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Frontiers in Bioscience (Landmark... Jan 2016The epidermal growth factor receptor (EGFR) family plays an important role in colorectal cancer (CRC). EGFR participates in the key process of tumorigenesis and... (Review)
Review
The epidermal growth factor receptor (EGFR) family plays an important role in colorectal cancer (CRC). EGFR participates in the key process of tumorigenesis and invasion, and its expression correlates with the prognosis of CRC. EGFR-targeted therapy has been widely utilized in stage III and IV CRC. The EGFR antibodies, cetuximab and panitumumab, are widely used in treatment of CRC. There are clinical trials and in vivo studies being carried out on the efficacy and mechanism of their action in CRC treatment. In this review, we will describe the EGFR-targeted therapy used in CRC, focusing on the efficacy and mechanisms of the most commonly used EGFR antibodies, cetuximab and panitumumab.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Humans; Panitumumab
PubMed: 26709782
DOI: 10.2741/4397 -
The British Journal of Ophthalmology May 2024In experimental studies, intravitreally applied antibodies against epidermal growth factor (EGF), EGF family members (amphiregulin, neuregulin-1, betacellulin, epigen,...
BACKGROUND
In experimental studies, intravitreally applied antibodies against epidermal growth factor (EGF), EGF family members (amphiregulin, neuregulin-1, betacellulin, epigen, epiregulin) and against the EGF receptor (EGFR) were associated with a reduction in lens-induced axial elongation and decrease in physiological eye elongation in guinea pigs and in non-human primates. Here, we investigated the intraocular tolerability and safety of a fully human monoclonal IgG2-antibody against EGFR, already in clinical use in oncology, as a potential future therapeutic approach for axial elongation in adult eyes with pathological myopia.
METHODS
The clinical, monocentre, open-label, multiple-dose, phase-1 study included patients with myopic macular degeneration of stage 4, who received intravitreal injections of panitumumab in various doses and in intervals ranging between 2.1 months and 6.3 months.
RESULTS
The study included 11 patients (age:66.8±6.3 years), receiving panitumumab injections in doses of 0.6 mg (4 eyes; 1×1 injection, 3×2 injections), 1.2 mg (4 eyes; 1×1 injection, 2×2 injections, 1×3 injections) and 1.8 mg (3 eyes; 1×1 injection, 2×2 injections), respectively. None of the participants showed treatment-emergent systemic adverse events or intraocular inflammatory reactions. Best-corrected visual acuity (1.62±0.47 logarithm of the minimal angle of resolution (logMAR) vs 1.28±0.59 logMAR; p=0.08) and intraocular pressure (13.8±2.4 mm Hg vs 14.3±2.6 mm Hg; p=0.20) remained unchanged. In nine patients with a follow-up of >3 months (mean:6.7±2.7 months), axial length did not change significantly (30.73±1.03 mm vs 30.77±1.19 mm; p=0.56).
CONCLUSIONS
In this open-labelled, phase-1 study with a mean follow-up of 6.7 months, panitumumab repeatedly administered intravitreally up to a dose of 1.8 mg was not associated with intraocular or systemic adverse effects. During the study period, axial length remained unchanged.
TRIAL REGISTRATION NUMBER
DRKS00027302.
Topics: Humans; Panitumumab; Intravitreal Injections; Female; Male; Aged; Middle Aged; Visual Acuity; Myopia, Degenerative; Tomography, Optical Coherence; Treatment Outcome; Macular Degeneration; ErbB Receptors; Dose-Response Relationship, Drug; Follow-Up Studies
PubMed: 37429701
DOI: 10.1136/bjo-2023-323383 -
The Oncologist Jun 2021Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient...
LESSONS LEARNED
Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted.
BACKGROUND
The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance.
METHODS
In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab.
RESULTS
Twenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3-7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5-14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib.
CONCLUSION
The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.
Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Panitumumab; Proto-Oncogene Proteins p21(ras); Pyridines; Vascular Endothelial Growth Factor A
PubMed: 33469991
DOI: 10.1002/onco.13678 -
Revista Da Associacao Medica Brasileira... Jul 2018The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to... (Review)
Review
The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Evidence-Based Medicine; Humans; Panitumumab; Practice Guidelines as Topic
PubMed: 30365654
DOI: 10.1590/1806-9282.64.07.568 -
Expert Opinion on Biological Therapy May 2019The combination of oxaliplatin, irinotecan, fluorouracil (5-FU), and leucovorin (FOLFOXIRI) results in improved outcomes compared with standard chemotherapy when used in... (Review)
Review
INTRODUCTION
The combination of oxaliplatin, irinotecan, fluorouracil (5-FU), and leucovorin (FOLFOXIRI) results in improved outcomes compared with standard chemotherapy when used in frontline to treat patients with metastatic colorectal cancer (mCRC). FOLFOXIRI has been recently combined with biologic agents aiming further improvement in outcomes.
AREAS COVERED
This manuscript provides a comprehensive review of the results achieved by the FOLFOXIRI+biologic combination when used as first-line treatment in patients with mCRC. The search retrieved 19 clinical trial reports and 7 ongoing trials. The results are discussed focusing on secondary resection of metastatic disease, impact of sidedness (right-left primary tumor site), and impact of biomarkers.
EXPERT OPINION
Panitumumab is the only biologic that has proved its value when added to FOLFOXIRI in a randomized clinical trial. FOLFOXIRI-bevacizumab has the widest data from two large randomized phase III trials, being an option to be used in both the palliative and the conversion-therapy settings. However, the true benefit from adding bevacizumab remains to be established as it has not been evaluated in a randomized setting yet. Data on response rates and secondary resection rates are promising with the FOLFOXIRI-anti-EGFR combinations and may constitute a valuable option. Results of ongoing head-to-head studies will shed additional light on this issue.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Panitumumab
PubMed: 30887844
DOI: 10.1080/14712598.2019.1595580 -
Annales de Dermatologie Et de... Jun 2024
Topics: Aged; Female; Humans; Antineoplastic Agents, Immunological; Collagen Diseases; Drug Eruptions; Panitumumab
PubMed: 38678770
DOI: 10.1016/j.annder.2024.103271 -
Journal of Clinical Oncology : Official... Jun 2023Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with wild-type metastatic colorectal cancer (mCRC) receiving... (Randomized Controlled Trial)
Randomized Controlled Trial
Consensus Molecular Subtypes as Biomarkers of Fluorouracil and Folinic Acid Maintenance Therapy With or Without Panitumumab in Wild-Type Metastatic Colorectal Cancer (PanaMa, AIO KRK 0212).
PURPOSE
Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with wild-type metastatic colorectal cancer (mCRC) receiving fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) after Pmab + mFOLFOX6 induction within the randomized phase II PanaMa trial.
METHODS
CMSs were determined in the safety set (ie, patients that received induction) and full analysis set (FAS; ie, randomly assigned patients who received maintenance) and correlated with median progression-free survival (PFS) and overall survival (OS) since the start of induction or maintenance treatment and objective response rates (ORRs). Hazard ratios (HRs) and 95% CI were calculated by univariate/multivariate Cox regression analyses.
RESULTS
Of 377 patients of the safety set, 296 (78.5%) had available CMS data: CMS1/2/3/4: 29 (9.8%)/122 (41.2%)/33 (11.2%)/112 (37.8%) and unclassifiable: 17 (5.7%). The CMSs were prognostic biomarkers in terms of PFS ( < .0001), OS ( < .0001), and ORR ( = .02) since the start of induction treatment. In FAS patients (n = 196), with CMS2/4 tumors, the addition of Pmab to FU/FA maintenance therapy was associated with longer PFS (CMS2: HR, 0.58 [95% CI, 0.36 to 0.95], = .03; CMS4: HR, 0.63 [95% CI, 0.38 to 1.03], = .07) and OS (CMS2: HR, 0.88 [95% CI, 0.52 to 1.52], = .66; CMS4: HR, 0.54 [95% CI, 0.30 to 0.96], = .04). The CMS interacted significantly with treatment in terms of PFS (CMS2 CMS1/3: = .02; CMS4 CMS1/3: = .03) and OS (CMS2 CMS1/3: = .03; CMS4 CMS1/3: < .001).
CONCLUSION
The CMS had a prognostic impact on PFS, OS, and ORR in wild-type mCRC. In PanaMa, Pmab + FU/FA maintenance was associated with beneficial outcomes in CMS2/4, whereas no benefit was observed in CMS1/3 tumors.
Topics: Humans; Panitumumab; Colorectal Neoplasms; Leucovorin; Fluorouracil; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37018649
DOI: 10.1200/JCO.22.02582 -
European Journal of Cancer (Oxford,... Aug 2023In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient's perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS
We applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4-6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone.
RESULTS
Out of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance.
CONCLUSIONS
Most of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.
Topics: Humans; Bevacizumab; Colorectal Neoplasms; Panitumumab; Camptothecin; Colonic Neoplasms; Rectal Neoplasms; Fluorouracil; Antineoplastic Combined Chemotherapy Protocols; Leucovorin
PubMed: 37301718
DOI: 10.1016/j.ejca.2023.05.001 -
Advances in Therapy Jul 2021Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), thereby inhibiting the growth and survival of tumors... (Review)
Review
Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), thereby inhibiting the growth and survival of tumors expressing EGFR. Panitumumab received approval in the USA in 2006 for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS) metastatic colorectal cancer. Over the last 10 years, the pharmacokinetic and pharmacodynamic profile of panitumumab has been studied to further evaluate its safety, efficacy, and optimal dosing regimen. In this review, we summarize the key clinical pharmacokinetic and pharmacology data for panitumumab, and considerations for its use in special populations. Panitumumab has a nonlinear pharmacokinetic profile and its approved dosing regimen (6 mg/kg every 2 weeks) is based on body weight; dose adjustments are not needed based on sex, age, or renal or hepatic impairment. Drug interactions do not occur when panitumumab is combined with chemotherapy drugs including irinotecan, paclitaxel, and carboplatin. The level of tumor EGFR expression was found to have no effect on panitumumab pharmacokinetics or efficacy. The incidence of anti-panitumumab antibodies is low; when anti-panitumumab antibodies are produced, they do not affect the efficacy, safety, or pharmacokinetics of panitumumab. In summary, the pharmacokinetic and pharmacodynamic profile of panitumumab is well suited for standard dosing, and the approved body weight-based dosing regimen maintains efficacy and safety in the treatment of wild-type RAS metastatic colorectal cancer across a broad range of patients.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Irinotecan; Panitumumab
PubMed: 34152568
DOI: 10.1007/s12325-021-01809-4 -
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