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1.  Panitumumab: the evidence for its use in the treatment of metastatic colorectal cancer 
Core Evidence  2010;5:61-76.
Panitumumab is the first fully human monoclonal antibody to Epidermal Growth Factor Receptor (EGFR) to enter clinical trials for the treatment of solid tumors. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal (CRC). Preclinical and clinical studies have established a role for panitumumab in metastatic colorectal cancer (mCRC) refractory to multiple chemotherapeutic regimens. Based on these encouraging findings, panitumumab was approved by the US Food and Drug Administration for the treatment of patients with epidermal growth factor receptor-expressing mCRC refractory to fluoropyrimidine-, oxaliplatin-, and/or irinotecan-containing chemotherapeutic regimens. The improvement in progression free survival (PFS) and response rate (RR) produced by panitumumab monotherapy was significantly greater in patients with non mutated (wild-type) K-RAS than in those with mutant K-RAS. Therefore implementing routine K-RAS screening and limiting the use of EGFR inhibitors to patients with wild-type K-RAS appears the better strategy for select only the patients who could benefit from the therapy with panitumumab and also may have the potential for cost savings. The purpose of this review was to evaluate the patient-related, disease-related and economic-related evidence for the use of panitumumab in the treatment of metastatic colorectal cancer in clinical practice.
PMCID: PMC2963923  PMID: 21042543
colorectal cancer; EGFR; K-RAS; panitumumab
2.  No Survival Benefit from Adding Cetuximab or Panitumumab to Oxaliplatin-Based Chemotherapy in the First-Line Treatment of Metastatic Colorectal Cancer in KRAS Wild Type Patients: A Meta-Analysis 
PLoS ONE  2012;7(11):e50925.
Background
The efficacy of combined therapies of oxaliplatin-based chemotherapy and anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (MAbs) remains controversial in colorectal cancer (CRC). The aim of this study is to estimate the efficacy and safety of adding cetuximab or panitumumab to oxaliplatin-based chemotherapy in the first line treatment in KRAS wild type patients with metastatic colorectal cancer (mCRC) through meta-analysis.
Methods
Medline, EMBASE, and Cochrane library, American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) were searched. Eligible studies were randomized controlled trials (RCTs) which evaluated oxaliplatin-based chemotherapy with or without anti-EGFR drugs (cetuximab or panitumumab) in untreated KRAS wild type patients with mCRC. The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities. Hazard ratios (HR) and risk ratio (RR) were used for the meta-analysis and were expressed with 95% confidence intervals.
Results
This meta-analysis included four RCTs with 1270 patients, and all of the patients were administered oxaliplatin-based chemotherapy regimens with or without anti-EGFR MAbs. The result of heterogeneity of OS was not significant. Compared with chemotherapy alone, the addition of cetuximab or panitumumab didn’t result in significant improvement in OS (HR = 1.00, 95%CI [0.88, 1.13], P = 0.95) or PFS (HR = 0.86, 95%CI [0.71, 1.04], P = 0.13). The subgroup analysis of cetuximab also revealed no significant benefit in OS (HR = 1.02, 95%CI [0.89, 1.18], P = 0.75) or in PFS (HR = 0.87, 95%CI [0.65, 1.17], P = 0.36). Patients who received combined therapy didn’t have a higher ORR (Risk Ratio = 1.08, 95%CI [0.86, 1.36]). Toxicities slightly increased in anti-EGFR drugs group.
Conclusions
The addition of cetuximab or panitumumab to oxaliplatin-based chemotherapy in first-line treatment of mCRC in wild type KRAS population did not improve efficacy in survival benefit and response rate. More RCTs are warranted to evaluate the combination of chemotherapy and targeted therapy.
doi:10.1371/journal.pone.0050925
PMCID: PMC3511401  PMID: 23226426
3.  Vascular Endothelial Growth Factor plus Epidermal Growth Factor Receptor Dual Targeted Therapy in Metastatic Colorectal Cancer: Synergy or Antagonism? 
Journal of Oncology  2009;2009:937305.
There has been an intensive effort to develop novel therapies for the treatment of metastatic colorectal cancer (mCRC). The anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab have demonstrated clinical efficacy and acceptable toxicity in the treatment of mCRC as single agents or in combination with chemotherapy. Recent clinical trials have explored the efficacy and safety of treatment regimens incorporating chemotherapy in combination with bevacizumab and either panitumumab or cetuximab in patients with mCRC. Results from the BOND-2 trial, which investigated cetuximab, bevacizumab, and chemotherapy in mCRC, provided support for this therapeutic approach. Two large randomized phase 3 trials were initiated to evaluate firstline treatment of mCRC. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study investigated the efficacy and safety of oxaliplatin- or irinotecan-based chemotherapy and bevacizumab with or without panitumumab; CAIRO2 assessed the efficacy and safety of capecitabine/oxaliplatin and bevacizumab with or without cetuximab. In both trials, the combination of bevacizumab, an EGFR-specific antibody, and chemotherapy in first-line treatment of mCRC was associated with increased toxicity and no improvement in patient outcome. These results suggest that these specific combinations should not be used in first-line mCRC outside investigational studies.
doi:10.1155/2009/937305
PMCID: PMC2792961  PMID: 20016807
4.  Efficacy of the monoclonal antibody EGFR inhibitors for the treatment of metastatic colorectal cancer 
Current Oncology  2010;17(Suppl 1):S3-S17.
Two anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) have been approved in Canada for the treatment of metastatic colorectal cancer (mCRC) – cetuximab, a mouse-human chimeric MoAb, and panitumumab, a fully human MoAb. This paper reviews the efficacy of the anti-EGFR monoclonal antibodies cetuximab and panitumumab – both as monotherapy and in combination with cytotoxic chemotherapy – in the treatment of mCRC. Both cetuximab and panitumumab have demonstrated clinical efficacy in monotherapy in patients with mCRC, an advantage that has recently been found to be limited largely to those with wild-type KRAS tumors. Advantages of using these agents in monotherapy include reduced cost and toxicity. While the addition of cetuximab to irinotecan has shown superior progression-free survival and response compared with cetuximab monotherapy, there is currently no evidence for a benefit of panitumumab in combination with irinotecan.
PMCID: PMC2901794  PMID: 20680105
BRAF; KRAS; EGFR; colorectal carcinoma; cetuximab; panitumumab
5.  Randomized Phase 3 Study of Panitumumab With FOLFIRI vs. FOLFIRI Alone as Second-Line Treatment in Patients With Metastatic Colorectal Cancer 
Background:
Panitumumab is a fully human anti-epidermal growth factor receptor monoclonal antibody approved as monotherapy for patients with metastatic colorectal cancer. The 181 study was designed to evaluate the efficacy and safety of panitumumab with FOLFIRI vs. FOLFIRI alone as second-line treatment for metastatic colorectal cancer according to tumor KRAS mutational status.
Methods:
This was a randomized, multicenter, phase 3 study. Patients were randomized 1:1 to receive panitumumab 6.0 mg/kg Q2W+FOLFIRI vs. FOLFIRI alone. Patients had metastatic adenocarcinoma of the colon or rectum; only 1 previous chemotherapy regimen for mCRC; ECOG 0-2 and available tumor tissue for biomarker testing. Randomization was stratified by ECOG 0-1 vs. 2, previous oxaliplatin, and previous bevacizumab exposure. The co-primary end points were progression-free survival and overall survival and were independently tested. Originally designed to compare the treatment effect in the all-randomized population, the study was amended to focus on hypothesis testing in the wild-type KRAS subset. KRAS status was determined by a blinded central laboratory using allele-specific PCR prior to the first efficacy analysis.
Results:
From June 2006 to March 2008, a total of 1,186 patients were randomized, signed informed consent, and received treatment. Overall demographics included 61% men, median (range) age 61 years (28–86), 48% ECOG 0, 45% ECOG 1. 1083/1186 pts (91%) had available tumor sample results for KRAS: 597 (55%) wild-type, 486 (45%) mutant. Preliminarily, across both arms, the most common grade 3 or 4 adverse events were neutropenia (19%), diarrhea (12%), rash (8%), fatigue (6%), and dermatitis acneiform (4%).
Conclusions:
Efficacy and safety data will be presented by KRAS status and treatment arm.
PMCID: PMC3047039
6.  Epidermal growth factor receptor and metastatic colorectal cancer: Insights into target therapies 
Colorectal cancer (CRC) has high incidence and mortality worldwide. In 2012, CRC was the second most prevalent cancer among males (9%) and the third among females (8%). In recent decades, standard chemotherapies protocols combining 5-fluorouracil, leucovorin, irinotecan and oxaliplatin were important for improve survival in this set of patients. Further, biological drugs throughout epidermal growth factor receptor (EGFR) pathways showed interesting results in metastatic disease (mCRC) control when in association to standard chemotherapy regimens. Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phase III trials. This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard.
doi:10.3748/wjg.v19.i38.6315
PMCID: PMC3801301  PMID: 24151349
Colorectal cancer; Epidermal growth factor receptor; KRAS mutation; Chemotherapy; Cetuximab; Panitumumab
7.  Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment 
British Journal of Cancer  2011;105(10):1495-1502.
Background:
Panitumumab in combination with chemotherapy was evaluated in two pivotal clinical trials in first- and second-line treatment of metastatic colorectal cancer (mCRC), respectively. This analysis compared the health-related quality of life (HRQoL) of patients with or without panitumumab in the two trials.
Methods:
Patients with mCRC were randomised to FOLFOX (first-line trial) or FOLFIRI (second-line trial)±panitumumab. The EuroQoL 5-Dimensions Health State Index (EQ-5D HSI) and Visual Analogue Scale (EQ-5D VAS) were assessed at baseline and monthly follow-up until disease progression. Patients with wild-type KRAS mCRC with baseline and post-baseline HRQoL scores were included. Difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models.
Results:
In the first-line trial, 576 patients with wild-type KRAS mCRC (284 panitumumab+FOLFOX4 and 292 FOLFOX4 alone) were included in the HRQoL analyses. In the second-line trial, 530 patients with wild-type KRAS mCRC were included in these analyses (263 panitumumab+FOLFIRI and 267 FOLFIRI alone). There was no significant difference in the change in EQ-5D HSI and VAS scores between treatment groups in either trial.
Conclusion:
The addition of panitumumab to FOLFOX4 or FOLFIRI in first- or second-line treatment of wild-type KRAS mCRC significantly improved progression-free survival without compromising HRQoL.
doi:10.1038/bjc.2011.409
PMCID: PMC3242525  PMID: 21989186
colorectal cancer; panitumumab; quality of life
8.  Alternate Dosing of Cetuximab for Patients With Metastatic Colorectal Cancer 
ABSTRACT
BACKGROUND:
Many chemotherapeutic regimens used to treat colorectal cancer (CRC), including 5-fluorouracil plus leucovorin in combination with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX), are administered on an every-other-week (q2w) dosing schedule. Chemotherapy in combination with a monoclonal antibody (mAb) directed toward the epidermal growth factor receptor (EGFR) has emerged as an effective treatment option. There are currently 2 anti-EGFR mAbs approved by the United States Food and Drug Administration: cetuximab and panitumumab. Mutations of KRAS, a downstream protein in the EGFR pathway, predict resistance to EGFR mAbs. Thus, cetuximab and panitumumab are indicated for patients without a KRAS mutation (KRAS wild-type). Whereas panitumumab is approved on a q2w dosing schedule, cetuximab is approved as a weekly dose. However, only cetuximab is approved with FOLFIRI for frontline metastatic CRC, whereas panitumumab is approved for third-line. Because concomitant therapies are often administered q2w, the weekly dosing of cetuximab results in additional medical office visits.
DESIGN:
Several studies have assessed the safety and efficacy of cetuximab q2w. For this review, a comprehensive literature search of studies evaluating cetuximab q2w dosing was conducted. Safety and efficacy results of these trials and retrospective analyses were summarized and reviewed.
RESULTS:
In general, results with cetuximab q2w were comparable to those obtained with the weekly regimen.
CONCLUSION:
These data suggest that for patients for whom weekly treatment with cetuximab presents a substantial burden to their quality of life, q2w dosing of cetuximab is a viable treatment option with a benefit:risk profile similar to that of the weekly regimen.
PMCID: PMC3674463  PMID: 23745159
9.  Panitumumab in the management of patients with KRAS wild-type metastatic colorectal cancer 
The past 15 years has seen a marked increase in available therapeutic options for patients with metastatic colorectal cancer resulting in improvements in median survival from 12 to 24 months. One of these new options is panitumumab, which is a fully humanized monoclonal antibody that binds to the epidermal growth factor receptor of tumor cells and inhibits downstream cell signaling with antitumor effects of inhibition of tumor growth, induction of apoptosis and inhibition of angiogenesis. Large randomized clinical trials have demonstrated significant improvements in tumor response rates and progression-free survival when panitumumab is combined with chemotherapy and as monotherapy in chemorefractory metastatic colorectal cancer. Clinical benefit with panitumumab is limited to patients with nonmutated KRAS tumors. Rash is a common toxicity of panitumumab treatment but can potentially be ameliorated with the use of prophylactic strategies. The role of panitumumab in the overall treatment of metastatic colorectal cancer is evolving and future clinical trials will focus on improved patient selection through use of novel predictive biomarkers, and the optimal timing of treatment.
doi:10.1177/1756283X13498660
PMCID: PMC3871277  PMID: 24381645
colorectal; EGFR; KRAS; panitumumab; review
10.  KRAS G13D Mutation and Sensitivity to Cetuximab or Panitumumab in a Colorectal Cancer Cell Line Model 
ABSTRACT
BACKGROUND:
The treatment of metastatic colorectal cancer (mCRC) includes drugs targeting the epidermal growth factor receptor (EGFR). Mutation in codon 12 or 13 in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, downstream of the EGFR, evokes constitutive activation of the RAS/RAF/MAPK signaling pathway and correlates with resistance to anti-EGFR monoclonal antibody (mAb) therapies. However, a retrospective study reported that a proportion of patients with the KRAS G13D mutation may respond to cetuximab. A similar analysis for panitumumab was not as conclusive. We sought to determine the sensitivity of CRC cell lines to cetuximab or panitumumab treatment and to investigate the correlation of the KRAS mutational status of the CRC cell lines to the responsiveness to cetuximab or panitumumab.
METHODS:
To determine the responsiveness of CRC cell lines to cetuximab or panitumumab, cell lines were treated with an optimized concentration of each mAb, and proliferation assays were conducted.
RESULTS:
After treatment with cetuximab or panitumumab, at the optimum concentration of 8 μg/well, the KRAS G13D mutant cell lines HCT-116, LoVo, and T84 showed intermediate sensitivity to both treatments, between the resistant KRAS G12V mutant cell line SW480 and the sensitive KRAS wild-type cell line LIM1215. One of the G13D cell lines was significantly more sensitive to panitumumab than to cetuximab (P = .02).
CONCLUSION:
The specific KRAS mutation determines the responsiveness to anti-EGFR monoclonal antibody treatment, corresponding to reported clinical observations.
PMCID: PMC3930148  PMID: 24558511
11.  How to select the optimal treatment for first line metastatic colorectal cancer 
Choice of first line treatment for patients with metastatic colorectal cancer (mCRC) is based on tumour and patient related factors and molecular information for determination of individual treatment aim and thus treatment intensity. Recent advances (e.g., extended RAS testing) enable tailored patient assignment to the most beneficial treatment approach. Besides fluoropyrimidines, irinotecan and oxaliplatin, a broad variety of molecular targeting agents are currently available, e.g., anti-angiogenic agents (bevacizumab) and epidermal growth factor receptor (EGFR) antibodies (cetuximab, panitumumab) for first line treatment of mCRC. Although some combinations should be avoided (e.g., oral or bolus fluoropyrimidines, oxaliplatin and EGFR antibodies), treatment options range from single agent to highly effective four-drug regimen. Preliminary data comparing EGFR antibodies and bevacizumab, both with chemotherapy, seem to favour EGFR antibodies in RAS wildtype disease. However, choosing the most appropriate treatment approach for mCRC patients remains a complex issue, with numerous open questions.
doi:10.3748/wjg.v20.i4.899
PMCID: PMC3921543  PMID: 24574764
Colorectal cancer; Metastatic; Induction chemotherapy; Epidermal growth factor receptor
12.  Targeting colorectal cancer with anti-epidermal growth factor receptor antibodies: focus on panitumumab 
OncoTargets and therapy  2009;2:161-170.
The tumor biology targeted therapies have improved outcomes in colorectal cancer (CRC). The epidermal growth factor receptor (EGFR) inhibitors represent one of these successful strategies. EGFR is frequently overexpressed in CRCs and associated with a malignant phenotype. Two EGFR inhibitors have shown efficacy in metastatic CRC, cetuximab and panitumumab. Cetuximab is a human–mouse chimeric monoclonal antibody that binds to the extracellular domain of the EGF-receptor. Similarly, panitumumab is a fully humanized monoclonal IgG2 antibody, directed against EGFR. Being fully humanized, panitumumab does not contain mouse protein reducing the risk of hypersensitivity. In a pivotal clinical trial, panitumumab was well tolerated and effective, demonstrating an objective response rate of 10% vs best supportive care (ORR = 0%; P < 0.0001). Panitumumab was approved for the treatment of mCRC by the FDA in 2006. Studies combining panitumumab with cytotoxic chemotherapy and other targeted therapies have been completed while others are ongoing to further evaluate the clinical utility of this agent. Recently it has been demonstrated that mutations in KRAS predict the efficacy of panitumumab and cetuximab, limiting their use to CRC patients with wild-type KRAS, and moving the clinical field towards personalized cancer care.
PMCID: PMC2886332  PMID: 20616903
colorectal cancer; epidermal growth factor receptor; panitumumab; cetuximab; KRAS
13.  Panitumumab monotherapy compared with cetuximab and irinotecan combination therapy in patients with previously treated KRAS wild-type metastatic colorectal cancer 
Current Oncology  2013;20(6):326-332.
Background
The survival benefit for single-agent anti–epidermal growth factor receptor (egfr) therapy compared with combination therapy with irinotecan in KRAS wildtype (wt) metastatic colorectal cancer (mcrc) patients in the third-line treatment setting is not known. The objective of the present study was to describe the characteristics of, and to compare survival outcomes in, two cohorts of patients treated with either singleagent panitumumab or combination therapy with cetuximab and irinotecan.
Methods
The study enrolled patients with KRAS wt mcrc previously treated with both irinotecan and oxaliplatin who had received either panitumumab or combination cetuximab–irinotecan before April 1, 2011, at the BC Cancer Agency (bcca). Patients were excluded if they had received anti-egfr agents in earlier lines of therapy. Data were prospectively collected, except for performance status (ps), which was determined by chart review. Information about systemic therapy was extracted from the bcca Pharmacy Database.
Results
Of 178 eligible patients, 141 received panitumumab, and 37 received cetuximab–irinotecan. Compared with patients treated with cetuximab–irinotecan, panitumumab-treated patients were significantly older and more likely to have an Eastern Cooperative Oncology Group (ecog) ps of 2 or 3 (27.7% vs. 2.7%, p = 0.001). Other baseline prognostic variables and prior and subsequent therapies were similar. Median overall survival was 7.7 months for the panitumumab group and 8.3 months for the cetuximab–irinotecan group. Multivariate analysis demonstrated that survival outcomes were similar regardless of the therapy selected (hazard ratio: 1.28; p = 0.34). An ecog ps of 2 or 3 compared with 0 or 1 was the only significant prognostic factor in this treatment setting (hazard ratio: 3.37; p < 0.01).
Conclusions
Single-agent panitumumab and cetuximab–irinotecan are both reasonable third-line treatment options, with similar outcomes, for patients with chemoresistant mcrc.
doi:10.3747/co.20.1600
PMCID: PMC3851344  PMID: 24311948
Chemotherapy; multivariate analysis; anti-egfr; survival; panitumumab; irinotecan; cetuximab; mcrc
14.  Randomized Phase 3 Study of Panitumumab With FOLFOX4 Compared to FOLFOX4 Alone as 1st-line Treatment (tx) for Metastatic Colorectal Cancer (mCRC): The PRIME Trial 
Background:
Panitumumab (pmab) is a fully human anti-epidermal growth factor receptor monoclonal antibody approved as monotherapy for patients (pts) with mCRC. The PRIME trial was designed to evaluate the efficacy and safety of pmab with FOLFOX4 vs. FOLFOX4 alone as first-line treatment for mCRC according to tumor KRAS mutational status.
Methods:
This was a randomized, multicenter, phase 3 study. Pts were randomized 1:1 to receive pmab 6.0 mg/kg Q2W+FOLFOX (Arm 1) vs. FOLFOX alone (Arm 2). Pts had metastatic adenocarcinoma of the colon or rectum; no previous chemotherapy for mCRC; no previous oxaliplatin therapy; ECOG 0-2; and available tumor tissue for biomarker testing. Randomization was stratified by ECOG 0-1 vs. 2 and region (Western EU, Canada, and Australia vs. rest of world). The primary end point was progression-free survival (PFS). Originally designed to compare the tx effect in the all-randomized population, the study was formally amended to focus on hypothesis testing in the wild-type (WT) KRAS subset. KRAS status was determined by a blinded central laboratory using allele-specific PCR after the completion of accrual, but prior to the primary analysis.
Results:
From August 2006 to February 2008, a total of 1,183 pts were randomized, signed informed consent, and received tx: 593 Arm 1, 590 Arm 2. Overall demographics included 63% men, median age 62 years (range: 24–85); 55% ECOG 0; 40% ECOG 1; 5% ECOG 2. 1096/1183 pts (93%) had available tumor sample results for KRAS: 656 (60%) WT, 440 (40%) mutant. Preliminarily, across both arms, the most common grade 3 or 4 adverse events were: neutropenia (40%), diarrhea (14%), rash (8%), paresthesia (7%), and hypokalemia (7%).
Conclusions:
Efficacy and safety data will be presented by KRAS status and treatment arm.
PMCID: PMC3047033
15.  Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer 
Fluoropyrimidines, oxaliplatin, irinotecan and biologic therapies (Bevacizumab, Panitumumab, and Cetuximab) represent the backbone of metastatic colorectal cancer (CRC) treatment. The improvement in survival for mCRC patient led to two main outstanding issues: 1) there is a significant number of patients progressing beyond the third or fourth line of treatment still suitable for further therapy when enrollment into clinical trial is not possible. In this situation, the role of any therapy rechallenge (either chemotherapy alone, chemotherapy and biologic therapy or biologic therapy alone) is still not clear, particularly in patients who had previously responded, and if treatment choice is based on traditional dogma of primary and secondary resistance, rechallenge does not seem to be justified. 2) Prolonged intensive treatment is burdened from the high risk of cumulative toxicity, worsening in quality of life and a not well defined possibility of early acquired resistance.
Different hypothesis could justify the research of different strategy in treatment of mCRC:
1) Epigenetic changes might drive resistance and treatment could induce these changes. Re-expression of silenced tumor suppressive genes might resensitize tumors to therapy. It is therefore possible that a drug holiday (intermittent treatment) could allow reversion to a previous epigenetic profile. Moreover an intermittent treatment could delay acquired resistance. 2) It is plausible that tumor grows as a polyclonal mass. If it responds but then becomes resistant to one or more treatments, retreatment might be successful if changing therapies allows to that clone of cells to re-emerge. On these basis, we focused this review on the actual evidences in management of mCRC patients in terms of chemotherapy or biological therapies rechallenge and intermittent treatment. Moreover, we will discuss the potential biological mechanisms of the observed results of early clinical trials.
doi:10.1186/1756-9966-32-92
PMCID: PMC3874688  PMID: 24245912
Colorectal cancer; Drug resistance; Rechallenge therapy; Intermittent treatment
16.  Health-related quality of life and colorectal cancer-specific symptoms in patients with chemotherapy-refractory metastatic disease treated with panitumumab 
Purpose
Panitumumab monotherapy is approved for chemotherapy-refractory wild-type KRAS metastatic colorectal cancer (mCRC). Patient-reported outcomes—although important in the palliative setting—have not been reported in this patient population.
Methods
In a phase 3 trial (n = 463), patients with chemotherapy-refractory mCRC were randomized 1:1 to panitumumab plus best supportive care (BSC) or BSC alone. Patient-reported outcomes were assessed using the NCCN/FACT CRC Symptom Index (FCSI) and EQ-5D Index. KRAS tumor status was analyzed in a prospectively defined, retrospective analysis. Average difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models.
Results
KRAS tumor status and post-baseline patient-reported outcomes were available for 363 patients. Linear mixed models indicated significant differences in the FCSI score (difference in least-squares [LS] adjusted means [95% CI]; 5.62 [2.38, 8.86]) and the EQ-5D Index (difference in LS adjusted means [95% CI]; 0.22 [0.12, 0.32]) favoring panitumumab over BSC in patients with wild-type KRAS mCRC. By pattern-mixture analysis, the advantage of panitumumab over BSC was more pronounced in those patients with wild-type KRAS mCRC who did not drop out of the study early. In patients with mutant KRAS mCRC, no differences were observed between groups.
Conclusions
Panitumumab-treated patients with wild-type KRAS mCRC maintained better control of CRC symptoms and quality of life compared with BSC alone, extending our understanding of the benefits of panitumumab treatment beyond improvements in progression-free survival.
doi:10.1007/s00384-010-1112-5
PMCID: PMC3024508  PMID: 21190026
Panitumumab; KRAS; Colorectal cancer; Symptoms; HRQoL
17.  KRAS mutation testing in the treatment of metastatic colorectal cancer with anti-EGFR therapies 
Current Oncology  2010;17(Suppl 1):S31-S40.
Survival of patients with metastatic CRC (mCRC) has improved steadily over the past several decades, due largely to the development of new combinations of standard chemotherapy, as well as to the introduction of new targeted therapies. Among the available targeted therapies are two monoclonal antibodies that target the epidermal growth factor receptor (EGFR) – cetuximab and panitumumab – which have demonstrated efficacy in the treatment of mCRC. These therapies are associated with a unique set of toxicities and costs, prompting the need for tools to select patients who are most likely to derive a benefit from them. Mutations in the KRAS oncogene have consistently been shown to predict non-response to cetuximab and panitumumab. The role of KRAS as a marker of efficacy of anti-EGFR therapies is reviewed.
PMCID: PMC2901795  PMID: 20680106
KRAS; EGFR; colorectal carcinoma; cetuximab; panitumumab; genetic testing methods
18.  Management of dermatologic toxicities associated with monoclonal antibody epidermal growth factor receptor inhibitors: A case review 
Introduction:
The epidermal growth factor receptor inhibitors (EGFRIs), cetuximab and panitumumab, represent an effective treatment option for patients affected by metastatic colorectal cancer (mCRC); furthermore, they are relatively devoid of systemic toxicities, which are commonly observed with standard cytotoxic chemotherapy. However, the majority of patients treated with these monoclonal antibodies (mAbs), will experience dermatologic toxicities, most notably the papulopustular skin rash, which can impact quality-of-life and affect adherence to therapy. This paper reviews the most recent practices in the management of skin rash related to anti-epidermal growth factor receptor (EGFR) mAbs, cetuximab and panitumumab, in the treatment of mCRC.
Materials and Methods:
We reviewed relevant literature regarding dermatologic toxicities associated with anti-EGFR mAbs in order to give important indications about prevention and reactive treatment of skin rash.
Results:
Two case reports were presented to show how skin rash could hamper mAb EGFRIs use in clinical practice, underscoring the need of implementing a comprehensive management strategy of skin toxicity in order to promote patients’ compliance with anti-EGFR therapy and maintain quality-of-life. Based on randomized data, recent guidelines established by the Multinational Association for Supportive Care in Cancer Skin Toxicity Study Group suggest that prophylactic use of oral doxycycline or minocycline reduces the risk and severity of skin rash, improving clinical outcomes.
Conclusions:
At the start of treatment with cetuximab and panitumumab, the proper patient education about the skin rash associated with these mAbs and the implementation of a pre-emptive, comprehensive skin toxicity program significantly contribute to improve adherence to therapy, optimize anti-EGFR therapy and maintain quality-of-life.
doi:10.4103/0976-500X.120966
PMCID: PMC3853676  PMID: 24347989
Cetuximab; dermatologic toxicity; panitumumab; rash; safety
19.  Consensus recommendations for the use of anti-egfr therapies in metastatic colorectal cancer 
Current Oncology  2010;17(6):39-45.
In January 2010, a panel of Canadian oncologists with particular expertise in colorectal cancer (crc) gathered to develop a consensus guideline on the use of therapies against the epidermal growth factor receptor (egfr) in the management of metastatic crc (mcrc). This paper uses a case-based approach to summarize the consensus recommendations developed during that meeting.
These are the consensus recommendations:
Testing for the KRAS status of the tumour should be performed as soon as an egfr inhibitor is being considered as an option for treatment.Anti-egfr therapies are not recommended for the treatment of patients with tumours showing mutated KRAS status.For a patient with wild-type KRAS and an Eastern Cooperative Oncology Group status of 0–2, whose mcrc has previously been treated with a fluoropyrimidine, irinotecan, and oxaliplatin, switching to an egfr inhibitor is a recommended strategy.Cetuximab, cetuximab plus irinotecan, and panitumumab are all options for third-line therapy in patients with wild-type KRAS, provided that tolerability is acceptable.
PMCID: PMC2993438  PMID: 21151408
Anti-egfr; metastatic colorectal cancer; cetuximab; panitumumab; Canadian consensus
20.  The Evolving Role of Monoclonal Antibodies in Colorectal Cancer: Early Presumptions and Impact on Clinical Trial Development 
The Oncologist  2010;15(1):73-84.
The article examines the role of molecular markers pertaining to the appropriate use of targeted biologic agents in the treatment of metastatic colorectal cancer and discusses cost-effectiveness issues related to these agents.
Targeted biologic agents have an established role in treating metastatic colorectal cancer (mCRC). Bevacizumab, a recombinant monoclonal antibody against the vascular endothelial growth factor ligand is approved by the U.S. Food and Drug Administration (FDA) for bevacizumab-naïve patients. Cetuximab, a chimeric monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) is FDA approved as a single agent, or in combination with irinotecan, in both irinotecan-naïve and refractory patients, and has additional efficacy in combination with oxaliplatin. Panitumumab, a fully human EGFR mAb, is FDA approved as a single agent in refractory patients but has additional efficacy in combination with chemotherapy. After reaching a temporary therapeutic plateau of FDA-approved agents for the treatment of mCRC, pivotal results have developed that critically affect the care for these patients. Correlative data from randomized trials of EGFR inhibitors across disease settings have demonstrated higher response rates, specifically for patients with wild-type K-RAS tumors. The interpretation of the B-RAF mutation and other molecular markers may further define the appropriateness of anti-EGFR therapy. Recent literature revealed that the first-line use of combined anti-EGFR therapy plus bevacizumab resulted in inferior outcomes and additional toxicities. Furthermore, the role of biologic agents for locally advanced colon cancer cannot be advocated at this time. With impending changes in the health care system, the economic impact of mAbs will continue to be scrutinized. Hence, as the significance of molecular markers continues to develop, their role as it pertains to the appropriate use of biologic agents in the treatment of mCRC will continue to evolve.
doi:10.1634/theoncologist.2009-0167
PMCID: PMC3227885  PMID: 20067946
Cetuximab; Bevacizumab; Panitumumab; EGFR; VEGF; Colorectal
21.  Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer 
Current Oncology  2010;17(Suppl 1):S18-S30.
The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, plays an important role in the control of cell growth and differentiation. Disruption of its signaling leads to neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis.
EGFR is overexpressed in a variety of solid tumors, including colorectal cancer (CRC), and its overexpression is associated with poorer prognosis. One class of agents that is currently used to target EGFR in the treatment of metastatic CRC (mCRC) is the monoclonal antibodies. While the monoclonal antibody EGFR inhibitors lack many of the severe side effects commonly observed with cytotoxic chemotherapy, they are associated with a set of unique dermatological toxicities. This paper reviews the safety profile of the anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of mCRC.
PMCID: PMC2901793  PMID: 20680104
epidermal growth factor receptor; skin toxicity; cetuximab; panitumumab
22.  The effect of anti-VEGF drugs (bevacizumab and aflibercept) on the survival of patients with metastatic colorectal cancer (mCRC) 
OncoTargets and therapy  2012;5:59-65.
Significant progression has been achieved in the treatment of metastatic colorectal cancer (mCRC) in recent years. This has been partly attributed to successfully incorporating new drugs into combination chemotherapy. In addition to the traditional cytotoxic chemotherapeutic agents, molecularly targeted agents began to play an important role in the treatment of advanced solid tumors. To date, two classes of molecularly targeted agents have been approved for treatment of patients with mCRC: (1) antivascular endothelial growth factor (anti-VEGF) agents (such as bevacizumab and aflibercept) and (2) antiendothelial cell growth factor receptor (anti-EGFR) agents (such as cetuximab and panitumumab). Aflibercept is a new member of anti-VEGF agents which has demonstrated efficacy for treatment of mCRC. With the commencement of clinical trials and basic research into aflibercept, more data from the bedside and the bench have been obtained. This review will outline the application of anti-VEGF agents by reviewing clinic experiences of bevacizumab and aflibercept, and try to add perspectives on the use of anti-VEGF agents in mCRC.
doi:10.2147/OTT.S29719
PMCID: PMC3345882  PMID: 22570554
chemotherapy; tumors; antiangiogenic
23.  Panitumumab: the evidence of its therapeutic potential in metastatic colorectal cancer care 
Core Evidence  2007;2(2):81-88.
Introduction:
Colorectal cancer is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. Panitumumab (ABX-EGF) is the first fully human monoclonal antibody developed for use in colorectal cancer that targets the extracellular domains of epidermal growth factor receptor.
Aims:
The goal of this article is to review the published evidence for the use of panitumumab in the treatment of metastatic colorectal cancer to define its therapeutic potential.
Evidence review:
The major evidence of panitumumab activity in colorectal cancer has appeared in meeting report abstracts. One phase II study in monotherapy, one in combination with chemotherapy, and one phase III study have included only patients with metastatic colorectal cancer.
Clinical potential:
To date, in phase II clinical studies panitumumab has demonstrated antitumor activity in advanced, refractory colorectal cancer. As monotherapy it resulted in a 10% response rate with 38% of patients having stable disease, and a 36% response rate with 46% stable disease when combined with chemotherapy. A phase III study indicates a clinically significant advantage of panitumumab as third-line monotherapy over best supportive care. Panitumumab appears to have a good tolerability profile, with no maximum tolerated dose yet defined.
PMCID: PMC3012427  PMID: 21221177
ABX-EGF; human monoclonal antibody; metastatic colorectal cancer; panitumumab
24.  Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial 
The Lancet Oncology  2013;14(8):749-759.
Summary
Background
Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer.
Methods
In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks (300 mg/m2 if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876.
Results
Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83–1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64–0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group.
Interpretation
Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents.
Funding
Cancer Research UK, Amgen Inc.
doi:10.1016/S1470-2045(13)70163-3
PMCID: PMC3699713  PMID: 23725851
25.  Medical treatment of advanced colorectal cancer in 2009 
The treatment options currently available in the medical therapy of advanced colorectal cancer (CRC) appear to be an abundance of riches. The integration of oxaliplatin and irinotecan as conventional cytotoxic agents as well as bevacizumab and the epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, as novel targeted agents into standard medical therapy have improved median overall survival in metastatic CRC beyond 2 years. It cannot be overemphasized that these significant improvements in outcome of patients with CRC are closely linked to the number of active drugs available to treat this disease. The abundance of treatment options, however, comes with specific challenges for the practical management of palliative medical therapy in advanced CRC, in particular with regard to the utilization of targeted agents. In this context, bevacizumab has established itself as the standard component of first-line chemotherapy. It is of interest for clinical practice that so far no predictive marker for the activity of bevacizumab in metastatic CRC has been identified. The key questions surrounding the use of bevacizumab in the palliative setting are whether its continuation beyond tumor progression provides clinical benefit, and which patient group is at higher risk for bevacizumab-related toxicities. Cetuximab and panitumumab have demonstrated efficacy both in combination with chemotherapy or – in contrast to bevacizumab – as single agent. In unselected patients, the effect of both EGFR antibodies on time-related parameters, progression free survival and overall survival, is moderate at best with emphasis more on the induction of tumor responses in a select group of patients. Therefore, until recently, EGFR antibodies were mainly regarded as salvage therapy options, in particular, since there did not appear to be a loss of activity when used in later lines of therapy. The finding that CRC harboring KRAS (and BRAF) mutations are resistant to EGFR antibodies, has allowed us to enrich the patient population with CRC that have a chance to benefit from cetuximab or panitumumab therapy. Biomarker-based treatment decisions are therefore now an integral part of clinical practice and trial design in CRC. In conclusion, targeted agents have become an integral part of medical therapy for advanced CRC. The challenge for current oncologic practice is to develop a rationale and biomarker-based treatment algorithm utilizing all potentially active agents as individualized therapy.
doi:10.1177/1758834009343302
PMCID: PMC3125994  PMID: 21789113
colorectal cancer; chemotherapy; targeted agents; liver metastasis; palliative

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