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Annals of Oncology : Official Journal... Jan 2015The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into... (Review)
Review
The tumor antigen (TA)-targeted monoclonal antibodies (mAb) cetuximab and panitumumab target the human epidermal growth factor receptor and have been integrated into treatment regimens for advanced squamous cell carcinoma of the head and neck (SCCHN). The therapeutic efficacy of these mAbs has been found to be enhanced when combined with radiotherapy and chemotherapy. However, clinical trials indicate that these findings are limited to fewer than 20% of treated patients. Therefore, identifying patients who are likely to benefit from these agents is crucial to improving therapeutic strategies. Interestingly, it has been noted that TA-targeted mAbs mediate their effects by contributing to cell-mediated cytotoxicity in addition to inhibition of downstream signaling pathways. Here, we describe the potential immunogenic mechanisms underlying these clinical findings, their role in the varied clinical response and identify the putative biomarkers of antitumor activity. We review potential immunological biomarkers that affect mAb therapy in SCCHN patients, the implications of these findings and how they translate to the clinical scenario, which are critical to improving patient selection and ultimately outcomes for patients undergoing therapy.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Antineoplastic Agents; Biomarkers; Carcinoma, Squamous Cell; Cetuximab; Combined Modality Therapy; ErbB Receptors; Head and Neck Neoplasms; Histocompatibility Antigens Class I; Humans; Macrophages; Panitumumab; Papillomavirus Infections; Receptors, IgG; STAT3 Transcription Factor; Squamous Cell Carcinoma of Head and Neck; T-Lymphocytes, Regulatory; Tumor Escape
PubMed: 24997207
DOI: 10.1093/annonc/mdu156 -
Toxicologic Pathology Jan 2014The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer (CRC) are leading to the... (Review)
Review
The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer (CRC) are leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing CRCs for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of CRC and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers).
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Humans; Panitumumab; Prognosis; Proto-Oncogene Proteins; Signal Transduction
PubMed: 24178577
DOI: 10.1177/0192623313505155 -
Theranostics 2018To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. We conducted two phase I trials for anti-epidermal growth factor...
To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m, cohort 2 received 25 mg/m, and cohort 3 received 62.5 mg/m. For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab-IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data.
Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Benzenesulfonates; Cetuximab; ErbB Receptors; Female; Fluorescence; Fluorescent Antibody Technique; Head and Neck Neoplasms; Humans; Indoles; Male; Middle Aged; Panitumumab
PubMed: 29721094
DOI: 10.7150/thno.24487 -
Health Technology Assessment... Jun 2017Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit... (Review)
Review
The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation.
BACKGROUND
Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix, Amgen UK Ltd, Cambridge, UK).
OBJECTIVE
To investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma () wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer.
DATA SOURCES
The assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library.
REVIEW METHODS
Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer with WT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed.
RESULTS
The searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results for WT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are WT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for WT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates.
LIMITATIONS
The trials included WT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks.
CONCLUSIONS
Although cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial for WT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients with WT.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42015016111.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Humans; Male; Neoplasm Metastasis; Panitumumab; Technology Assessment, Biomedical; Treatment Outcome
PubMed: 28682222
DOI: 10.3310/hta21380 -
Biomedicine & Pharmacotherapy =... Apr 2023The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative....
The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative. Radiotherapy with pain palliation can temporize bone metastases but is generally considered a short-term solution and retreatment is difficult. Surgery is often necessary, yet recovery times might exceed life expectancy. Therefore, there is a need to develop new approaches to bone metastases that are effective but minimally invasive. Near-infrared photoimmunotherapy (NIR-PIT) uses antibodies labeled with IRDye700DX (IR700) which is activated by NIR light, resulting in rapid cell membrane damage and immunogenic cell death. NIR-PIT using an anti-epidermal growth factor receptor (EGFR) antibody-IR700 conjugate in patients with recurrent head and neck cancer received qualified approval in Japan in 2020 and is now widely used there. However, no bone metastases have yet been treated. In this study, the efficacy of NIR-PIT for bone metastases was investigated using a bone metastases mouse model successfully established by caudal artery injection of a human triple-negative breast cancer cell line, MDAMB468-GFP/luc. The bone metastatic lesions were treated with NIR-PIT using the anti-EGFR antibody, panitumumab-IR700 conjugate. Bioluminescence imaging and histological evaluation showed that EGFR-targeted NIR-PIT has a therapeutic effect on bone metastatic lesions in mice. In addition, micro-CT showed that repeated NIR-PIT led to repair of metastasis-induced bone destruction and restored bone cortex continuity consistent with healing. These data suggest that NIR-PIT has the potential for clinical application in the treatment of bone metastases.
Topics: Humans; Animals; Mice; Photosensitizing Agents; Cell Line, Tumor; Phototherapy; Immunotherapy; Panitumumab; Bone Neoplasms; Xenograft Model Antitumor Assays
PubMed: 36791566
DOI: 10.1016/j.biopha.2023.114390 -
Medicine Dec 2016Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor, is used in combination with chemotherapy for patients with metastatic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Panitumumab, a fully human monoclonal antibody targeting epidermal growth factor receptor, is used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the effects of panitumumab in combination with irrinotecan-based chemotherapy remain uncertain. Therefore, we conducted this meta-analysis to assess the efficacy and safety of combination treatment of panitumumab plus chemotherapy in the treatment of mCRC.
METHODS
By searching electronic databases (PubMed, Embase, and Web of Science), all clinical trials which assessed the effects of panitumumab plus irrinotecan-based chemotherapy in mCRC would be included. Main outcome measures included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and adverse events. Pooled estimates were calculated by a fixed-effects model or random-effects model, according to the heterogeneity among the included studies.
RESULTS
Eleven trials with a total number of 1338 patients met the inclusion criteria and were included in this meta-analysis. The combination treatment of panitumumab and irrinotecan-based chemotherapy was associated with a median PFS of 5.83 months, OS of 11.15 months, and ORR of 33%. Subgroup analysis showed that, in the first-line and second-line treatment, the combination therapy for PFS was 9.27 and 5.01 months, for OS was 8.87 and 11.68 months, and for ORR was 61% and 26%, respectively. In the wild-type and mutant KRAS populations, the combination therapy for PFS was 5.76 and 5.27 months, for OS was 11.15 and 10.64 months, and for ORR was 37% and 18%, respectively. Moreover, combination therapy also induced an incidence of 56% treatment-related adverse events.
CONCLUSION
Panitumumab plus irrinotecan-based chemotherapy is effective and well-tolerated in the treatment of patients with mCRC, especially in those with wild-type KRAS tumors.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Irinotecan; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Panitumumab; Prognosis; Survival Rate; Treatment Outcome
PubMed: 27977573
DOI: 10.1097/MD.0000000000005284 -
Cell Communication and Signaling : CCS Sep 2022Anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibodies (mAbs) are of great significance for RAS and BRAF wild-type metastatic colorectal cancer (mCRC)... (Review)
Review
Anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibodies (mAbs) are of great significance for RAS and BRAF wild-type metastatic colorectal cancer (mCRC) patients. However, the generation of primary and secondary resistance to anti-EGFR mAbs has become an important factor restricting its efficacy. Recent studies have revealed that non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are implicated in anti-EGFR antibodies resistance, affecting the sensitivity of CRC cells to Cetuximab and Panitumumab. This paper briefly reviewed the research advance of the expression, signaling network and functional mechanism of ncRNAs related to anti-EGFR mAbs resistance in CRC, as well as their relationship with clinical prognosis and the possibility of therapeutic targets. In addition, some ncRNAs that are involved in the regulation of signaling pathways or genes related to anti-EGFR resistance, but need to be further verified by resistance experiments were also included in this review, thereby providing more ideas and basis for ncRNAs as CRC prognostic markers and anti-EGFR therapy sensitizers. Video Abstract.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Humans; MicroRNAs; Mutation; Panitumumab; Proto-Oncogene Proteins B-raf; RNA, Circular; RNA, Long Noncoding; RNA, Untranslated
PubMed: 36131281
DOI: 10.1186/s12964-022-00960-x -
Clinical Colorectal Cancer Dec 2021MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of...
INTRODUCTION
MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial.
METHODS
Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay.
RESULTS
Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression.
CONCLUSION
The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.
Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Panitumumab; Pyridones; Pyrimidinones
PubMed: 34417144
DOI: 10.1016/j.clcc.2021.07.004 -
BMC Cancer Nov 2017In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies - a physician... (Review)
Review
BACKGROUND
In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies - a physician survey and a medical records review (MRR) - were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associated RAS testing requirements in clinical practice.
METHODS
Both studies enrolled participants from nine European countries and were carried out in three consecutive rounds. Rounds 1 and 2 (2012-2013) examined KRAS (exon 2) testing only; the results have been published in full previously. Round 3 (2014-2015) examined full RAS testing (exons 2, 3, 4 of KRAS and NRAS) and was initiated following a change in prescribing guidelines, from requiring KRAS alone to requiring full RAS testing. For the physician survey, telephone interviews were conducted with oncologists who had prescribed panitumumab to patients with mCRC in the previous 6 months. For the MRR, oncologists were asked to provide anonymised clinical information, extracted from their patients' records.
RESULTS
In Round 3, 152 oncologists and 131 patients' records were included in the physician survey and MRR, respectively. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly identified that panitumumab should only be prescribed in RAS wild-type mCRC compared with 99.0% (n = 298) of 301 participants in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients included in the study had confirmed KRAS or RAS wild-type status prior to initiation of panitumumab compared with 97.7% (n = 299) of 306 patients in Rounds 1 and 2 (KRAS only). Of those patients in Round 3, 83.2% (n = 109) had been tested for RAS status and 16.8% (n = 22) had been tested for KRAS status only.
CONCLUSIONS
Physicians' adherence to prescribing guidelines has remained high over time in Europe, despite the change in indication for panitumumab treatment, from KRAS to RAS wild-type mCRC. Additionally, this study demonstrates the uptake of full RAS testing among the majority of oncologists and pathologists.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Colorectal Neoplasms; Europe; Female; GTP Phosphohydrolases; Genetic Testing; Guideline Adherence; Humans; Male; Medical Records; Membrane Proteins; Neoplasm Metastasis; Panitumumab; Physicians; Practice Guidelines as Topic; Practice Patterns, Physicians'; Proto-Oncogene Proteins p21(ras); Surveys and Questionnaires
PubMed: 29183279
DOI: 10.1186/s12885-017-3740-4 -
Future Oncology (London, England) Oct 2018Cutaneous toxicities associated with EGFR inhibitors (EGFRIs) have a significant impact on patient treatment continuation, quality of life and healthcare resource... (Review)
Review
Cutaneous toxicities associated with EGFR inhibitors (EGFRIs) have a significant impact on patient treatment continuation, quality of life and healthcare resource utilization. This paper reviews the current prophylaxis and management of EGFRI-induced cutaneous toxicities in patients with colorectal cancer, and combines these findings with the authors' clinical expertise to define a novel algorithm for healthcare professionals managing patients receiving EGFRIs. This tool includes a grading system based on the location, severity and psychological impact, and provides a standard prescription pack, advice on prophylaxis/self-management of cutaneous symptoms for patients initiating EGFRIs, and essential guidance on subsequent review and treatment escalation. It aims to optimize treatment of metastatic colorectal cancer by minimizing cutaneous toxicities to maintain dose intensity and efficacy of EGFRI-based chemotherapy.
Topics: Antineoplastic Agents, Immunological; Cetuximab; Colorectal Neoplasms; Drug Eruptions; ErbB Receptors; Humans; Panitumumab
PubMed: 29727211
DOI: 10.2217/fon-2018-0187