- Email: [email protected]
A Phase III Randomized, Open-Label, Controlled Trial of Chemotherapy and Bevacizumab with or Without Panitumumab in the First-Line Treatment of Patients with Metastatic Colorectal Cancer
Current
Trial
A Phase III Randomized, Open-Label, Controlled Trial of Chemotherapy and Bevacizumab with or Without Panitumumab in the First-Line Treatment of Patients with Metastatic Colorectal Cancer Zev Wainberg, J. Randolph Hecht Clinical Colorectal Cancer, Vol. 5, No. 5, 363-367, 2006 Key words: Epidermal growth factor receptor, 5-Fluorouracil, Irinotecan, Leucovorin, Oxaliplatin, Vascular endothelial growth factor
Introduction Despite recent progress, metastatic colorectal cancer (CRC) remains the second leading cause of cancer-related mortality in the Unites States, with approximately 60,000 deaths in 2005.1 Traditionally, chemotherapy has been the main approach for the treatment of CRC, but with the recent advent of targeted therapies, biologic treatments are becoming an area of intense interest. In the past 2 years alone, 2 molecularly targeted antibodies, bevacizumab and cetuximab, have been approved for CRC, targeting vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptor (EGFR), respectively. The basic combination of 5-fluorouracil (5-FU) and leucovorin (LV) remains the backbone of therapy for metastatic CRC. In recent years, studies combining 5-FU/LV with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) have demonstrated improvements in disease-free and overall survival (OS).2,3 A recent comparison of FOLFOX6 followed by FOLFIRI versus the reverse order as first-line treatment found that both sequences achieved a median survival of approximately 20 months and were similarly efficacious. The overall response rate in the FOLFIRI arm was 56%, with a progression-free survival (PFS) time of 8.5 months, compared with an overall response rate of 54% and a PFS of 8 months with FOLFOX6. These results suggest that GI Oncology Program, David Geffen School of Medicine, University of California, Los Angeles Submitted: Jan 11, 2006; Accepted: Jan 11, 2006 Address for correspondence: J. Randolph Hecht, MD, GI Oncology Program, David Geffen School of Medicine, University of California, Los Angeles, 2338G PVUB, 10945 Le Conte Ave, Los Angeles, CA 90095 Fax: 310-267-0151; e-mail: [email protected]
FOLFIRI and FOLFOX could be considered interchangeable for first- and second-line treatments of metastatic CRC.4 In 2004, the approval of bevacizumab, a humanized monoclonal antibody against VEGF-A, introduced the first biologic therapy for the initial treatment of metastatic CRC. Several studies have shown that bevacizumab improves PFS and OS when combined with chemotherapy.5,6 The addition of bevacizumab to the irinotecan-based IFL (irinotecan/5-FU/LV) regimen increased median survival from 15.6 months to 20.3 months, with a 34% reduction in the hazard of death (P < 0.0001). The combination of FOLFOX and bevacizumab in the first-line treatment of CRC also results in an apparent improvement in response rates,7 whereas a similar regimen had a clear benefit in response rate, PFS, and OS in the second-line setting.8 Safety analyses have also been reported and do not suggest excessive increased toxicities. These data have led to the use of FOLFOX or FOLFIRI with bevacizumab as the standard initial therapy for patients with metastatic CRC.
Epidermal Growth Factor Receptor Inhibition in Colorectal Cancer The EGFR is a member of the HER tyrosine kinase growth factor receptor family, and it has been shown to be overexpressed in many tumor types, including CRC.9 When tested by immunohistochemistry, approximately 75% of patients with CRC have tumors that overexpress EGFR.10 When bound by specific ligands, including EGF and transforming growth factor–α (TGF-α), EGFR undergoes heterodimerization and homodimerization and autophosphorylates several tyrosine residues. These tyrosines then serve as the binding sites for molecules that activate multiple signaling pathways, resulting in cellular proliferation, migration, and metastasis.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Phase III Trial of Panitumumab in Metastatic CRC Figure 1 Treatment Schema
Treatment Arm S C R E E N I N G
R A N D O M I Z E
Panitumumab 6 mg/kg + chemotherapy + Bevacizumab
Control Arm Chemotherapy + Bevacizumab alone
R E S P O N S E E V A L U A T I O N
Activation of the EGFR also leads to increased angiogenesis and secretion of VEGF.11 Inhibition of normal ligand binding to the EGFR blocks phosphorylation, leading to inhibition of tumor cell growth and apoptosis.12 In 2004, the Food and Drug Administration (FDA) approved cetuximab, a chimeric antibody directed at the EGFR, in combination with irinotecan for the treatment of EGFRexpressing metastatic CRC that is refractory to irinotecanbased chemotherapy.13 In addition, cetuximab can be used as monotherapy in patients who cannot tolerate irinotecan.14 Pilot studies in the first-line treatment of metastatic CRC have shown that cetuximab appears to improve efficacy with tolerable toxicity when combined with oxaliplatin or irinotecan chemotherapy. Furthermore, several recent phase II studies examining the combination of cetuximab with irinotecan- or oxaliplatin-based chemotherapy in previously untreated patients have been promising, without unexpected toxicity.15,16 One limitation of cetuximab is the development of human antichimeric antibodies and occasional severe infusion reactions. In fact, the FDA-approved labeling includes a boxed warning regarding infusion reactions, which have been reported to occur in 19%-25% of patients. As recently as September 2005, new additions to the package insert of cetuximab suggest longer waiting periods after the infusion.17
Panitumumab Panitumumab is a high-affinity (kDa = 5 × 10–11 mol/L), fully human immunoglobulin G2 monoclonal antibody to the extracellular domain of EGFR that was developed using Xenomouse® technology.18 Clinical activity has been observed in early-phase studies in a variety of malignancies including CRC.19 It has predictable pharmacokinetics with an optimal weekly dose of 2.5 mg/kg based on observations of clinical safety data and effective EGFR blockade. Updated results from a phase II study using panitumumab as monotherapy for metastatic CRC in which previous chemotherapy has failed have recently been reported.20 An objective response rate (RR) of 9% was seen, with a median duration of response of 18.1 weeks. There was no correlation between efficacy and previous therapy, and responses were seen in patients who had received as many as 4 lines of
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OR or SD
Response evaluation at 12 weeks. Follow-up for progression at weeks 18, 24, 48, and every 12 weeks thereafter
P R O G R E S S I O N
S U R V I V A L F O L L O W U P
previous therapy. Further phase I studies have shown similar tolerability and exposure profiles in patients receiving 2.5 mg/kg weekly, 6 mg/kg biweekly, and 9 mg/kg every 3 weeks.21 As expected, infusion reactions have been rare and clinically mild, and no cases of human antihuman antibodies have been reported. Preliminary results from a phase II, multicenter, openlabel study using panitumumab with IFL or FOLFIRI as firstline treatment for metastatic CRC showed that nearly half (47%) the patients treated with panitumumab and IFL responded, with 32% exhibiting stable disease.22 Skin rashes and diarrhea were the most common toxicities seen, although diarrhea was more common with IFL treatment. The incidence of diarrhea was much lower in combination with FOLFIRI. Although final efficacy data are still pending, combining panitumumab with an irinotecan-based regimen appears to be efficacious and generally well tolerated.
Study Rationale The combination of panitumumab and bevacizumab will inhibit 2 distinct but interacting biologic pathways. Preclinical models have shown synergy with combined blockade of EGFR and VEGF.23 Recently presented data from a randomized phase II trial comparing treatment with cetuximab/bevacizumab versus cetuximab/bevacizumab/ irinotecan for metastatic CRC in which previous chemotherapy had failed showed that this combination had impressive RRs of 20% and 37%, respectively, without any unexpected toxicities.24 The intent of this trial is to determine whether the addition of panitumumab to standard of care FOLFOX and FOLFIRI regimens will help patients being treated for previously untreated metastatic CRC. The Panitumumab Advanced Colorectal Cancer Evaluation trial is a phase III randomized multicenter study whose primary objective is to assess whether the addition of panitumumab to chemotherapy plus bevacizumab improves PFS compared with treatment with chemotherapy and bevacizumab alone (Figure 1). The secondary objectives are to assess whether the addition of panitumumab improves OS, RRs (complete and partial responses), time to progression, time to treatment failure, duration of response, and/or rate of stable disease.
Zev Wainberg, J. Randolph Hecht Table 1
Eligibility Criteria
Inclusion Criteria: • Tissue diagnosis of adenocarcinoma of the colon or rectum • Documented metastatic disease that is measurable by modified RECIST • ECOG performance status of 0 or 1 • Available paraffin-embedded tumor tissue (from primary tumor or metastasis) • Absolute neutrophil count ³ 1500/mL • Platelet count ³ 100,000/mL • Hemoglobin level ³ 9 g/dL • Serum creatinine level £ 1.5 ´ ULN • Alkaline phosphatase £ 3 ´ ULN (if liver metastases are present, £ 5 ´ ULN) • Aspartate aminotransferase £ 3 ´ ULN (if liver metastases are present, £ 5 ´ ULN) • Alanine aminotransferase £ 3 ´ ULN (if liver metastases are present, £ 5 ´ ULN) • Bilirubin level £ 2 ´ ULN • Ability to give informed consent Exclusion Criteria: • Previous chemotherapy or biologic (ie, antibody or vaccine) treatment for metastatic CRC • Last dose of adjuvant or radiosensitizing chemotherapy < 6 months before randomization • Radiation therapy within 14 days before randomization • Elective and/or planned major surgical procedure to be performed during the course of this trial (surgery that arises as needed during the course of the study, not agreed to a priori, will not make the subject ineligible) • Major surgery within 28 days before randomization • Central nervous system metastases • History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest radiograph or computed tomography scan • Clinically significant ascites • Preexisting bleeding diathesis or coagulopathy or the need for full-dose anticoagulation • Any of the following within 1 year before randomization – Myocardial infarction – Unstable angina – Symptomatic congestive heart failure – Serious uncontrolled cardiac arrhythmia – Cerebrovascular accident or transient ischemic attack – Gastrointestinal ulcer or hemorrhage – Hemoptysis – Pulmonary embolism – Deep vein thrombosis or other significant thromboembolic event • Regular use of nonsteroidal antiinflammatory agents • Female subject of childbearing potential, not abstinent and not willing to use contraceptives during the course of the study and for 6 months after the last dose of first-line treatment • Female subject who is breast-feeding or who has positive serum pregnancy test 72 hours before randomization • Male subject, not abstinent and not willing to use adequate contraception upon enrollment into this study and for 6 months after the last dose of first-line treatment • Patient known to be positive for human immunodeficiency virus • Patient allergic to panitumumab or any components of the panitumumab formulation Abbreviations: ECOG = Eastern Cooperative Oncology Group; RECIST = Response Evaluation Criteria on Solid Tumors; ULN = upper limit of normal
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Phase III Trial of Panitumumab in Metastatic CRC Trial Design Subjects who are eligible will be enrolled and randomized centrally, and enrollment will be limited to 800 patients receiving oxaliplatin-based chemotherapy and 200 receiving irinotecan-based chemotherapy. In the past year, FOLFOX/bevacizumab has become the most commonly used regimen for the first-line treatment of metastatic CRC. However, with the increasing use of oxaliplatin-based regimens in the adjuvant setting, irinotecan-based therapy has remained an acceptable and often preferred treatment for first-line treatment. Thus, investigators can choose to enroll patients in oxaliplatin-based or irinotecan-based cohorts. Eligible patients will be randomized on a 1:1 basis to receive panitumumab or not. Panitumumab will be administered as a 30-60–minute intravenous infusion at a dose of 6 mg/kg once every 2 weeks on the same day as the chemotherapy and bevacizumab. All panitumumab will be administered without premedication and will precede the chemotherapy infusions by ≥ 1 hour. Clinical evaluations, lab assessments, and radiologic studies to assess clinical status and response will be performed at visits on weeks 12, 24, 36, and 48 and thereafter every 12 weeks and at the time of discontinuation of therapy. Evaluation of the clinical status of the subjects will be performed until one of the following occurs: disease progression, death, or the withdrawal of consent by the subject. Disease progression and response determination will be based on clinical assessment by the study investigator, and all measurable and nonmeasurable lesions will be followed by modified Response Evaluation Criteria in Solid Tumors.
Patient Characteristics Patients with previously untreated symptomatic or asymptomatic metastatic CRC can be registered if they meet the eligibility criteria (Table 1). All patients must have histologically proven adenocarcinoma of the colon or rectum and evidence of metastatic disease.
Anticipated Toxicities Previous trials with panitumumab indicate that the drug is generally well tolerated. The most frequently reported adverse event was a dose-related, reversible, acneiform or maculopapular rash that can occur in as many as 90% of patients. The rash is a specific toxicity of EGFR inhibition. Similar toxicities have been observed with chimeric and humanized monoclonal anti-EGFR antibodies (cetuximab and matuzumab) as well as with small-molecule tyrosine kinase inhibitors of EGFR (gefitinib and erlotinib). In fact, rash incidence and severity appear to correlate with efficacy in patients treated with anti-EGFR therapies.2,25 Unlike the chimeric monoclonal antibody cetuximab, the administration of panitumumab does not require premedication, and the incidence of infusion reactions has been very low (< 1%), without any fatalities. Likewise, unlike gefitinib, only 1 case (0.1%) of interstitial lung disease related to panitumumab has been reported, and this case occurred in a patient with
366 • Clinical Colorectal Cancer January 2006
preexisting pulmonary fibrosis. In addition, no human antihuman antibody responses have been seen in > 200 subjects who have had baseline and postbaseline blood tested.21
Proposed Statistical Analysis The primary analysis of this trial is based on PFS of 800 subjects receiving oxaliplatin-based chemotherapy plus bevacizumab with and without panitumumab. Two hundred patients will be enrolled in the irinotecan-based therapy arm of this study. Safety can be observed in the 100 patients who receive irinotecan, bevacizumab, and panitumumab, whereas the other 100 will serve as a control arm. Although the primary objective for enrolling the patients who have received irinotecan-based therapy is to collect safety data, efficacy data will be analyzed as well.
References 1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005 [published erratum in CA Cancer J Clin 2005; 55:259]. CA Cancer J Clin 2005; 55:10-30. 2. Saltz LB, Cox DO, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343:905-914. 3. Rothenberg ML, Oza AM, Gegelo R, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21:2059-2069. 4. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX or the reverse sequence in advanced colorectal cancer. J Clin Oncol 2004; 22:229-237. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2334-2342. 6. Kabbinavar FF, Hurwitz H, Fehrenbacher L, et al. Phase II randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2004; 21:60-65. 7. Hochster HS, Welles L, Hart L, et al. Safety and efficacy of bevacizumab (Bev) when added to oxaliplatin/fluoropyrimidine (O/F) regimens as first-line treatment of metastatic colorectal cancer (mCRC): TREE 1 & 2 studies. J Clin Oncol 2005; 23(suppl 16):249s (Abstract #3515). 8. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 2005; 23(suppl 16):1s (Abstract #2). 9. Real FX, Rettig WJ, Chesa PG, et al. Expression of epidermal growth factor receptor in human cultured cells and tissues: relationship to cell lineage and stage of differentiation. Cancer Res 1986; 46:4726-4731. 10. Yasui W, Sumiyoshi H, Hata J, et al. Expression of epidermal growth factor receptor in human gastric and colonic carcinomas. Cancer Res 1988; 48:137-141. 11. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127-137. 12. Yokoi K, Thaker PH, Yazici S, et al. Inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Res 2005; 65:3716-3725. 13. 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; 351:337-345. 14. 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; 22:1201-1208.
Zev Wainberg, J. Randolph Hecht 15. 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. Proc Am Soc Clin Oncol 2004; 23:248 (Abstract #3512). 16. Rougier P, Raoul JL, et al. Cetuximab+FOLFIRI as first-line treatment for metastatic colorectal cancer CA. Proc Am Soc Clin Oncol 2004; 23:248 (Abstract #3513). 17. ErbituxTM [package insert]. Branchburg, NJ/Princeton, NJ: ImClone Systems Inc/Bristol-Myers-Squibb; 2005. 18. Lynch DH, Yang XD. Therapeutic potential of ABX-EGF: a fully human anti-epidermal growth factor receptor monoclonal antibody for cancer treatment. Semin Oncol 2002; 29:47-506. 19. Figlin RA, Belldegrun AS, Crawford J, et al. ABX-EGF, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: phase 1 clinical results. Proc Am Soc Clin Oncol 2002; 21:10a (Abstract #35). 20. 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(suppl 16):251s (Abstract #3520). 21. Weiner LM, Belldegrun A, Rowinsky E, et al. Updated results from
22.
23.
24.
25.
a dose and schedule study of panitumumab (ABX-EGF) monotherapy in patients with advanced solid malignancies. J Clin Oncol 2005; 23(suppl 16):206s (Abstract #3059). Berlin J, Malik I, Piens J, et al. Panitumumab therapy with irinotecan, 5-FU and leucovorin in patients with metastatic colorectal cancer. Presented at: the 9th Annual Meeting of the European Society for Medical Oncology; October 29–November 2, 2004; Vienna, Austria. Starling N, Cunningham D. Monoclonal antibodies against vascular endothelial growth factor and epidermal growth factor receptor in advanced colorectal cancers: present and future directions. Curr Opin Oncol 2004; 16:385-390. Saltz L, Lenz H, Kindler HL, et al. Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. Presented at: the American Society of Clinical Oncology 2005 Gastrointestinal Cancers Symposium; January 27-29, 2005; Hollywood, Florida. Abstract #169b. Cohen R, Falcey J, Paulter V, et al. Safety profile of the monoclonal antibody (MoAb) IMC-C225, and anti-epidermal growth factor receptor (EGFR) used in the treatment of EGFR-positive tumors. Proc Am Soc Clin Oncol 2000; 19:474a (Abstract #1862).
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Trial
A Phase III Randomized, Open-Label, Controlled Trial of Chemotherapy and Bevacizumab with or Without Panitumumab in the First-Line Treatment of Patients with Metastatic Colorectal Cancer Zev Wainberg, J. Randolph Hecht Clinical Colorectal Cancer, Vol. 5, No. 5, 363-367, 2006 Key words: Epidermal growth factor receptor, 5-Fluorouracil, Irinotecan, Leucovorin, Oxaliplatin, Vascular endothelial growth factor
Introduction Despite recent progress, metastatic colorectal cancer (CRC) remains the second leading cause of cancer-related mortality in the Unites States, with approximately 60,000 deaths in 2005.1 Traditionally, chemotherapy has been the main approach for the treatment of CRC, but with the recent advent of targeted therapies, biologic treatments are becoming an area of intense interest. In the past 2 years alone, 2 molecularly targeted antibodies, bevacizumab and cetuximab, have been approved for CRC, targeting vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptor (EGFR), respectively. The basic combination of 5-fluorouracil (5-FU) and leucovorin (LV) remains the backbone of therapy for metastatic CRC. In recent years, studies combining 5-FU/LV with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) have demonstrated improvements in disease-free and overall survival (OS).2,3 A recent comparison of FOLFOX6 followed by FOLFIRI versus the reverse order as first-line treatment found that both sequences achieved a median survival of approximately 20 months and were similarly efficacious. The overall response rate in the FOLFIRI arm was 56%, with a progression-free survival (PFS) time of 8.5 months, compared with an overall response rate of 54% and a PFS of 8 months with FOLFOX6. These results suggest that GI Oncology Program, David Geffen School of Medicine, University of California, Los Angeles Submitted: Jan 11, 2006; Accepted: Jan 11, 2006 Address for correspondence: J. Randolph Hecht, MD, GI Oncology Program, David Geffen School of Medicine, University of California, Los Angeles, 2338G PVUB, 10945 Le Conte Ave, Los Angeles, CA 90095 Fax: 310-267-0151; e-mail: [email protected]
FOLFIRI and FOLFOX could be considered interchangeable for first- and second-line treatments of metastatic CRC.4 In 2004, the approval of bevacizumab, a humanized monoclonal antibody against VEGF-A, introduced the first biologic therapy for the initial treatment of metastatic CRC. Several studies have shown that bevacizumab improves PFS and OS when combined with chemotherapy.5,6 The addition of bevacizumab to the irinotecan-based IFL (irinotecan/5-FU/LV) regimen increased median survival from 15.6 months to 20.3 months, with a 34% reduction in the hazard of death (P < 0.0001). The combination of FOLFOX and bevacizumab in the first-line treatment of CRC also results in an apparent improvement in response rates,7 whereas a similar regimen had a clear benefit in response rate, PFS, and OS in the second-line setting.8 Safety analyses have also been reported and do not suggest excessive increased toxicities. These data have led to the use of FOLFOX or FOLFIRI with bevacizumab as the standard initial therapy for patients with metastatic CRC.
Epidermal Growth Factor Receptor Inhibition in Colorectal Cancer The EGFR is a member of the HER tyrosine kinase growth factor receptor family, and it has been shown to be overexpressed in many tumor types, including CRC.9 When tested by immunohistochemistry, approximately 75% of patients with CRC have tumors that overexpress EGFR.10 When bound by specific ligands, including EGF and transforming growth factor–α (TGF-α), EGFR undergoes heterodimerization and homodimerization and autophosphorylates several tyrosine residues. These tyrosines then serve as the binding sites for molecules that activate multiple signaling pathways, resulting in cellular proliferation, migration, and metastasis.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Phase III Trial of Panitumumab in Metastatic CRC Figure 1 Treatment Schema
Treatment Arm S C R E E N I N G
R A N D O M I Z E
Panitumumab 6 mg/kg + chemotherapy + Bevacizumab
Control Arm Chemotherapy + Bevacizumab alone
R E S P O N S E E V A L U A T I O N
Activation of the EGFR also leads to increased angiogenesis and secretion of VEGF.11 Inhibition of normal ligand binding to the EGFR blocks phosphorylation, leading to inhibition of tumor cell growth and apoptosis.12 In 2004, the Food and Drug Administration (FDA) approved cetuximab, a chimeric antibody directed at the EGFR, in combination with irinotecan for the treatment of EGFRexpressing metastatic CRC that is refractory to irinotecanbased chemotherapy.13 In addition, cetuximab can be used as monotherapy in patients who cannot tolerate irinotecan.14 Pilot studies in the first-line treatment of metastatic CRC have shown that cetuximab appears to improve efficacy with tolerable toxicity when combined with oxaliplatin or irinotecan chemotherapy. Furthermore, several recent phase II studies examining the combination of cetuximab with irinotecan- or oxaliplatin-based chemotherapy in previously untreated patients have been promising, without unexpected toxicity.15,16 One limitation of cetuximab is the development of human antichimeric antibodies and occasional severe infusion reactions. In fact, the FDA-approved labeling includes a boxed warning regarding infusion reactions, which have been reported to occur in 19%-25% of patients. As recently as September 2005, new additions to the package insert of cetuximab suggest longer waiting periods after the infusion.17
Panitumumab Panitumumab is a high-affinity (kDa = 5 × 10–11 mol/L), fully human immunoglobulin G2 monoclonal antibody to the extracellular domain of EGFR that was developed using Xenomouse® technology.18 Clinical activity has been observed in early-phase studies in a variety of malignancies including CRC.19 It has predictable pharmacokinetics with an optimal weekly dose of 2.5 mg/kg based on observations of clinical safety data and effective EGFR blockade. Updated results from a phase II study using panitumumab as monotherapy for metastatic CRC in which previous chemotherapy has failed have recently been reported.20 An objective response rate (RR) of 9% was seen, with a median duration of response of 18.1 weeks. There was no correlation between efficacy and previous therapy, and responses were seen in patients who had received as many as 4 lines of
364 • Clinical Colorectal Cancer January 2006
OR or SD
Response evaluation at 12 weeks. Follow-up for progression at weeks 18, 24, 48, and every 12 weeks thereafter
P R O G R E S S I O N
S U R V I V A L F O L L O W U P
previous therapy. Further phase I studies have shown similar tolerability and exposure profiles in patients receiving 2.5 mg/kg weekly, 6 mg/kg biweekly, and 9 mg/kg every 3 weeks.21 As expected, infusion reactions have been rare and clinically mild, and no cases of human antihuman antibodies have been reported. Preliminary results from a phase II, multicenter, openlabel study using panitumumab with IFL or FOLFIRI as firstline treatment for metastatic CRC showed that nearly half (47%) the patients treated with panitumumab and IFL responded, with 32% exhibiting stable disease.22 Skin rashes and diarrhea were the most common toxicities seen, although diarrhea was more common with IFL treatment. The incidence of diarrhea was much lower in combination with FOLFIRI. Although final efficacy data are still pending, combining panitumumab with an irinotecan-based regimen appears to be efficacious and generally well tolerated.
Study Rationale The combination of panitumumab and bevacizumab will inhibit 2 distinct but interacting biologic pathways. Preclinical models have shown synergy with combined blockade of EGFR and VEGF.23 Recently presented data from a randomized phase II trial comparing treatment with cetuximab/bevacizumab versus cetuximab/bevacizumab/ irinotecan for metastatic CRC in which previous chemotherapy had failed showed that this combination had impressive RRs of 20% and 37%, respectively, without any unexpected toxicities.24 The intent of this trial is to determine whether the addition of panitumumab to standard of care FOLFOX and FOLFIRI regimens will help patients being treated for previously untreated metastatic CRC. The Panitumumab Advanced Colorectal Cancer Evaluation trial is a phase III randomized multicenter study whose primary objective is to assess whether the addition of panitumumab to chemotherapy plus bevacizumab improves PFS compared with treatment with chemotherapy and bevacizumab alone (Figure 1). The secondary objectives are to assess whether the addition of panitumumab improves OS, RRs (complete and partial responses), time to progression, time to treatment failure, duration of response, and/or rate of stable disease.
Zev Wainberg, J. Randolph Hecht Table 1
Eligibility Criteria
Inclusion Criteria: • Tissue diagnosis of adenocarcinoma of the colon or rectum • Documented metastatic disease that is measurable by modified RECIST • ECOG performance status of 0 or 1 • Available paraffin-embedded tumor tissue (from primary tumor or metastasis) • Absolute neutrophil count ³ 1500/mL • Platelet count ³ 100,000/mL • Hemoglobin level ³ 9 g/dL • Serum creatinine level £ 1.5 ´ ULN • Alkaline phosphatase £ 3 ´ ULN (if liver metastases are present, £ 5 ´ ULN) • Aspartate aminotransferase £ 3 ´ ULN (if liver metastases are present, £ 5 ´ ULN) • Alanine aminotransferase £ 3 ´ ULN (if liver metastases are present, £ 5 ´ ULN) • Bilirubin level £ 2 ´ ULN • Ability to give informed consent Exclusion Criteria: • Previous chemotherapy or biologic (ie, antibody or vaccine) treatment for metastatic CRC • Last dose of adjuvant or radiosensitizing chemotherapy < 6 months before randomization • Radiation therapy within 14 days before randomization • Elective and/or planned major surgical procedure to be performed during the course of this trial (surgery that arises as needed during the course of the study, not agreed to a priori, will not make the subject ineligible) • Major surgery within 28 days before randomization • Central nervous system metastases • History of interstitial pneumonitis or pulmonary fibrosis or evidence of interstitial pneumonitis or pulmonary fibrosis on baseline chest radiograph or computed tomography scan • Clinically significant ascites • Preexisting bleeding diathesis or coagulopathy or the need for full-dose anticoagulation • Any of the following within 1 year before randomization – Myocardial infarction – Unstable angina – Symptomatic congestive heart failure – Serious uncontrolled cardiac arrhythmia – Cerebrovascular accident or transient ischemic attack – Gastrointestinal ulcer or hemorrhage – Hemoptysis – Pulmonary embolism – Deep vein thrombosis or other significant thromboembolic event • Regular use of nonsteroidal antiinflammatory agents • Female subject of childbearing potential, not abstinent and not willing to use contraceptives during the course of the study and for 6 months after the last dose of first-line treatment • Female subject who is breast-feeding or who has positive serum pregnancy test 72 hours before randomization • Male subject, not abstinent and not willing to use adequate contraception upon enrollment into this study and for 6 months after the last dose of first-line treatment • Patient known to be positive for human immunodeficiency virus • Patient allergic to panitumumab or any components of the panitumumab formulation Abbreviations: ECOG = Eastern Cooperative Oncology Group; RECIST = Response Evaluation Criteria on Solid Tumors; ULN = upper limit of normal
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Phase III Trial of Panitumumab in Metastatic CRC Trial Design Subjects who are eligible will be enrolled and randomized centrally, and enrollment will be limited to 800 patients receiving oxaliplatin-based chemotherapy and 200 receiving irinotecan-based chemotherapy. In the past year, FOLFOX/bevacizumab has become the most commonly used regimen for the first-line treatment of metastatic CRC. However, with the increasing use of oxaliplatin-based regimens in the adjuvant setting, irinotecan-based therapy has remained an acceptable and often preferred treatment for first-line treatment. Thus, investigators can choose to enroll patients in oxaliplatin-based or irinotecan-based cohorts. Eligible patients will be randomized on a 1:1 basis to receive panitumumab or not. Panitumumab will be administered as a 30-60–minute intravenous infusion at a dose of 6 mg/kg once every 2 weeks on the same day as the chemotherapy and bevacizumab. All panitumumab will be administered without premedication and will precede the chemotherapy infusions by ≥ 1 hour. Clinical evaluations, lab assessments, and radiologic studies to assess clinical status and response will be performed at visits on weeks 12, 24, 36, and 48 and thereafter every 12 weeks and at the time of discontinuation of therapy. Evaluation of the clinical status of the subjects will be performed until one of the following occurs: disease progression, death, or the withdrawal of consent by the subject. Disease progression and response determination will be based on clinical assessment by the study investigator, and all measurable and nonmeasurable lesions will be followed by modified Response Evaluation Criteria in Solid Tumors.
Patient Characteristics Patients with previously untreated symptomatic or asymptomatic metastatic CRC can be registered if they meet the eligibility criteria (Table 1). All patients must have histologically proven adenocarcinoma of the colon or rectum and evidence of metastatic disease.
Anticipated Toxicities Previous trials with panitumumab indicate that the drug is generally well tolerated. The most frequently reported adverse event was a dose-related, reversible, acneiform or maculopapular rash that can occur in as many as 90% of patients. The rash is a specific toxicity of EGFR inhibition. Similar toxicities have been observed with chimeric and humanized monoclonal anti-EGFR antibodies (cetuximab and matuzumab) as well as with small-molecule tyrosine kinase inhibitors of EGFR (gefitinib and erlotinib). In fact, rash incidence and severity appear to correlate with efficacy in patients treated with anti-EGFR therapies.2,25 Unlike the chimeric monoclonal antibody cetuximab, the administration of panitumumab does not require premedication, and the incidence of infusion reactions has been very low (< 1%), without any fatalities. Likewise, unlike gefitinib, only 1 case (0.1%) of interstitial lung disease related to panitumumab has been reported, and this case occurred in a patient with
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preexisting pulmonary fibrosis. In addition, no human antihuman antibody responses have been seen in > 200 subjects who have had baseline and postbaseline blood tested.21
Proposed Statistical Analysis The primary analysis of this trial is based on PFS of 800 subjects receiving oxaliplatin-based chemotherapy plus bevacizumab with and without panitumumab. Two hundred patients will be enrolled in the irinotecan-based therapy arm of this study. Safety can be observed in the 100 patients who receive irinotecan, bevacizumab, and panitumumab, whereas the other 100 will serve as a control arm. Although the primary objective for enrolling the patients who have received irinotecan-based therapy is to collect safety data, efficacy data will be analyzed as well.
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