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Contemporary Oncology (Poznan, Poland) 2014Efficacy of monoclonal anti-EGFR antibodies (cetuximab, panitumumab) used in combination with chemotherapy or alone has been demonstrated in clinical trials of patients... (Review)
Review
Efficacy of monoclonal anti-EGFR antibodies (cetuximab, panitumumab) used in combination with chemotherapy or alone has been demonstrated in clinical trials of patients with mCRC. Both drugs block signaling EGFR pathway in malignant cells (blocking ligand binding and EGFR dimerization). Obtaining treatment responses with anti-EGFR agents is possible only in a selected subgroup of patients with mCRC. Successful treatment with cetuximab and panitumab is possible almost exclusively in patients without RAS mutations. Research on predictive value of EGFR gene copy number, PI3KCA gene mutations, P53 and PTEN, and EGFR their ligands concentrations is ongoing. Cetuximab, as IgG1 class antibody, can cause antibody dependent cellular cytotoxicity against neoplasm cells, while panitumumab, as IgG2 class antibody, does not induce such effect. Therefore a potential predictor cetuximab therapy may be the presence of different polymorphic forms of the genes for receptor immunoglobulin Fc fragments: FcγRIIa and FcγRIII subclasses.
PubMed: 24876815
DOI: 10.5114/wo.2013.38566 -
Drugs May 2015Tumour biomarker status is being used more and more frequently to guide treatment decisions in patients with metastatic colorectal cancer (mCRC). Continued cycles of... (Review)
Review
Tumour biomarker status is being used more and more frequently to guide treatment decisions in patients with metastatic colorectal cancer (mCRC). Continued cycles of hypothesis generation and biomarker testing in retrospective, prospective-retrospective and prospective analyses from studies of the epidermal growth factor (EGFR)-targeted monoclonal antibodies (mAbs), panitumumab and cetuximab, have resulted in improved patient selection in mCRC. Initial data suggested EGFR-targeted mAb treatment should be limited to patients with KRAS exon 2 wild-type (WT) tumours, but the availability of tumour samples from large phase III studies permitted evaluation of additional potential biomarkers of activity for these agents. Subsequent analyses further refined the target population to those patients whose tumours were WT for KRAS and NRAS exons 2, 3 and 4 (i.e., those with RAS WT status). Here, we review key clinical data for panitumumab in mCRC across the lines of treatment, assessing in detail the impact of more comprehensive RAS selection on patient outcomes. Panitumumab data across first- to third-line therapy consistently demonstrate that by testing tumour RAS status, it is possible to select patients more likely to benefit from treatment.
Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; ErbB Receptors; Humans; Panitumumab; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; ras Proteins
PubMed: 25895463
DOI: 10.1007/s40265-015-0386-x -
Clinical Pharmacokinetics Apr 2018Despite progress in the treatment of metastatic colorectal cancer (mCRC) in the last 15 years, it is still a condition with a relatively low 5-year survival rate.... (Review)
Review
Despite progress in the treatment of metastatic colorectal cancer (mCRC) in the last 15 years, it is still a condition with a relatively low 5-year survival rate. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is able to prolong survival in patients with mCRC. Panitumumab is used in different lines of therapy in combination with chemotherapy, and as monotherapy for the treatment of wild-type (WT) RAS mCRC. It is administered as an intravenous infusion of 6 mg/kg every 2 weeks and has a t of approximately 7.5 days. Elimination takes place via two different mechanisms, and immunogenicity rates are low. Only RAS mutations have been confirmed as a negative predictor of efficacy with anti-EGFR antibodies. Panitumumab is generally well tolerated and has a manageable toxicity profile, despite a very high prevalence of dermatologic side effects. This article presents an overview of the clinical pharmacokinetics and pharmacodynamics of panitumumab, including a description of the studies that led to its approval in the different lines of therapy of mCRC.
Topics: Antineoplastic Agents, Immunological; Colorectal Neoplasms; Drug Administration Schedule; ErbB Receptors; Genes, ras; Humans; Infusions, Intravenous; Mutation; Panitumumab; Treatment Outcome
PubMed: 28853050
DOI: 10.1007/s40262-017-0590-9 -
Annals of Internal Medicine Jan 2011KRAS mutations have been extensively investigated as predictive biomarkers for treatment of advanced colorectal cancer with the anti-epidermal growth factor receptor... (Review)
Review
BACKGROUND
KRAS mutations have been extensively investigated as predictive biomarkers for treatment of advanced colorectal cancer with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab.
PURPOSE
To summarize whether KRAS mutation status modifies effects of anti-EGFR-based treatments for patients with advanced colorectal cancer and whether KRAS status predicts clinical outcomes among such patients.
DATA SOURCES
MEDLINE and 2 curated genetics databases (through 24 March 2010) were searched for observational studies. MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects (through 1 September 2010) were searched for randomized, controlled trials. No search was restricted by language.
STUDY SELECTION
Three reviewers screened titles and abstracts to identify published studies assessing KRAS mutations as predictors of overall and progression-free survival or treatment failure for patients who received anti-EGFR-based therapy for metastatic colorectal cancer.
DATA EXTRACTION
Three investigators extracted data on population and study-design characteristics, including quality items, and on outcomes of interest. Random-effects meta-analyses were done on nonoverlapping studies.
DATA SYNTHESIS
In 4 reanalyses of randomized trials of anti-EGFR-based therapy versus best supportive care or cytotoxic chemotherapy, no significant benefit was found for overall or progression-free survival from anti-EGFR-based treatment among KRAS-positive patients (hazard ratio [HR], 1.0). However, evidence favors anti-EGFR therapy among KRAS wild-type patients; the relative HR across KRAS-positive and wild-type patients was 1.30 (95% CI, 0.95 to 1.78) for overall survival and 2.22 (CI, 1.74 to 2.84) for progression-free survival by random-effects meta-analysis. In 13 cohorts of patients who received anti-EGFR antibodies, the summary HR for overall survival was 1.79 (CI, 1.48 to 2.17), with better survival in wild-type patients. The corresponding HR for progression-free survival was 2.11 (CI, 1.74 to 2.55 [16 cohorts]). In random-effects bivariate meta-analysis of 22 studies, the summary sensitivity of KRAS mutations for predicting lack of response was 0.49 (CI, 0.43 to 0.55), and summary specificity was 0.93 (CI, 0.87 to 0.97).
LIMITATIONS
Limited evidence from randomized studies exists. Patient-level data are needed to assess modifiers of the mutation-by-treatment interaction. Publication bias could be a concern.
CONCLUSION
KRAS mutations are consistently associated with reduced overall and progression-free survival and increased treatment failure rates among patients with advanced colorectal cancer treated with anti-EGFR antibodies.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; ErbB Receptors; Humans; Mutation; Panitumumab; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Treatment Failure; ras Proteins
PubMed: 21200037
DOI: 10.7326/0003-4819-154-1-201101040-00006 -
Cancer Discovery Nov 2014The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS, NRAS, and BRAF and amplification of ERBB2 and... (Review)
Review
UNLABELLED
The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.
SIGNIFICANCE
Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Panitumumab
PubMed: 25293556
DOI: 10.1158/2159-8290.CD-14-0462 -
Journal of Medical Economics 2021To compare the cost of biweekly regimens of first-line (1L) treatments of cetuximab-folinic acid, fluorouracil, and irinotecan (FOLFIRI) panitumumab-folinic acid,... (Comparative Study)
Comparative Study
Cost-minimization analysis of biweekly dosing of cetuximab and FOLFIRI compared with panitumumab and FOLFOX for first-line treatment of patients with KRAS wild-type metastatic colorectal cancer in the United States.
AIM
To compare the cost of biweekly regimens of first-line (1L) treatments of cetuximab-folinic acid, fluorouracil, and irinotecan (FOLFIRI) panitumumab-folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients with Kirsten's rat sarcoma wild type (KRAS WT) metastatic colorectal cancer (mCRC) in the United States, across varying weights and body surface areas (BSAs).
MATERIALS AND METHODS
Cost-minimization analysis (CMA) was performed to estimate per-patient cost differences of cetuximab-FOLFIRI panitumumab-FOLFOX. The CMA estimated the costs of RAS testing, premedication, drug acquisition, treating infusion reactions (IRs), supportive therapy, and biweekly administration of chemotherapy, cetuximab (500 mg/m), and panitumumab (6 mg/kg) over 43 weeks (median progression-free survival). To calculate dose and cost, weight and height data were gathered from an electronic health record-derived de-identified database ( = 7,669; January 2013-October 2020). Base case analysis utilized mean weight/BSA of the overall cohort (82.04 kg/1.92 m), and alternate scenarios were based on 88.18 kg/2.03 m (men, = 4,477) and 73.43 kg/1.76 m (women, = 3,192).
RESULTS
For the base case, total treatment costs were $167,853 for cetuximab-FOLFIRI and $168,254 for panitumumab-FOLFOX; cost savings per patient receiving cetuximab-FOLFIRI was $400. Cost savings in alternate scenarios (men, $15,138; women, $15,004) resulted from lower drug acquisition costs for cetuximab (men, $14,833; women $14,854) and administration cost ($440) panitumumab. Cost savings of cetuximab-FOLFIRI in treating IR ($353) were similar across all scenarios.
LIMITATIONS
With no head-to-head clinical trial data in the 1L setting, assumptions of similarity in efficacy and safety of cetuximab panitumumab were based on published network meta-analysis and the ASPECCT trial. This model did not consider a lifetime horizon. Costs of managing all adverse events (except IR) were not included.
CONCLUSIONS
Biweekly cetuximab-FOLFIRI offers cost savings compared with panitumumab-FOLFOX for 1L therapy of patients with KRAS WT mCRC in the United States. These cost differences were observed for the overall population and across different BSA and weights for men and women.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Costs and Cost Analysis; Fluorouracil; Humans; Leucovorin; Panitumumab; Proto-Oncogene Proteins p21(ras); United States
PubMed: 34529522
DOI: 10.1080/13696998.2021.1982181 -
Cancer Chemotherapy and Pharmacology Oct 2021Panitumumab is a human monoclonal antibody targeting the epidermal growth factor receptor for the treatment of wild-type RAS metastatic colorectal cancer (mCRC).... (Meta-Analysis)
Meta-Analysis
PURPOSE
Panitumumab is a human monoclonal antibody targeting the epidermal growth factor receptor for the treatment of wild-type RAS metastatic colorectal cancer (mCRC). Currently, no dedicated clinical studies have evaluated the effect of organ impairment on the pharmacokinetics of panitumumab. Here, we present data from late phase studies of panitumumab in patients with mCRC and analyses of the effect of hepatic or renal impairment on the exposure of panitumumab.
METHODS
From three multicenter, open-label, phase 2 and phase 3 studies, 349 and 351 patients were included in hepatic and renal function subgroup analyses, respectively. Patients who received IV panitumumab and serum exposures were compared to patients with varying degrees of hepatic and renal organ dysfunction.
RESULTS
The C and C values for patients with mild (n = 119) and moderate (n = 4) hepatic impairment were within the range of serum concentrations of panitumumab for the normal hepatic function subgroup. The distributions of serum concentration of panitumumab in patients with mild (n = 85) or moderate (n = 19) renal impairment were similar to the serum concentrations of panitumumab in the normal renal function subgroup. Population pharmacokinetic modeling and covariate analysis results were also consistent with lack of any significant effect of renal or hepatic impairment on the pharmacokinetics of panitumumab. Additionally, real-world evidence from case studies of patients with mCRC and severe hepatic or renal impairment, which is a rare patient population to study, indicated lack of clinically relevant differences in exposure of panitumumab compared with patients with mCRC and normal hepatic or renal function.
CONCLUSIONS
Mild-to-moderate hepatic or renal dysfunction had no clinically meaningful impact on the pharmacokinetics of panitumumab in patients with mCRC. No dose adjustments for panitumumab are warranted in patients with mCRC with mild-to-moderate hepatic or renal dysfunction.
TRIAL REGISTRATION
ClinicalTrials.gov; NCT00083616, NCT00089635, NCT00113763.
Topics: Administration, Intravenous; Aged; Antineoplastic Agents, Immunological; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Panitumumab; Randomized Controlled Trials as Topic; Severity of Illness Index; ras Proteins
PubMed: 34213592
DOI: 10.1007/s00280-021-04319-w -
Molecular Imaging and Biology Feb 2021The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic...
PURPOSE
The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic antibodies that are FDA-approved with known toxicity, only a limited number of antibody-dye conjugates have been introduced to the clinic. Thorough evaluation of the safety, stability, and pharmacokinetics of antibody conjugates in the clinical setting compared with their parental components could accelerate the clinical approval of antibodies as agents for molecular imaging. Here we investigate the safety and stability of a near-infrared fluorescent dye (IRDye800CW) conjugated panitumumab, an approved therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients.
PROCEDURES
Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014, and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas, and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard-of-care surgery were infused with doses between 0.06 to 2.83 mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-day post-infusion for analysis.
RESULTS
Eighty-one patients underwent infusion of the study drug at a range of doses. Six patients (7.4 %) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged QTc interval which occurred in three patients (3.7 %). Panitumumab-IRDye800CW had two OOS results at 42 and 54 months while meeting all other stability testing criteria.
CONCLUSIONS
Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4 %) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies.
Topics: Adult; Aged; Aged, 80 and over; Benzenesulfonates; Female; Humans; Indoles; Male; Middle Aged; Molecular Imaging; Optical Imaging; Panitumumab
PubMed: 32880818
DOI: 10.1007/s11307-020-01536-2 -
Cancer Apr 2009The authors explored the association of skin toxicity (ST) severity as measured by patient-reported ST and Common Terminology Criteria for Adverse Events (CTCAE) grading... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The authors explored the association of skin toxicity (ST) severity as measured by patient-reported ST and Common Terminology Criteria for Adverse Events (CTCAE) grading with efficacy of panitumumab, a fully human antiepidermal growth factor receptor antibody, from a phase 3 metastatic colorectal cancer (CRC) trial.
METHODS
Patients were randomized to panitumumab plus best supportive care (BSC) vs BSC alone. ST by modified National Cancer Institute CTCAE v3.0 and modified Dermatology Life Quality Index (mDLQI), health-related quality of life (HRQOL), and CRC symptoms were measured. ST was analyzed using a landmark approach. Associations by KRAS mutational status were also assessed.
RESULTS
Of 463 patients, 208 of 231 (90%) panitumumab patients and 184 of 232 (79%) BSC patients had > or = 1 postbaseline patient-reported outcome (PRO) assessment. Panitumumab patients with more severe ST had significantly longer overall survival (OS) (grade 2-4:grade 1; hazard ratio, 0.60; P = .0033). Lower mDLQI scores (< 67; more bothersome ST) were associated with longer OS (Cox model, P < .0001). Similar results were observed with progression-free survival (PFS). An inverse relation between mDLQI and HRQOL scores was observed, suggesting that ST bother correlated with better HRQOL. KRAS and PRO data were available in 363 patients (188 panitumumab; 175 BSC). Longer OS was associated with lower mDLQI scores, regardless of KRAS status. Longer PFS was associated with more severe ST (lower mDLQI scores and higher CTCAE grade ST) in patients with wild-type (WT) KRAS tumors, but not in patients with mutant KRAS tumors.
CONCLUSIONS
More severe ST, by both clinical grading and PRO, is associated with better CRC symptoms and HRQOL and with longer OS and PFS among panitumumab-treated patients. The associations for PFS were more pronounced in patients with WT KRAS tumors.
Topics: Antibodies, Monoclonal; Colorectal Neoplasms; Disease-Free Survival; ErbB Receptors; Genes, ras; Humans; Mutation; Panitumumab; Quality of Life; Skin Diseases; Survival Analysis; Treatment Outcome
PubMed: 19189371
DOI: 10.1002/cncr.24088 -
Theranostics 2021Sentinel lymph node biopsy (SLNB) is a well-established minimally invasive staging procedure that maps the spread of tumour metastases from their primary site to the...
Sentinel lymph node biopsy (SLNB) is a well-established minimally invasive staging procedure that maps the spread of tumour metastases from their primary site to the regional lymphatics. Currently, the procedure requires the local peri-tumoural injection of radiolabelled and/or optical agents, and is therefore operator dependent, disruptive to surgical workflow and restricted largely to a small subset of malignancies that can be readily accessed externally for local tracer injection. The present study set out to determine whether intravenous (IV) infusion of a tumor-targeted tracer could identify sentinel and metastatic lymph nodes (LNs) in order to overcome these limitations. We examined 27 patients with oral squamous cell carcinoma (OSCC), 18 of whom were clinically node negative (cN0). Patients were infused intravenously with 50mg of Panitumumab-IRDye800CW prior to surgical resection of their primary tumour with neck dissection and/or SLNB. Lymphadenectomy specimens underwent fluorescence molecular imaging to evaluate tracer distribution to LNs. A total of 960 LNs were analysed, of which 34 (3.5%) contained metastatic disease. Panitumumab-IRDye800CW preferentially localized to metastatic and sentinel LNs as evidenced by a higher fluorescent signal relative to other lymph nodes. The median MFI of metastatic LNs was significantly higher than the median MFI of benign LNs (0.06 versus 0.02, p < 0.05). Furthermore, selecting the highest five fluorescence intensity LNs from individual specimens resulted in 100% sensitivity, 85.8% specificity and 100% negative predictive value (NPV) for the detection of occult metastases and 100% accuracy for clinically staging the neck. In the cN+ cohort, assessment of the highest 5 fluorescence LNs per patient had 87.5% sensitivity, 93.2% specificity and 99.1% NPV for the detection of metastatic nodes. When intravenously infused, a tumour-targeted tracer localized to sentinel and metastatic lymph nodes. Further validation of an IV tumor-targeted tracer delivery approach for SLNB could dramatically change the practice of SLNB, allowing its application to other malignancies where the primary tumour is not accessible for local tracer injection.
Topics: Administration, Intravenous; Aged; Benzenesulfonates; Female; Head and Neck Neoplasms; Humans; Indoles; Lymphatic Metastasis; Male; Middle Aged; Panitumumab; Sentinel Lymph Node Biopsy; Squamous Cell Carcinoma of Head and Neck
PubMed: 34158844
DOI: 10.7150/thno.55389