degree of tumor EGFR expression by immunohistochemistry did not appear to correlate with probability of response; in fact, there are limited data from Lenz et al that suggest that EGFR-negative tumors may respond to cetuximab, with the presumption that current immunohistochemistry bioassays may not be sensitive enough to determine accurately all tumors’ EGFR status (unpublished data). (They have launched a new trial to determine the role of cetuximab in EGFR-negative tumors.) However, the development of rash does appear to predict for tumor response.
CA225-006 is a true second-line study in patients refractory to first-line oxaliplatin. As cetuximab is generally well tolerated, the possibility of treating patients who would not otherwise qualify for palliative chemotherapy is worthy of exploration. The National Cancer Institute of Canada CO-17 trial is randomizing patients who are unsuitable for further chemotherapy to cetuximab monotherapy or best supportive care. Oxaliplatin is the other obvious cytotoxic agent as potential combination partner with cetuximab. The EGFR-Positive Colorectal Carcinoma (EXPLORE) study CA225014 is currently accruing patients with metastatic CRC who have received first-line treatment with irinotecan. A planned total of 1,100 patients will be randomized to oxalplatin/5-fluorouracil/leucovorin (FOLFOX4 regimen) plus cetuximab or FOLFOX4 alone. A preliminary safety analysis of Badarinath et al22 (n ⫽ 38) did not demonstrate any unexpected toxicities. As a result of progress made in patients with previously treated advanced CRC, cetuximab also is being evaluated in the first-line setting. The Crystal trial is one such trial that will randomize treatment-naive patients to first-line therapy with irinotecan and the irinotecan-containing, modified “de Gramont” infusional 5-fluorouracil/leucovorin (FOLFIRI) regimen plus cetuximab versus FOLFIRI alone.
Ongoing and Future Trials
References
The role of cetuximab in specific CRC treatment settings is being evaluated. The successor trial to the BOND study is currently randomizing irinotecan-refractory patients to irinotecan plus cetuximab and the anti-VEGF agent bevacizumab; or cetuximab plus bevacizumab. The target accrual is 150 patients. This study will provide valuable efficacy and safety data on the targeting of EGFR in tandem with VEGF. The EPIC trial CA225-006 is a randomized phase III study examining irinotecan plus cetuximab versus irinotecan alone in irinotecan-naive patients with advanced CRC who are refractory to oxaliplatin. In contrast to the BOND study where most patients received cetuximab as third-line therapy,
Conclusion The efficacy of cetuximab in patients with irinotecan-refractory disease is compelling. The clinical data currently support the use of cetuximab in patients who are refractory to irinotecan-based chemotherapy– either in combination with irinotecan or as monotherapy (eg, in patients not able to tolerate reintroduction of irinotecan). The demonstration of efficacy in pretreated patients has led to further trials both in first-line and subsequent treatment of advanced CRC. These trials are exploring settings such as irinotecan-naive disease, combination treatment with oxaliplatin, comparison to best supportive care, and tandem targeting with either EGFR tyrosine kinase inhibitors or bevacizumab. The targeting of EGFR-mediated signaling with cetuximab will continue to form an integral part of therapeutic strategies for advanced CRC.
1. Konishi A, Berk BC: Epidermal growth factor receptor transactivation is regulated by glucose in vascular smooth muscle cells. J Biol Chem 278:35049-35056, 2003 2. Yarden Y: The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37:S3-S8, 2001 (suppl 4) 3. Messa C, Russo F, Caruso MG, et al: EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 37:285-289, 1998 4. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factorrelated peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995 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
S58 6. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21: 2787-2799, 2003 7. El Rayes BF, LoRusso PM: Targeting the epidermal growth factor receptor. Br J Cancer 91:418-424, 2004 8. Datta SR, Dudek H, Tao X, et al: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231-241, 1997 9. Cardone MH, Roy N, Stennicke HR, et al: Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318-1321, 1998 10. Fesik SW: Insights into programmed cell death through structural biology. Cell 103:273-282, 2000 11. Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127-137, 2001 12. Prewett M, Rockwell P, Rockwell RF, et al: The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma. J Immunother Emphasis Tumor Immunol 19:419-427, 1996 13. Petit AM, Rak J, Hung MC, et al: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases downregulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: Angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523-1530, 1997 14. Matsumoto T, Perrotte P, Bar-Eli M: Blockade of EGF-R signaling with anti-EGFR monoclonal antibody C225 inhibits matrix metalloproteinase-9 expression and invasion of human transitional cell carcinoma in vitro and in vivo. Proc Am Assoc Cancer Res 39:83, 1998 (abstr)
G. Chong and D. Cunningham 15. Saltz LB, Rubin M, Hochster H, et al: Cetuximab plus irinotecan is active in CPT-11-refractory colorectal cancer that expresses epidermal growth factor receptor. Proc Am Soc Clin Oncol 20: 3a, 2001 (abstr 7) 16. 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 17. 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 18. Lenz HJ, Mayer RJ, Gold PJ, et al: Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. Proc Am Soc Clin Oncol 23:248, 2004 (abstr 3510) 19. Saltz LB, Kies M, Abbruzzesse JL, et al: The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 22:204, 2003 (abstr 817) 20. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304: 1497-1500, 2004 21. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non– small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 22. Badarinath S, Mitchell EP, Jennis A, et al: Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): Preliminary safety analysis of a randomized phase III trial. Proc Am Soc Clin Oncol 23:253, 2004 (abstr 3531)
O
ncologists now have access to multiple agents that have been shown to benefit patients with advanced colorectal cancer (CRC), including cytotoxic chemotherapeutics as well as agents that target specific signaling pathways within cancer cells. As a result of recent progress with these agents, the median survival of patients with advanced CRC has been extended to almost 2 years in randomized trials. Yet, much still needs to be learned about the best way to integrate targeted therapies into our current therapeutic armamentarium. This task poses significant challenges, especially because there are currently numerous ongoing trials testing diverse strategies in this patient population. Recent data have shown the efficacy of cetuximab in patients with chemotherapy-resistant advanced CRC. This article will summarize the current evidence relating to cetuximab in patients who have previously been treated for advanced CRC.
Targeting the Epidermal Growth Factor Receptor The epidermal growth factor receptor (EGFR) is a 145 to 170-kilodalton transmembrane receptor with an extracelluRoyal Marsden Hospital, London and Surrey, United Kingdom. Dr Cunningham has no significant financial relationships to disclose. Address reprint requests to David Cunningham, MD, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK; E-mail: [email protected]
0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.04.020
lar ligand-binding domain, a transmembrane domain, and a cytoplasmic tyrosine kinase domain.1,2 EGFR is expressed in 60% to 70% of CRCs, and it plays a key role in driving cell growth and division via tyrosine kinase-mediated signalling.3,4 The expression of EGFR has been associated with poorer survival in CRC patients.5 Two principal strategies have been used to abrogate EGFR-mediated tumor growth: (1) inhibition of receptor dimerization by monoclonal antibodies directed against the extracellular EGFR domain, and (2) inhibition of the intracellular tyrosine kinase component by competitive binding to the adenosine triphosphate binding pocket, thereby inhibiting autophosphorylation and the activation of downstream signaling pathways. The downstream effects of EGFR inhibition are mediated predominantly by three intracellular pathways.6,7 The first involves modulation of cyclin-D levels within the nucleus; the inhibition of which leads to inhibition of cell cycling. Normally, phosphorylation of the EGFR tyrosine kinase activates the oncoprotein ras that activates mitogen-activated protein (MAP) kinase via a sequence of phosphorylations. MAP kinase enters the cell nucleus and causes the accumulation of cyclin D that, in association with cyclin-dependent kinases (CDK), stimulates the cell to proceed into cycle. Inhibition of this pathway by inactivation of EGFR therefore suppresses tumor cell division. Simultaneously, EGFR inhibition causes inhibition of phosphatidylinositol 3-kinase (PI3K), and subsequently activin-like kinase (AKT). Normally, phosphorylated (activated) AKT inactivates pro-apopS55
G. Chong and D. Cunningham
S56
Table 1 Response to Cetuximab Monotherapy or Combination Therapy in Pretreated Metastatic Colorectal Cancer: Clinical Trial Data Study Monotherapy Saltz et al, 200417 Cunningham et al, 200416* Lenz et al, 200418 Combination therapy Saltz et al, 200115 Cunningham et al, 200416*
Chemotherapy Resistance
Treatment Arm
No. of Patients
Partial Responses
Stable Disease
Irinotecan Irinotecan Oxaliplatin/irinotecan
Cetuximab Cetuximab Cetuximab
57 111 346
9% 10.8% 11.6%
36.8% 21.6% 31.8%
Irinotecan Irinotecan
Cetuximab/irinotecan Cetuximab/irinotecan
121 218
17% 22.9%
31% 32.6%
*Single-treatment arm from the randomized Bowel Oncology with Cetuximab Antibody (BOND) study.
totic molecules such as bcl-xL/bcl-2–associated death promoter (BAD) and caspase-9.8,9 Therefore, inhibition of this anti-apoptotic pathway has the potential to shift the tumor cell towards apoptosis.10 The third pathway normally involves activation of the Jak/Stat/protein kinase C pathway, which leads to the transcription of genes that are responsible for cell division, survival, motility, and invasion.11 Cetuximab is a chimeric, monoclonal antibody that binds to EGFR, competes with natural ligand binding, and induced receptor dimerization and down-regulation.12 This results in cell-cycle arrest and apoptosis because of inhibition of the pathways described above. In addition, cetuximab-mediated blockade of EGFR activation results in reduced production of angiogenic factors, such as basic fibroblast growth factor and vascular endothelial growth factor (VEGF).13 Cetuximab may also inhibit tumor cell invasion and metastasis by blocking production of matrix metalloproteinases that are important tumor cell adhesion molecules.14
Clinical Trials of Cetuximab in Advanced CRC Response rates with cetuximab alone or with irinotecan in patients with pretreated metastatic CRC are summarized in Table 1.15-18 Two clinical studies showed the ability of cetuximab to restore chemosensitivity in irinotecan-refractory patients with advanced CRC.15,16 Saltz et al15 first conducted a phase II study of 121 patients with CRC who were refractory to both 5-fluorouracil and irinotecan.15 Each patient was treated with cetuximab 400 mg/m2 (loading dose), followed by 250 mg/m2 weekly (maintenance) in combination with the same irinotecan dose and schedule on which the patient had previously progressed. Overall, 17% of patients achieved a partial response (PR), with a median duration of 84 days. An additional 31% of patients achieved disease stabilization. Grade 1/2 rash occurred in 53% of patients, and 8% had a grade 3 rash. The second study was the Bowel Oncology with Cetuximab Antibody (BOND) study, a randomized phase II study of 329 patients with EGFR-expressing irinotecan-refractory advanced CRC.16 Patients were randomized in a 2-to-1 ratio to receive either irinotecan re-treatment in combination with cetuximab (n ⫽ 218); or cetuximab monotherapy (n ⫽ 111).
The cetuximab schedule was identical to the study by Saltz et al15 described above. Crossover from cetuximab monotherapy to irinotecan plus cetuximab was permitted on disease progression. The response rate in patients treated with combination therapy was higher than those randomized to monotherapy: 22.9% (95% confidence interval (CI), 17.5% to 29.1%) versus 10.8% (95% CI, 5.7% to 18.1%; P ⫽ .007). There was no evidence of improved response rate with either a greater percentage of EGFR-expressing cells based on immunohistochemistry (P ⫽ .87) or greater intensity of EGFR staining (P ⫽ .64). Essentially, patients had the same chance of response in a given arm, regardless of their degree of cellular EGFR expression. Median time to progression was significantly longer in the combination therapy group: 4.1 versus 1.5 months (P ⬍.001). However, there was no difference in median survival time, probably because of the crossover of patients in the monotherapy arm to combination therapy once tumor progression had occurred. Both treatments were well tolerated. Grade 3/4 diarrhea and neutropenia occurred more frequently in the combination arm, whereas grade 3/4 dyspnea and hypersensitivity reactions occurred more frequently in the cetuximab monotherapy arm. Acne-like rash occurred in approximately 80% of patients in each arm; however, grade 3/4 rash occurred in only 9.4% of combination therapy and 5.2% of monotherapy patients. Upon analysis and based on grades none versus 1/2 versus 3/4 toxicities; there was a trend toward improved response rate with greater rash severity (P ⫽ .001). Similar findings were obtained using the less specific toxicity of “skin reaction.” These post-hoc analyses suggest that patients who experience the characteristic skin toxicity of cetuximab may have a greater chance of tumor response, although the mechanism of this effect remains unclear. A previous analysis of four clinical trials of cetuximab in different tumor types by Saltz et al19 also found a relationship between the development of acneiform rash and survival. Saltz et al17 also conducted another phase II study that confirmed the modest single-agent activity of cetuximab in EGFR-expressing patients who were refractory to irinotecan. In this study, 57 patients received the standard cetuximab schedule. Five patients (9%; 95% CI, 3% to 19%) achieved a PR, with an additional 21 achieving minor responses or disease stabilization.
Cetuximab in advanced colorectal cancer
S57
Lenz et al18 recently presented data that showed the activity of cetuximab monotherapy in patients who were refractory to both irinotecan and oxaliplatin. A total of 346 patients who were heavily pretreated (median, four prior regimens administered) received cetuximab monotherapy until either disease progression or unacceptable toxicity. The objective response rate in these patients was 11.6% (95% CI, 8.4% to 15.4%), with an additional 31.8% having disease stabilization. The median overall survival was 6.7 months (95% CI, 5.9 to 7.8 months). Notably, nine patients who enrolled in this study had tumors that did not have detectable EGFR on bioassay. One patient had a confirmed PR, while three patients had stabilization of disease. While this cohort represented only 3% of the study population, it is interesting that the response rate to cetuximab in EGFR-negative patients appeared to be similar to that of EGFR-positive patients. The EGFR gene sequence analyses of 35 patients with a PR, stable disease, and progressive disease identified two sequence variants in patients with stable disease. Neither was of the type of mutations that were previously reported from clinical experiences with gefitinib in non–small cell lung cancer patients.20,21 None of 18 patients who achieved a PR had detectable EGFR mutations. In this study, 90% of all patients developed acneiform rash; however, only 6% had grade 3/4 rash. In the studies described, cetuximab was well tolerated, with asthenia and the characteristic acneiform rash constituting the most frequent toxicities. Restoration of irinotecan sensitivity occurred in approximately 20% of irinotecan-refractory patients who received irinotecan combined with cetuximab. Cetuximab monotherapy had a consistent response rate of approximately 10% in pretreated patients with metastatic CRC. In the BOND study, the degree of tumor EGFR expression by immunohistochemistry did not appear to correlate with probability of response; in fact, there are limited data from Lenz et al that suggest that EGFR-negative tumors may respond to cetuximab, with the presumption that current immunohistochemistry bioassays may not be sensitive enough to determine accurately all tumors’ EGFR status (unpublished data). (They have launched a new trial to determine the role of cetuximab in EGFR-negative tumors.) However, the development of rash does appear to predict for tumor response.
CA225-006 is a true second-line study in patients refractory to first-line oxaliplatin. As cetuximab is generally well tolerated, the possibility of treating patients who would not otherwise qualify for palliative chemotherapy is worthy of exploration. The National Cancer Institute of Canada CO-17 trial is randomizing patients who are unsuitable for further chemotherapy to cetuximab monotherapy or best supportive care. Oxaliplatin is the other obvious cytotoxic agent as potential combination partner with cetuximab. The EGFR-Positive Colorectal Carcinoma (EXPLORE) study CA225014 is currently accruing patients with metastatic CRC who have received first-line treatment with irinotecan. A planned total of 1,100 patients will be randomized to oxalplatin/5-fluorouracil/leucovorin (FOLFOX4 regimen) plus cetuximab or FOLFOX4 alone. A preliminary safety analysis of Badarinath et al22 (n ⫽ 38) did not demonstrate any unexpected toxicities. As a result of progress made in patients with previously treated advanced CRC, cetuximab also is being evaluated in the first-line setting. The Crystal trial is one such trial that will randomize treatment-naive patients to first-line therapy with irinotecan and the irinotecan-containing, modified “de Gramont” infusional 5-fluorouracil/leucovorin (FOLFIRI) regimen plus cetuximab versus FOLFIRI alone.
Ongoing and Future Trials
References
The role of cetuximab in specific CRC treatment settings is being evaluated. The successor trial to the BOND study is currently randomizing irinotecan-refractory patients to irinotecan plus cetuximab and the anti-VEGF agent bevacizumab; or cetuximab plus bevacizumab. The target accrual is 150 patients. This study will provide valuable efficacy and safety data on the targeting of EGFR in tandem with VEGF. The EPIC trial CA225-006 is a randomized phase III study examining irinotecan plus cetuximab versus irinotecan alone in irinotecan-naive patients with advanced CRC who are refractory to oxaliplatin. In contrast to the BOND study where most patients received cetuximab as third-line therapy,
Conclusion The efficacy of cetuximab in patients with irinotecan-refractory disease is compelling. The clinical data currently support the use of cetuximab in patients who are refractory to irinotecan-based chemotherapy– either in combination with irinotecan or as monotherapy (eg, in patients not able to tolerate reintroduction of irinotecan). The demonstration of efficacy in pretreated patients has led to further trials both in first-line and subsequent treatment of advanced CRC. These trials are exploring settings such as irinotecan-naive disease, combination treatment with oxaliplatin, comparison to best supportive care, and tandem targeting with either EGFR tyrosine kinase inhibitors or bevacizumab. The targeting of EGFR-mediated signaling with cetuximab will continue to form an integral part of therapeutic strategies for advanced CRC.
1. Konishi A, Berk BC: Epidermal growth factor receptor transactivation is regulated by glucose in vascular smooth muscle cells. J Biol Chem 278:35049-35056, 2003 2. Yarden Y: The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities. Eur J Cancer 37:S3-S8, 2001 (suppl 4) 3. Messa C, Russo F, Caruso MG, et al: EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 37:285-289, 1998 4. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factorrelated peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995 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
S58 6. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21: 2787-2799, 2003 7. El Rayes BF, LoRusso PM: Targeting the epidermal growth factor receptor. Br J Cancer 91:418-424, 2004 8. Datta SR, Dudek H, Tao X, et al: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231-241, 1997 9. Cardone MH, Roy N, Stennicke HR, et al: Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318-1321, 1998 10. Fesik SW: Insights into programmed cell death through structural biology. Cell 103:273-282, 2000 11. Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127-137, 2001 12. Prewett M, Rockwell P, Rockwell RF, et al: The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma. J Immunother Emphasis Tumor Immunol 19:419-427, 1996 13. Petit AM, Rak J, Hung MC, et al: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases downregulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: Angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151:1523-1530, 1997 14. Matsumoto T, Perrotte P, Bar-Eli M: Blockade of EGF-R signaling with anti-EGFR monoclonal antibody C225 inhibits matrix metalloproteinase-9 expression and invasion of human transitional cell carcinoma in vitro and in vivo. Proc Am Assoc Cancer Res 39:83, 1998 (abstr)
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