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Current Problems in Cancer Aug 2023The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes... (Review)
Review
The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.
Topics: Animals; Mice; Humans; Proto-Oncogene Proteins B-raf; Mutation; Antineoplastic Agents; Panitumumab; Colorectal Neoplasms
PubMed: 37285606
DOI: 10.1016/j.currproblcancer.2023.100960 -
The Oncologist Dec 2023Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to...
INTRODUCTION
Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC.
METHODS
Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status.
RESULTS
No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment.
CONCLUSIONS
The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).
Topics: Humans; Panitumumab; Colorectal Neoplasms; Benzimidazoles; Colonic Neoplasms; Rectal Neoplasms; ErbB Receptors; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras)
PubMed: 37597246
DOI: 10.1093/oncolo/oyad210 -
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 -
Molecular Imaging and Biology Aug 2022Immuno-positron emission tomography (immunoPET) combines the specificity of an antibody with the sensitivity of PET to image dysregulated pathways in cancer. This study...
PURPOSE
Immuno-positron emission tomography (immunoPET) combines the specificity of an antibody with the sensitivity of PET to image dysregulated pathways in cancer. This study examines the performance of immunoPET using the radioimmunoconjugate [Zr]Zr-DFO-Panitumumab to detect epidermal growth factor receptor (EGFR) expression in an orthotopic model of bladder cancer (BCa).
PROCEDURES
Expression and quantification of EGFR receptors were confirmed in four different BCa cell lines. Binding assays validated [Zr]Zr-DFO-Panitumumab specificity for EGFR-expressing UMUC3 BCa cells. Subcutaneous and orthotopic UMUC3 xenografts were then used for PET imaging and ex vivo biodistribution of the radioimmunoconjugate. Control cohorts included non-tumor mice, Zr-labeled non-specific IgG, and blocking experiments.
RESULTS
[Zr]Zr-DFO-Panitumumab binds specifically to EGFR-expressing UMUC3 cells with a B value of 5.9 × 10 EGFRs/cell in vitro. ImmunoPET/CT images show localization of the antibody in subcutaneous UMUC3 xenografts and murine bladder tumors. In the orthotopic model, the immunoPET signal correlates with the respective tumor volume. Ex vivo biodistribution analysis further confirmed imaging results.
CONCLUSION
The preclinical data presents a proof of concept for utilizing EGFR-targeted immunoPET to image BCa with altered EGFR protein levels.
Topics: Animals; Cell Line, Tumor; ErbB Receptors; Humans; Immunoconjugates; Mice; Panitumumab; Positron-Emission Tomography; Tissue Distribution; Urinary Bladder Neoplasms; Zirconium
PubMed: 35147837
DOI: 10.1007/s11307-022-01708-2 -
Oncology 2018Over the last few years only one large randomized phase III study has tried to prospectively assess the safety of cetuximab and panitumumab in a head-to-head comparison.... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
Over the last few years only one large randomized phase III study has tried to prospectively assess the safety of cetuximab and panitumumab in a head-to-head comparison. Despite the similar overall toxicity profile, cetuximab and panitumumab retain peculiar safety characteristics that deserve to be deeply investigated.
METHODS
We conducted a systematic review for randomized trials in PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and EMBASE using the terms ("cetuximab" or "panitumumab") AND ("colorectal cancer" OR "colorectal carcinoma"). Data of adverse events were aggregated to obtain pooled incidence rates of prespecified adverse events. Incidence of skin toxicities was the primary outcome. A χ2 test was used for comparisons of proportions and an odds ratio (OR) was calculated for comparison.
RESULTS
A total of 38 studies were included for analysis. Cetuximab was associated with fewer G3-4 skin toxicities (OR = 0.62, 95% CI 0.53-0.62; p < 0.001), slightly more frequent G3-4 acne-like rash (OR = 1.24, 95% CI 1.04-1.48; p = 0.04), and paronychia (OR 1.36, 95% CI 1.1-1.7), but fewer cases of skin fissures (OR = 0.64, 95% CI 0.44-0.93; p = 0.02) and pruritus (OR = 0.45, 95% CI 0.35-0.58; p < 0.001) than PANI.
CONCLUSIONS
In conclusion, this meta-analysis shows that cetuximab- and panitumumab-based chemotherapy have different toxicity profiles in terms of the rate of severe adverse events.
Topics: Acne Vulgaris; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cetuximab; Colorectal Neoplasms; Drug Eruptions; Humans; Panitumumab; Paronychia; Pruritus; Randomized Controlled Trials as Topic
PubMed: 29393280
DOI: 10.1159/000486338 -
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 -
Science Translational Medicine Jun 2023Epidermal growth factor receptor (EGFR) inhibitors are used to treat many advanced-stage epithelial cancers but induce severe skin toxicities in most treated patients....
Epidermal growth factor receptor (EGFR) inhibitors are used to treat many advanced-stage epithelial cancers but induce severe skin toxicities in most treated patients. These side effects lead to a deterioration in the quality of life of the patients and compromise the anticancer treatment. Current treatment strategies for these skin toxicities focus on symptom reduction rather than preventing the initial trigger that causes the toxicity. In this study, we developed a compound and method for treating "on-target" skin toxicity by blocking the drug at the site of toxicity without reducing the systemic dose reaching the tumor. We first screened for small molecules that effectively blocked the binding of anti-EGFR monoclonal antibodies to EGFR and identified a potential candidate, SDT-011. In silico docking predicted that SDT-011 interacted with the same residues on EGFR found to be important for the binding of EGFR inhibitors cetuximab and panitumumab. Binding of SDT-011 to EGFR reduced the binding affinity of cetuximab to EGFR and could reactivate EGFR signaling in keratinocyte cell lines, ex vivo cetuximab-treated whole human skin, and A431-injected mice. Specific small molecules were topically applied and were delivered via a slow-release system derived from biodegradable nanoparticles that penetrate the hair follicles and sebaceous glands, within which EGFR is highly expressed. Our approach has the potential to reduce skin toxicity caused by EGFR inhibitors.
Topics: Humans; Animals; Mice; Cetuximab; Quality of Life; Antibodies, Monoclonal; Panitumumab; Antineoplastic Agents; Neoplasms; Skin Diseases
PubMed: 37285403
DOI: 10.1126/scitranslmed.abo0684 -
Oral Oncology Jan 2024The well-studied role of epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and non-small cell lung cancer (NSCLC) has enabled the...
The well-studied role of epidermal growth factor receptor (EGFR) in metastatic colorectal cancer (mCRC) and non-small cell lung cancer (NSCLC) has enabled the development of drugs that target this molecule, including panitumumab for the former and osimertinib for the latter. Oral adverse events due to those agents are rarely described in the literature and their exact characterization is hampered by inadequate reporting and/or incorrect terminology used. We report two cases of panitumumab- and osimertinib-associated oral ulcerations with emphasis on their possible pathogenesis and optimal management.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Panitumumab; Lung Neoplasms; Antineoplastic Agents; Aniline Compounds; Mutation; Protein Kinase Inhibitors
PubMed: 38086198
DOI: 10.1016/j.oraloncology.2023.106660 -
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 -
The Journal of Urology Mar 2019In this prospective study we evaluated the safety and efficacy of concurrent radiotherapy and panitumumab following neoadjuvant/induction chemotherapy and pelvic lymph...
PURPOSE
In this prospective study we evaluated the safety and efficacy of concurrent radiotherapy and panitumumab following neoadjuvant/induction chemotherapy and pelvic lymph node dissection as a bladder preserving therapy for invasive bladder cancer.
MATERIALS AND METHODS
Patients with cT1-4N0-2M0 bladder cancer were treated with pelvic lymph node dissection and 4 cycles of platinum based induction chemotherapy followed by a 6½-week schedule of weekly panitumumab (2.5 mg/kg) and concurrent radiotherapy to the bladder (33 × 2 Gy). As the primary objective we compared concurrent radiotherapy and panitumumab toxicity to a historical control toxicity rate of concurrent cisplatin/radiotherapy (less than 35% of patients with Grade 3-5 toxicity). A sample size of 31 patients was estimated. Secondary end points included complete remission at 3-month followup, the bladder preservation rate, EGFR (epidermal growth factor receptor) expression and RAS mutational status.
RESULTS
Of the 38 cases initially included in this study 34 were staged cN0. After pelvic lymph node dissection 7 cases (21%) were up staged to pN+. Of the 38 patients 31 started concurrent radiotherapy and panitumumab. During concurrent radiotherapy and panitumumab 5 patients (16%, 95% CI 0-31) experienced systemic or local grade 3-4 toxicity. Four patients did not complete treatment due to adverse events. Complete remission was achieved in 29 of 31 patients (94%, 95% CI 83-100). At a median followup of 34 months 4 patients had local recurrence, for which 3 (10%) underwent salvage cystectomy. Two tumors showed EGFR or RAS mutation while 84% showed positive EGFR expression.
CONCLUSIONS
Concurrent radiotherapy and panitumumab following induction chemotherapy and pelvic lymph node dissection has a safety profile that is noninferior to the historical profile of concurrent cisplatin/radiotherapy. The high complete remission and bladder preservation rates are promising and warrant further study.
Topics: Adult; Aged; Antineoplastic Agents, Immunological; Combined Modality Therapy; Female; Humans; Induction Chemotherapy; Lymph Node Excision; Male; Middle Aged; Neoplasm Invasiveness; Panitumumab; Prospective Studies; Urinary Bladder Neoplasms
PubMed: 30321552
DOI: 10.1016/j.juro.2018.10.007