Vascular Endothelial Growth Factor and Epidermal Growth Factor Signaling Pathways as Therapeutic Targets for Colorectal Cancer
2010; Elsevier BV; Volume: 138; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2010.02.005
ISSN1528-0012
AutoresThomas Winder, Heinz‐Josef Lenz,
Tópico(s)Cancer Treatment and Pharmacology
ResumoTreatment of colorectal cancer (CRC) has developed considerably over the past decade, especially in the areas of targeted therapeutics and biomarker development. Multiple cellular pathways influence the growth and metastatic potential of CRC. Targeted therapies have been designed to interfere with specific molecular events in pathways that mediate tumor growth and progression. Preclinical and clinical studies have shown that the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are valid therapeutic targets for patients with CRC. Monoclonal antibodies and tyrosine kinase inhibitors have been developed to target EGFR, VEGF, and VEGF receptors (VEGFRs) and are important additions to CRC treatment options. We review the most recent data on the VEGF and EGFR signaling pathways and therapeutic reagents designed to target them, provide insights into their mechanisms, and describe results from recent clinical trials. Treatment of colorectal cancer (CRC) has developed considerably over the past decade, especially in the areas of targeted therapeutics and biomarker development. Multiple cellular pathways influence the growth and metastatic potential of CRC. Targeted therapies have been designed to interfere with specific molecular events in pathways that mediate tumor growth and progression. Preclinical and clinical studies have shown that the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are valid therapeutic targets for patients with CRC. Monoclonal antibodies and tyrosine kinase inhibitors have been developed to target EGFR, VEGF, and VEGF receptors (VEGFRs) and are important additions to CRC treatment options. We review the most recent data on the VEGF and EGFR signaling pathways and therapeutic reagents designed to target them, provide insights into their mechanisms, and describe results from recent clinical trials. Heinz–Josef Lenz*,‡View Large Image Figure ViewerDownload Hi-res image Download (PPT) The systemic treatment options for patients with colorectal cancer (CRC) have progressed significantly; in 1995, patients were given only 5-fluorouracil (5-FU), but now they also receive cytotoxic chemotherapeutic and biologic agents. Despite significant improvements in response rate and survival over a little more than a decade, the efficacy of chemotherapeutic agents appears to have reached a plateau. This might be due to severe adverse effects that limit treatment duration and dose as well as drug resistance. As a result, patients with advanced or recurrent CRC need novel therapeutic agents that target specific biological pathways involved in tumor growth and dissemination. Targeted therapeutics include monoclonal antibodies (mAbs) and small molecules that interfere with factors expressed by the tumor cells and the tumor microenvironment. Reagents have been developed to target the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) signaling pathways, which mediate progression of CRC. We review the mechanisms of these pathways in tumor growth, the reagents that target them, and the safety and efficacy of inhibiting these pathways in patients with CRC. EGFR is a transmembrane receptor tyrosine kinase of the ErbB (also known as HER) family that is abnormally activated in many epithelial tumors. This receptor family comprises EGFR (ErbB1/EGFR/HER1), ErbB2 (Her2/neu), ErbB3 (HER3), and ErbB4 (Her4).1Mendelsohn J. Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer.J Clin Oncol. 2003; 21: 2787-2799Crossref PubMed Scopus (1210) Google Scholar, 2Yarden Y. Sliwkowski M.X. Untangling the ErbB signalling network.Nat Rev Mol Cell Biol. 2001; 2: 127-137Crossref PubMed Scopus (5818) Google Scholar The EGFR is activated by ligand-dependent, ligand-independent, and overexpression mechanisms. EGFR ligands include epidermal growth factor, transforming growth factor α, amphiregulin, betacellulin, and epiregulin; their binding induces a conformational change in EGFR that activates its tyrosine kinase activity. EGFR can be activated by urokinase plasminogen in a ligand-independent mechanism.3Liu D. Aguirre Ghiso J. Estrada Y. et al.EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma.Cancer Cell. 2002; 1: 445-457Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar Overexpression of EGFR by cancer cells results in ligand-independent dimerization and activation.1Mendelsohn J. Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer.J Clin Oncol. 2003; 21: 2787-2799Crossref PubMed Scopus (1210) Google Scholar Activated EGFR activates several signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway, which leads to cell proliferation, survival, and, in some cases, transformation.4Lewis T.S. Shapiro P.S. Ahn N.G. Signal transduction through MAP kinase cascades.Adv Cancer Res. 1998; 74: 49-139Crossref PubMed Google Scholar EGFR also activates the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, which regulates cell survival. This pathway is negatively regulated by the tumor suppressor phosphatase and tensin homologue gene (PTEN), a phosphatase whose major substrate is phosphatidylinositol-3,4,5-triphosphate, produced by the activation of PI3-K. Loss of PTEN function results in increased phosphatidylinositol-3,4,5-triphosphate concentration and subsequent AKT hyperactivation, which protects cancer cells from various apoptotic stimuli.5Di Cristofano A. Pandolfi P.P. The multiple roles of PTEN in tumor suppression.Cell. 2000; 100: 387-390Abstract Full Text Full Text PDF PubMed Scopus (1048) Google Scholar, 6Downward J. Mechanisms and consequences of activation of protein kinase B/Akt.Curr Opin Cell Biol. 1998; 10: 262-267Crossref PubMed Scopus (1194) Google Scholar EGFR also signals through the stress-activated protein kinase pathway, which includes protein kinase C and Jak and the Stat transcription factors. Activation of each of these pathways results in distinct transcriptional profiles that mediate multiple cellular responses, including apoptosis, differentiation, cellular proliferation, invasion, and DNA repair and survival (Figure 1).7Capdevila J. Elez E. Macarulla T. et al.Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment.Cancer Treat Rev. 2009; 35: 354-363Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar More than 20 years ago, Kawamoto et al proposed that the EGFR be targeted for cancer therapy.8Kawamoto T. Sato J.D. Le A. et al.Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody.Proc Natl Acad Sci U S A. 1983; 80: 1337-1341Crossref PubMed Scopus (725) Google Scholar Two classes of anti-EGFR agents have been shown to have anti-cancer activities in clinical trials. Cetuximab is a recombinant, chimeric, human-murine immunoglobulin (Ig)G1 mAb that binds specifically to the extracellular domain of EGFR in normal and tumor cells, promoting receptor internalization and degradation without receptor phosphorylation and activation.9Tabernero J. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents.Mol Cancer Res. 2007; 5: 203-220Crossref PubMed Scopus (382) Google Scholar Several studies have shown that cetuximab inhibits growth of EGFR-expressing tumor cells in vitro and in human tumor xenografts in mice. Cetuximab reversed resistance to irinotecan in human colorectal tumor xenografts in mice.10Prewett M.C. Hooper A.T. Bassi R. et al.Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts.Clin Cancer Res. 2002; 8: 994-1003PubMed Google Scholar This finding was followed by phase 2 trials in patients with metastatic CRC that showed cetuximab monotherapy produced notable antitumor activity (response rates of 9%–11.6%) in patients whose disease was refractory to irinotecan, oxaliplatin, and fluoropyrimidine therapies.11Lenz H.J. Van Cutsem E. Khambata-Ford S. et al.Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines.J Clin Oncol. 2006; 24: 4914-4921Crossref PubMed Scopus (485) Google Scholar, 12Saltz L.B. Meropol N.J. Loehrer P.J. 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: 1201-1208Crossref PubMed Scopus (1642) Google Scholar The phase 2 pivotal study Bowel Oncology with Cetuximab Antibody (BOND) compared the effects of cetuximab plus irinotecan with those of cetuximab alone.13Cunningham 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: 337-345Crossref PubMed Scopus (4689) Google Scholar The combination therapy was the most effective, with a response rate of 22.9% (vs 10.8% with cetuximab alone) and a median time to progression of 4.1 months (vs 1.5 months with cetuximab alone). The main toxicities reported with cetuximab in monotherapy and combination therapy were skin reactions—mainly an acneiform rash—in approximately 88% of patients and hypersensitivity reactions in approximately 10%. The acne-like or maculopapular rash arose because EGFR signaling maintains the integrity of the skin. Response and survival were correlated with the severity of the rash in phase 2 studies.13Cunningham 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: 337-345Crossref PubMed Scopus (4689) Google Scholar, 14Saltz L.B. Kies M. Abbruzzese J.L. et al.The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies (abstr 817).Proc Am Soc Clin Oncol. 2003; 22: 204Crossref Google Scholar, 15Tejpar S. Peeters M. Humblet Y. et al.Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): the EVEREST experience (preliminary data).J Clin Oncol. 2008; 26 (abstr 4001)Google Scholar These findings led to the approval of cetuximab for irinotecan-refractory CRC in the United States and Europe. The combination of cetuximab and standard chemotherapy was tested as a first-line therapy, as well as in patients who were refractory to previous therapies. The phase 3 Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial investigated the effectiveness of cetuximab in combination with standard irinotecan plus bolus and infusion fluorouracil and leucovorin (FOLFIRI), compared with FOLFIRI alone, as first-line therapy for patients with metastatic CRC. The study reported a significant improvement in median progression-free survival (8.9 months for the combination of FOLFIRI and cetuximab vs 8 months for FOLFIRI alone) and in response (46.9% for the combination of FOLFIRI and cetuximab vs 38.7% for FOLFIRI alone).16Van Cutsem E. Nowacki M. Lang I. et al.Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial.J Clin Oncol. 2007; 25 (abstr 4000)Google Scholar Cetuximab has also been evaluated as a first-line treatment in combination with oxaliplatin-based chemotherapy. The phase 2 OPUS trial compared the effects of the combination of cetuximab and leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) with those of FOLFOX-4 alone; the combination therapy met the primary end point of increased response rate (45.6%) compared with FOLFOX-4 alone (35.7%).17Bokemeyer C. Bondarenko I. Makhson A. et al.Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study.J Clin Oncol. 2007; 25 (abstr 4035)Google Scholar Activating mutations in K-Ras, a small G protein downstream of EGFR in the MAPK signaling cascade, can affect patients' response to EGFR inhibitors. A series of nonrandomized studies reported that patients with activating mutations in K-Ras had little or no response to anti-EGFR (cetuximab) therapy. Lievre et al then showed that in patients with metastatic CRC, the presence of K-ras mutations predicted resistance to cetuximab therapy and was associated with a worse prognosis.18Lievre A. Bachet J.B. Le Corre D. et al.KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res. 2006; 66: 3992-3995Crossref PubMed Scopus (1972) Google Scholar Results from the CRYSTAL trial have recently shown statistically significant differences between patients with wild-type K-Ras and those with mutant K-Ras in response to FOLFIRI plus cetuximab in terms of progression-free survival (9.9 vs 7.6 months) and best overall response (59% vs 36%).19Kohne C. Stroiakovski D. Chang-Chien C. et al.Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial (abstr 4068).J Clin Oncol. 2009; 27Google Scholar Moreover, Van Cutsem et al showed a significant difference in overall survival for patients with wild-type K-Ras who were treated with FOLFIRI plus cetuximab versus FOLFIRI alone (23.5 months vs 20 months; P = .0094).20Van Cutsem E. Rougier P. Köhne C. et al.A meta-analysis of the CRYSTAL and OPUS studies combining cetuximab with chemotherapy (CT) as 1st-line treatment for patients (pts) with metastatic colorectal cancer (mCRC): results according to KRAS and BRAF mutation status.Eur J Cancer Suppl. 2009; 7 (abstr 6077): 345Crossref Google Scholar Data from the OPUS trial showed that the combination of cetuximab and FOLFOX-4 has an overall response rate of 61% in patients with wild-type K-Ras compared with 33% in those with mutant K-Ras.21Bokemeyer C. Bondarenko I. Hartmann T.J. et al.KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience (abstr 4000).J Clin Oncol. 2008; 26Google Scholar Moreover, Karapetis et al showed that patients with colorectal tumors that express mutant K-Ras did not respond to cetuximab (overall response rate of 1.2%), whereas patients with tumors that expressed wild-type K-Ras did benefit from cetuximab (overall response rate of 12.8%); this study analyzed tumor samples from 394 patients who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone.22Karapetis C.S. Khambata-Ford S. Jonker D.J. et al.K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med. 2008; 359: 1757-1765Crossref PubMed Scopus (3210) Google Scholar Mutations in B-Raf, another component of the EGFR signaling pathway, have similar effects to those of K-Ras in patients treated with cetuximab.23Di Nicolantonio F. Martini M. Molinari F. et al.Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.J Clin Oncol. 2008; 26: 5705-5712Crossref PubMed Scopus (1476) Google Scholar However, the latest data on the CRYSTAL trial, presented at the 2009 annual meeting of the American Society of Clinical Oncology, did not confirm that B-Raf mutations can predict resistance to cetuximab treatment because of the limited sample size, which is due to the low B-Raf mutation frequency.19Kohne C. Stroiakovski D. Chang-Chien C. et al.Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial (abstr 4068).J Clin Oncol. 2009; 27Google Scholar A prospective randomized trial is required to fully evaluate this potential marker. Nonetheless, there is a large amount of clinical data showing that K-Ras mutations affect the response of patients with metastatic CRC to the combination of cetuximab and either irinotecan- or oxaliplatin-based chemotherapies (Table 1).Table 1Effect of Cetuximab in Phase 2 and 3 Studies of Patients With Metastatic CRCStudyPhaseDrugPatients (n)Overall response, % (median duration of response, mo)Median time to progression (mo)Median overall survival (mo)Saltz et al,12Saltz L.B. Meropol N.J. Loehrer P.J. 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: 1201-1208Crossref PubMed Scopus (1642) Google Scholar 20042Cetuximab57; refractory to irinotecan9 (4.2)1.46.4Cunningham et al,13Cunningham 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: 337-345Crossref PubMed Scopus (4689) Google Scholar BOND study, 20043Cetuximab + irinotecan218; refractory to irinotecan22.9 (5.7)4.18.6Cetuximab111; refractory to irinotecan10.8 (4.2)1.56.9Lenz et al,11Lenz H.J. Van Cutsem E. Khambata-Ford S. et al.Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines.J Clin Oncol. 2006; 24: 4914-4921Crossref PubMed Scopus (485) Google Scholar 20062Cetuximab346; refractory to irinotecan, oxaliplatin, and fluoropyrimidines12.4 (4.2)NR6.6Cetuximab in combination with standard chemotherapy in first-line treatment Van Cutsem et al,16Van Cutsem E. Nowacki M. Lang I. et al.Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial.J Clin Oncol. 2007; 25 (abstr 4000)Google Scholar CRYSTAL trial, 20073FOLFIRI60838.7NRNRFOLFIRI + cetuximab60946.9NRNR Bokemeyer et al,17Bokemeyer C. Bondarenko I. Makhson A. et al.Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study.J Clin Oncol. 2007; 25 (abstr 4035)Google Scholar OPUS trial, 20072FOLFOX-433735.7NRNRFOLFOX-4 + cetuximab45.6NRNRK-Ras status and efficacy of cetuximab with standard chemotherapy Karapetis et al,22Karapetis C.S. Khambata-Ford S. Jonker D.J. et al.K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med. 2008; 359: 1757-1765Crossref PubMed Scopus (3210) Google Scholar Advanced CRC, 20083Cetuximab + BSC81 mt K-Ras patients1.2HR = 0.99aHR for progression-free survival in the K-Ras mt cetuximab group as compared with the K-Ras mutant BSC group.4.5117 wt K-Ras patients12.8HR = 0.40bHR for progression-free survival in the K-Ras wt cetuximab group as compared with the K-Ras wild-type BSC group.4.5BSC alone83 mt K-Ras patients04.6113 wt K-Ras patients04.8 Kohne et al,19Kohne C. Stroiakovski D. Chang-Chien C. et al.Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial (abstr 4068).J Clin Oncol. 2009; 27Google Scholar first-line CRC treatment, CRYSTAL trial, 20093FOLFIRI + cetuximab172 K-Ras wt patients59HR = 0.68cProgression-free survival with cetuximab was reported as an HR relative to standard chemotherapy (FOLFIRI or FOLFOX).24.9FOLFIRI + cetuximab105 K-Ras mt patients36HR = 1.07cProgression-free survival with cetuximab was reported as an HR relative to standard chemotherapy (FOLFIRI or FOLFOX).17.5 Bokemeyer et al,21Bokemeyer C. Bondarenko I. Hartmann T.J. et al.KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience (abstr 4000).J Clin Oncol. 2008; 26Google Scholar first-line CRC treatment, OPUS trial, 20082FOLFOX + cetuximab61 K-Ras wt patients61HR = 0.57cProgression-free survival with cetuximab was reported as an HR relative to standard chemotherapy (FOLFIRI or FOLFOX).NRFOLFOX + cetuximab52 K-Ras mt patients33HR = 1.83cProgression-free survival with cetuximab was reported as an HR relative to standard chemotherapy (FOLFIRI or FOLFOX).NRNR, not reported; FOLFOX-4, oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 200 mg/m2 on days 1 + 2, 5-FU 400 mg/m2 intravenous bolus + 600 mg/m2 infusion over 22 hours (days 1 + 2) every 14 days; BSC, best supportive care; mt, mutant; wt, wild-type.a HR for progression-free survival in the K-Ras mt cetuximab group as compared with the K-Ras mutant BSC group.b HR for progression-free survival in the K-Ras wt cetuximab group as compared with the K-Ras wild-type BSC group.c Progression-free survival with cetuximab was reported as an HR relative to standard chemotherapy (FOLFIRI or FOLFOX). Open table in a new tab NR, not reported; FOLFOX-4, oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin 200 mg/m2 on days 1 + 2, 5-FU 400 mg/m2 intravenous bolus + 600 mg/m2 infusion over 22 hours (days 1 + 2) every 14 days; BSC, best supportive care; mt, mutant; wt, wild-type. More markers of cetuximab response could be identified by gaining a better understanding of its molecular mechanisms. Functional polymorphisms in the FCγ receptors FCGR2A-H131R and FCGR3A-V158F were associated with clinical outcome in a study of 39 patients with refractory metastatic CRC treated with single-agent cetuximab.24Zhang W. Gordon M. Schultheis A.M. et al.FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab.J Clin Oncol. 2007; 25: 3712-3718Crossref PubMed Scopus (421) Google Scholar This observation indicates that cetuximab might induce antibody-dependent, cell-mediated cytotoxicity. Moreover, in a retrospective phase 2 trial, Lurje et al were the first to show that the polymorphism G-765C in the gene that encodes cyclooxygenase-2 might predict outcome in patients with metastatic CRC treated with cetuximab as a single agent.25Lurje G. Nagashima F. Zhang W. et al.Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab.Clin Cancer Res. 2008; 14: 7884-7895Crossref PubMed Scopus (107) Google Scholar Larger trials of anti-EGFR therapies that include biomarker analyses are needed to validate these preliminary findings. The EPIC trial was conducted to determine whether the addition of cetuximab to irinotecan prolongs survival as a second-line therapy for patients with metastatic CRC who already received fluoropyrimidine and oxaliplatin.26Sobrero A.F. Maurel J. Fehrenbacher L. et al.EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer.J Clin Oncol. 2008; 26: 2311-2319Crossref PubMed Scopus (848) Google Scholar This phase 3 study showed that the combination of cetuximab and irinotecan was significantly more effective than irinotecan alone (median survival of 4 months vs 2.6 months and response rate of 16.4% vs 4.2%, respectively). Moreover, the combination therapy resulted in significantly better quality-of-life scores. Panitumumab is a fully human, recombinant κ IgG2 mAb that binds specifically and with high affinity to the extracellular domain of EGFR in normal and tumor cells. Through competitive binding to EGFR ligands, panitumumab prevents EGFR dimerization, autophosphorylation, and signaling, thereby inhibiting proliferation and promoting apoptosis.27Gravalos C. Cassinello J. Garcia-Alfonso P. et al.Integration of panitumumab into the treatment of colorectal cancer.Crit Rev Oncol Hematol. 2010; 74: 16-26Crossref PubMed Scopus (23) Google Scholar Panitumumab showed preliminary activity in phase 1 studies,28Weiner L.M. Belldegrun A.S. Crawford J. et al.Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies.Clin Cancer Res. 2008; 14: 502-508Crossref PubMed Scopus (109) Google Scholar so phase 2 trials were initiated in patients with CRC. In a phase 2 study of 148 patients with metastatic CRC that progressed despite chemotherapy (fluoropyrimidine and irinotecan or oxaliplatin), patients given panitumumab as a single agent (2.5 mg/kg weekly) had a response rate of 9% and a median progression-free survival of 2.5 months.29Hecht J.R. Patnaik A. Berlin J. et al.Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer.Cancer. 2007; 110: 980-988Crossref PubMed Scopus (191) Google Scholar The effects of panitumumab plus best supportive care were compared with those of best supportive care alone in a phase 3 study of 463 patients with metastatic CRC that was resistant to fluoropyrimidines, oxaliplatin, and irinotecan.30Van Cutsem E. Peeters M. Siena S. et al.Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.J Clin Oncol. 2007; 25: 1658-1664Crossref PubMed Scopus (1775) Google Scholar In this study, panitumumab was administered at a dosage of 6 mg/kg every 2 weeks until patients progressed or until the level of toxicity was unacceptable. After a medium follow-up period of at least 12 months, patients given panitumumab had a significantly higher response rate (10% vs 0% of those with best supportive care) and time of progression-free survival (8 weeks vs 7.3 weeks with best supportive care). The most common side effects were skin toxicity (90% of patients in the panitumumab group vs 9% in the best supportive care group), diarrhea (21% vs 11%), and hypomagnesemia (36% vs 1%). There were no infusion reactions. Panitumumab increases progression-free survival in patients with metastatic CRC that is resistant to chemotherapy compared with best supportive care; these results led to the approval of panitumumab for treatment of metastatic CRC in 2006 in the United States and Europe. A phase 2 study investigated the effects of panitumumab in combination with irinotecan-containing regimens as a first-line therapy for patients with metastatic CRC. In this trial, conducted by Berlin et al, the combination of panitumumab and FOLFIRI was well tolerated; the median time of progression-free survival was 10.9 months, and median overall survival time was 22.5 months.31Berlin J. Posey J. Tchekmedyian S. et al.Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer.Clin Colorectal Cancer. 2007; 6: 427-432Abstract Full Text PDF PubMed Scopus (93) Google Scholar As expected, given the biology of EGFR inhibitors, skin-related toxicities were common but mostly limited to grade 3. The most frequent noncutaneous toxicities were diarrhea, nail abnormalities, and hypomagnesemia, occurring in more than 20% of patients, whereas only 4% of the patients developed hypersensitivity reactions, which were serious in 1% of the patients. These findings are in contrast to those from studies of the combination of cetuximab with irinotecan-containing regimens, in which 19% of the patients developed hypersensitivity reactions, most likely because panitumumab is a humanized antibody and cetuximab is not. The phase 3 study PRIME evaluated the combination of panitumumab with FOLFOX-4 versus FOLFOX-4 alone as a first-line treatment of metastatic CRC; the combination therapy significantly improved progression-free survival time, compared with that of FOLFOX-4 alone, in patients with wild-type K-Ras (9.6 vs 8.0 months, respectively; P = .023).32Douillard J. Siena S. Cassidy J. et al.Randomized phase 3 study of panitumumab with FOLFOX-4 compared to FOLFOX-4 alone as 1st-line treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial (abstr 10LBA).Eur J Cancer Suppl. 2009; 7: 6Crossref Google Scholar The effects of a combination of panitumumab with FOLFIRI in second-line treatment of metastatic CRC is under investigation in the 20050181 study (Table 2).33Peeters M, Wilson G, Hotko Y, et al. Phase III study (20050181) of panitumumab with FOLFIRI compared to FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer (mCRC): preliminary safety results (abstr 335). Abstract presented at: ASCO Gastrointestinal Cancers Symposium; Orlando, FL; January 25–27, 2008.Google ScholarTable 2Effect of Panitumumab in Phase 2 and 3 Studies of Patients With Metastatic CRCStudyPhaseDrugPatients (n)Overall response, % (median duration of response, mo)Median time to progression (mo)Median overall survival (mo)Hecht et al,29Hecht J.R. Patnaik A. Berlin J. et al.Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer.Cancer. 2007; 110: 980-988Crossref PubMed Scopus (191) Google Scholar 20072Panitumumab148; refractory to fluoropyrimidine and irinotecan or oxaliplatin9 (5.2)2.58.6Van Cutsem et al,30Van Cutsem E. Peeters M. Siena S. et al.Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.J Clin Oncol. 2007; 25: 1658-1664Crossref PubMed Scopus (1775) Google Scholar 20073Panitumumab + BSC463; refractory to 5-FU, irinotecan, and ox
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