Panitumumab: in the treatment of metastatic colorectal cancer

Panitumumab is a fully human immunoglobulin G2 monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is overexpressed in 25-77% of colorectal cancers. This overexpression is frequently associated with a poor prognosis. In a large, randomised, nonblind, multicentre phase III study in pretreated adult patients with metastatic colorectal cancer and EGFR staining in >or=1% tumour cells, panitumumab 6 mg/kg every 2 weeks plus best supportive care (BSC) was significantly (p < 0.0001) more effective in improving progression-free survival than BSC alone; recipients of panitumumab plus BSC had a 46% lower disease progression rate than those receiving BSC alone after a median follow-up of 19 weeks. Panitumumab 6 mg/kg every 2 weeks or 2.5 mg/kg/week, administered as monotherapy, produced partial response rates of 8-13% and stable disease rates of 21-30% in pretreated patients with metastatic colorectal cancer in three noncomparative, multicentre phase II studies. Preliminary phase II results also suggest a potential role for panitumumab as first-line therapy in combination with fluorouracil, folinic acid and irinotecan in patients with metastatic colorectal cancer. Panitumumab was generally well tolerated. Grade 3/4 skin-related toxicities were reported in 14% of patients receiving panitumumab plus BSC in the phase III study (versus 0% of patients receiving BSC alone). An analysis of pooled data found that high-affinity binding antibodies to panitumumab were detected in <1% of patients.     

Panitumumab

Panitumumab, previously known as ABX-EGF, is the first fully human monoclonal antibody to be shown to be effective as a treatment for solid-tumor cancers. Its target is the epidermal growth factor receptor (EGFR), which when overactive may contribute to the development and progression of cancer and is expressed in several solid tumors, including colorectal cancer. In a recently reported phase III trial, patients with metastatic colorectal cancer who had failed previous treatment with oxaliplatin- and irinotecan-based therapy were randomized to receive single-agent panitumumab and best-supportive care, or best-supportive care alone. This trial demonstrated a significant improvement in progression-free survival with panitumumab treatment in these patients. A rash similar to that which occurs with the other anti-EGFR antibody, cetuximab, has been observed in up to 100% of patients treated with panitumumab in the various clinical trials. As with other EGFR antagonists, EGFR staining by immunohistochemistry has not been shown to be an effective method of selecting patients for treatment, whereas the severity of the rash appears to be predictive of outcome. Ongoing randomized trials are evaluating the use of panitumumab with combination treatment for the first-line treatment of metastatic colorectal cancer. This review summarizes the rationale for targeting the EGFR and the development of panitumumab in preclinical and early phase trials in several tumor types. Clinical trial results in colorectal cancer, in which the development of this agent is most advanced, will also be discussed, as will the rash associated with treatment.     

Panitumumab: the evidence of its therapeutic potential in metastatic colorectal cancer care

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.     

Review article: panitumumab - a fully human anti-EGFR monoclonal antibody for treatment of metastatic colorectal cancer

Background  Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).
Aim  To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).
Methods  Available literature identified from PubMed and conference websites was reviewed.
Results  In phase 2–3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8–13% in relapsed/refractory EGFR-expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44–0.66; P  <   0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab – and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild-type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti-panitumumab antibodies (0.3% by ELISA) and grade 3–4 infusion reactions (<1%) are rare.
Conclusion  Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR-expressing mCRC harbouring wild-type KRAS .     

Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is indicated for use as monotherapy in the treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression with standard chemotherapy. The currently indicated dose is 6 mg/kg given every 2 weeks. Panitumumab is mainly distributed into the vascular space and exhibits nonlinear pharmacokinetics that are consistent with target-mediated drug disposition, involving saturable binding to EGFR and subsequent internalization and degradation inside the cells. Panitumumab is also cleared in a linear fashion by the reticuloendothelial system, similarly to other endogenous immunoglobulins. After single-dose administration of panitumumab as a 1-hour intravenous infusion, the area under the serum concentration-time curve increases in a greater-than-dose-proportional manner as the dose increases from 0.75 to 5 mg/kg; however, at doses above 2 mg/kg, the exposure to panitumumab increases in a dose-proportional manner. Panitumumab pharmacokinetics are not meaningfully affected by the tumour type, EGFR membrane expression, tumour KRAS mutation, sex, age, race or renal or hepatic dysfunction. In addition, irinotecan-containing and paclitaxel/carboplatin-containing chemotherapeutic regimens do not appear to affect panitumumab pharmacokinetics. The results of population pharmacokinetic analyses have shown that bodyweight is the most influential covariate on panitumumab exposure, supporting the current use of bodyweight-adjusted doses (mg/kg). The relationship between the weekly dose of panitumumab and skin rash, an on-target pharmacodynamic effect of EGFR inhibition, reaches a plateau at 2.5 mg/kg, indicating that this is the optimal weekly dose. Two less-frequent dosing regimens (6 mg/kg given every 2 weeks and 9 mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achieved by 2.5 mg/kg given every week, ensuring maximal EGFR coverage. Anti-panitumumab antibody production is uncommon and does not appear to have an impact on the pharmacokinetics of panitumumab.     

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-na?ve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.     

Panitumumab

In December 2007 the European Medicines Agency (EMEA) approved panitumumab (Vectibix) for the treatment of metastatic colorectal cancer. Panitumumab has a conditional approval as monotherapy for the treatment of patients with EGFR-expressing tumours with non-mutated (wild-type) K-ras genes after failure of standard chemotherapy regimens. This specific subgroup of patients showed a more favourable outcome in a controlled, open-label, randomized phase III study. Patients treated with panitumumab plus best supportive care had a significantly prolonged progression-free survival compared to patients receiving best supportive care alone.     

Preparation of clinical‐grade 89Zr‐panitumumab as a positron emission tomography biomarker for evaluating epidermal growth factor receptor‐targeted therapy

Panitumumab is a fully human monoclonal antibody approved for the treatment of epidermal growth factor receptor (EGFR) positive colorectal cancer. Recently, panitumumab has been radiolabeled with ⁸⁹Zr and evaluated for its potential to be used as immuno‐positron emission tomography (PET) probe for EGFR positive cancers. Interesting preclinical results published by several groups of researchers have prompted us to develop a robust procedure for producing clinical‐grade ⁸⁹Zr‐panitumumab as an immuno‐PET probe to evaluate EGFR‐targeted therapy. In this process, clinical‐grade panitumumab is bio‐conjugated with desferrioxamine chelate and subsequently radiolabeled with ⁸⁹Zr resulting in high radiochemical yield (>70%, n = 3) and purity (>98%, n = 3). All quality control (QC) tests were performed according to United States Pharmacopeia specifications. QC tests showed that ⁸⁹Zr‐panitumumab met all specifications for human injection. Herein, we describe a step‐by‐step method for the facile synthesis and QC tests of ⁸⁹Zr‐panitumumab for medical use. The entire process of bioconjugation, radiolabeling, and all QC tests will take about 5 h. Because the synthesis is fully manual, two rapid, in‐process QC tests have been introduced to make the procedure robust and error free. Copyright © 2013 John Wiley & Sons, Ltd.     

Vandetanib: An overview of its clinical development in NSCLC and other tumors

Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis. Phase I studies indicated that the recommended dose of vandetanib as a single agent is 300 mg/day. Rash, diarrhea, hypertension and asymptomatic Q-Tc prolongation were the most common adverse events. Four randomized phase III clinical trials evaluated the efficacy of vandetanib in non-small cell lung cancer (NSCLC) in combination with docetaxel (ZODIAC), pemetrexed (ZEAL) or as a single agent (ZEST and ZEPHYR). Only the ZODIAC trial met its primary endpoint (progression-free survival [PFS]), while no study showed an advantage in overall survival with vandetanib. No significant antitumor activity has been observed in small cell lung cancer, advanced ovarian, colorectal, breast, prostate cancer and multiple myeloma. In advanced metastatic medullary thyroid cancer, one randomized phase III clinical trial has demonstrated that vandetanib can significantly improve response rate, PFS and time to worsening of pain. Several key questions remain to be addressed regarding the identification of clinical or molecular biomarkers predictive of response, the choice of the optimal dose or schedule of vandetanib and the safety of long-term administration. The results of ongoing trials in untreated patients with advanced NSCLC and other tumors should better define the optimal clinical application of vandetanib.     

Novel modalities in the treatment of patients with KRAS-mutated colorectal cancer

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene are a well-described mechanism of resistance to monoclonal antibodies that target the epidermal growth factor receptor in patients with metastatic and nonoperable colorectal cancer. Treatment options in this population are limited to conventional chemotherapy regimens and antiangiogenesis compounds. Numerous strategies have been proposed in preclinical models as being effective in the presence of KRAS mutations. As basic and translational research further unravels the complex interactions and regulation points in the pathways downstream of epidermal growth factor receptor, more drugs become available for clinical testing. Indeed, there are many ongoing clinical trials that focus on the safety and efficacy of novel compounds in patients with KRAS-mutated colorectal cancer. This is a review of the literature with regard to the rationale of various approaches on this topic and also a summary of the current active clinical trials limited to patients with KRAS-mutated colorectal cancer.     

Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer

Lapatinib is an oral dual tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), both frequently overexpressed in human cancer. Preclinical data have shown that lapatinib is a potent and selective inhibitor of the tyrosine kinase domain of EGFR and HER2, and tumor cells that overexpress these receptors are growth inhibited by lapatinib both in vitro and in vivo. Phase I clinical trials have shown that lapatinib is well tolerated, with mild diarrhea and rash the most frequent toxicities, and early evidence of clinical efficacy has been reported especially in HER2-positive breast cancer. Phase II studies have shown activity for lapatinib in trastuzumab-refractory breast cancer either alone or in combination with trastuzumab. When used as first-line monotherapy for advanced breast cancer, objective tumor responses have been seen in 28% of patients with untreated HER2-positive advanced breast cancer. An extensive phase III program in advanced breast cancer is now in progress both for refractory disease and as first-line therapy in combination with chemotherapy with and without trastuzumab, and with endocrine therapy. Phase II studies have also been conducted in a variety of other tumors, including renal cell cancer. Parallel biomarker studies are starting to elucidate predictive molecular phenotypes that may indicate likelihood of response to lapatinib, and these may direct future trials with this oral tyrosine kinase inhibitor.     

HER2-positive breast cancer: current and future treatment strategies

In the year 2006, breast cancer was estimated to affect >200,000 American women and cause nearly 56,000 deaths. Furthermore, breast cancer is the most common cancer diagnosed and second most common cause of cancer-related deaths in women. The current treatment armamentarium for breast cancer includes chemotherapy, endocrine therapy and biological therapy. Treatment has become more individualised based on characteristics of the tumour including overexpression of the human epidermal growth factor receptor (HER)-2. Between 20 and 30% of all breast cancers overexpress HER2, which means 40,000 - 60,000 patients will have this type of cancer.Previously, overexpression of HER2 was a negative prognostic and predictive risk factor for survival; however, with the advent of trastuzumab, patients' prognosis is improving in all treatment settings. Much controversy exists in the use of trastuzumab, including (i) the sequence of adjuvant trastuzumab (concurrent with chemotherapy or sequential); (ii) the treatment duration (<1 year, 1 year or 2 years); and (iii) the treatment choice upon disease progression (whether to continue or not with trastuzumab and add another cytotoxic agent). Current trials are ongoing to help answer these questions.Furthermore, there has been interest in predicting which HER2-positive patients would require anthracycline therapy, and which could avoid anthracycline therapy and its toxicities. Novel therapeutics, such as lapatinib, an oral tyrosine kinase inhibitor, which blocks both the epidermal growth factor receptor and HER2 receptor has recently been approved by the US FDA. Whereas pertuzumab, a humanised monoclonal antibody, directed against heterodimerisation of HER2 and HER3 has entered phase II and III clinical trials.     

Targeted therapy for colorectal cancer

There has been a revolution in the treatment of colorectal cancer over the last decade. Part of this revolution has been the discovery of agents that target particular aspects of cancer, namely vascular endothelial growth factor and epidermal growth factor receptor. Novel targeted agents have been evaluated in clinical trials and have demonstrated significant anticancer activity. Furthermore, a number of these compounds have been approved for clinical use. Data supporting the use of targeted agents in the treatment of colorectal cancer are reviewed, and the "future for potential novel agents and pathways are discussed.     

Rationale and clinical validation of epidermal growth factor receptor as a target in the treatment of head and neck cancer

Recurrent/metastatic head and neck cancer is an area of high, unmet treatment need. There is a strong rationale for targeting the epidermal growth factor receptor (EGFR) in head and neck cancer as most of these tumors express high levels of EGFR relative to normal tissue, with high expression correlating with poor patient outcome. This rationale has been validated in extensive preclinical studies. Two small molecules with EGFR inhibitory activity, gefitinib ('Iressa', ZD1839) and erlotinib ('Tarceva', OSI-774), and a humanized monoclonal antibody against the EGFR extracellular domain, cetuximab ('Erbitux', C225), are in clinical trials for advanced head and neck cancer. The initial results of these trials are promising. Gefitinib and erlotinib show activity as monotherapy in patients with recurrent or metastatic head and neck cancer, and have an acceptable safety profile compared with conventional chemotherapy. Gefitinib, which can be given at doses below the maximum tolerated dose, is associated with slightly lower rates of adverse events than erlotinib, which is dosed at the maximum tolerated dose. Combinations of cetuximab with radiotherapy or platinum-based chemotherapy have also shown activity in phase I/II studies. Both gefitinib and cetuximab have entered phase III studies. The results of these trials, which will mature over the next few years, will help determine the optimal use of EGFR agents in head and neck cancers.     

Lack of usefulness of epidermal growth factor receptor expression determination for cetuximab therapy in patients with colorectal cancer

In patients with metastatic colorectal cancer, the use of cetuximab currently requires a documented tumoral epidermal growth factor receptor positivity. Responses to cetuximab, however, have been described in patients with epidermal growth factor receptor-negative tumors. We have used cetuximab in all eligible patients with metastatic colorectal cancer, whether their tumor expressed epidermal growth factor receptor or not. We assessed the cetuximab efficacy with regard to tumoral epidermal growth factor receptor expression. Twenty patients with metastatic colorectal cancer were treated off study with cetuximab and irinotecan after failure of oxaliplatin- and irinotecan-based regimens. Tumors were analyzed in all patients for epidermal growth factor receptor expression by immunohistochemistry. Tumors were positive for epidermal growth factor receptor in 12 cases and negative in eight cases. An objective response to cetuximab-based therapy was obtained in four patients (20%). Tumors of these four patients were negative for epidermal growth factor receptor expression. These results provide further evidence for the lack of usefulness of epidermal growth factor receptor detection by immunohistochemistry for cetuximab therapy in patients with metastatic colorectal cancer.     

A review of oxaliplatin and its clinical use in colorectal cancer

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, ～ 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.     

Targeted therapy in colorectal cancer: current status and future challenges

Treatment of metastatic colorectal cancer (mCRC) has progressed significantly over the last years, particularly with the introduction of targeted therapies. Two groups of agents targeting either the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor (VEGF) have been integrated into clinical practice. Currently available agents with established role include the anti-EGFR monoclonal antibodies (mAbs) cetuximab / panitumumab and the anti-VEGF mAb bevacizumab. This review presents an update on the clinical studies evaluating the role of anti-EGFR and anti-VEGF agents in mCRC. Moreover, we provide current data regarding the mechanism of action and pathways mediating resistance to these agents. In addition, we present recent data with respect to biomarkers and we discuss future therapeutic strategies.     

Advanced therapies on BRAF-mutated and KRAS-mutated metastatic colorectal cancer

Colorectal cancer(CRC) is one of the most-diagnosed cancer worldwide, and 30% of patients with CRC have showed a metastatic situation. Monoclonal antibodies(mAbs) that target vascular endothelial growth factor(VEGF) and the epidermal growth factor receptor(EGFR) can achieveantitumor efficacy via antivascular and anticellular effects respectively and have been added into first-line chemotherapy for patients with metastatic colorectal cancer(mCRC). Investigations found that unlike VEGF inhibitors, the efficacy of EGFR inhibitors,such as Cetuximab and panitumumab, is limited to patients with wild-type-KRAS tumors without BRAF mutant. Studies revealed that resistance to EGFR inhibitors result in the poor response to anti-EGFR therapiesthrough acquired mutations of KRAS and BRAF.Considering this situation, in this review, we will focus onresistance mechanism to anti-EGFR therapies and advanced therapies for BRAF-mutated and KRAS-mutated mCRC patients.     

Clinical outcomes with erlotinib in patients with epidermal growth factor receptor mutation

The epidermal growth factor receptor (EGFR) mutation is the first recognized molecular target in non-small cell lung cancer that makes personalized therapy feasible. This molecular alteration has been demonstrated to be more frequent in Asians, non-smokers and patients with adenocarcinoma histology. Several retrospective and subgroup analyses of phase III trials have shown the single agent, erlotinib, to be associated with higher response rates and longer progression-free survival in patients harbouring an EGFR mutation. Two prospective randomized phase III studies from China and Europe have confirmed the role of first-line erlotinib in patients with the mutations. Erlotinib has also been evaluated in combination with chemotherapy in either a concurrent or intercalated regimen. Earlier trials were limited by little information on the EGFR mutational status of the enrolled patients, and an ongoing phase III trial with translational biomarker analysis will provide more comprehensive data on the combination.     

A review of oxaliplatin and its clinical use in colorectal cancer

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, approximately 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.