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Cancer Control : Journal of the Moffitt... Jan 2013Gastrointestinal (GI) cancers are the most common human tumors encountered worldwide. The majority of GI cancers are unresectable at the time of diagnosis, and in the... (Review)
Review
BACKGROUND
Gastrointestinal (GI) cancers are the most common human tumors encountered worldwide. The majority of GI cancers are unresectable at the time of diagnosis, and in the subset of patients undergoing resection, few are cured. There is only a modest improvement in survival with the addition of modalities such as chemotherapy and radiation therapy. Due to an increasing global cancer burden, it is imperative to integrate alternative strategies to improve outcomes. It is well known that cancers possess diverse strategies to evade immune detection and destruction. This has led to the incorporation of various immunotherapeutic strategies, which enable reprogramming of the immune system to allow effective recognition and killing of GI tumors.
METHODS
A review was conducted of the results of published clinical trials employing immunotherapy for esophageal, gastroesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers.
RESULTS
Monoclonal antibody therapy has come to the forefront in the past decade for the treatment of colorectal cancer. Immunotherapeutic successes in solid cancers such as melanoma and prostate cancer have led to the active investigation of immunotherapy for GI malignancies, with some promising results.
CONCLUSIONS
To date, monoclonal antibody therapy is the only immunotherapy approved by the US Food and Drug Administration for GI cancers. Initial trials validating new immunotherapeutic approaches, including vaccination-based and adoptive cell therapy strategies, for GI malignancies have demonstrated safety and the induction of antitumor immune responses. Therefore, immunotherapy is at the forefront of neoadjuvant as well as adjuvant therapies for the treatment and eradication of GI malignancies.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Cancer Vaccines; Cetuximab; Combined Modality Therapy; Gastrointestinal Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive; Panitumumab; Trastuzumab
PubMed: 23302905
DOI: 10.1177/107327481302000106 -
Molecular Cancer Therapeutics Sep 2020Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with...
Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. This study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, IHC, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared with 5-ALA ( = 0.0079). SDs for core and margin regions of interest in 5-ALA-treated tissues were significantly higher than those found in panitumumab-IRDye800CW-treated tissues ( = 0.0240 and = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were more than 10% higher than those of 5-ALA. Higher AUC for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared with 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescence intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in patients with GBM compared with 5-ALA.
Topics: Aminolevulinic Acid; Animals; Antineoplastic Agents, Immunological; Female; Glioblastoma; Humans; Mice; Mice, Nude; Optical Imaging; Panitumumab; Photosensitizing Agents
PubMed: 32606015
DOI: 10.1158/1535-7163.MCT-19-0819 -
Health Technology Assessment... Apr 2013Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually... (Comparative Study)
Comparative Study Review
The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology...
BACKGROUND
Colorectal cancer is the third most commonly diagnosed cancer in the UK after breast and lung cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Recently, targeted agents have become available including anti-epidermal growth factor receptor (EGFR) agents, for example cetuximab and panitumumab, and anti-vascular endothelial growth factor (VEGF) receptor agents, for example bevacizumab.
OBJECTIVE
To investigate the clinical effectiveness and cost-effectiveness of panitumumab monotherapy and cetuximab (mono- or combination chemotherapy) for Kirsten rat sarcoma (KRAS) wild-type (WT) patients, and bevacizumab in combination with non-oxaliplatin chemotherapy, for the treatment of metastatic colorectal cancer after first-line chemotherapy.
DATA SOURCES
The assessment comprises 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 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library, from 2005 to November 2010.
REVIEW METHODS
Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab, bevacizumab or panitumumab in participants with EGFR-expressing metastatic colorectal cancer with KRAS WT status that has progressed after first-line chemotherapy (for cetuximab and panitumumab) or participants with metastatic colorectal cancer that has progressed after first-line chemotherapy (bevacizumab). All steps in the review were performed by one reviewer and checked independently by a second. Synthesis was mainly narrative. An economic model was developed focusing on third-line and subsequent lines of treatment. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed.
RESULTS
The searches identified 7745 titles and abstracts. Two clinical trials (reported in 12 papers) were included. No data were available for bevacizumab in combination with non-oxaliplatin-based chemotherapy in previously treated patients. Neither of the included studies had KRAS status performed prospectively, but the studies did report retrospective analyses of the results for the KRAS WT subgroups. Third-line treatment with cetuximab plus best supportive care or panitumumab plus best supportive care appears to have statistically significant advantages over treatment with best supportive care alone in patients with KRAS WT status. For the economic evaluation, five studies met the inclusion criteria. The base-case incremental cost-effectiveness ratio (ICER) for KRAS WT patients for cetuximab compared with best supportive care is £98,000 per quality-adjusted life-year (QALY), for panitumumab compared with best supportive care is £150,000 per QALY and for cetuximab plus irinotecan compared with best supportive care is £88,000 per QALY. All ICERs are sensitive to treatment duration.
LIMITATIONS
In the specific populations of interest, there is a lack of evidence on bevacizumab, cetuximab and cetuximab plus irinotecan used second line and on bevacizumab and cetuximab plus irinotecan used third line. For cetuximab plus irinotecan treatment for KRAS WT people, there is no direct evidence on progression-free survival, overall survival and duration of treatment.
CONCLUSIONS
Although cetuximab and panitumumab appear to be clinically beneficial for KRAS WT patients compared with best supportive care, 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 for patients with KRAS WT status receiving cetuximab plus irinotecan.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Clinical Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Cost-Benefit Analysis; Disease-Free Survival; Humans; Models, Economic; Panitumumab; Quality-Adjusted Life Years; United Kingdom
PubMed: 23547747
DOI: 10.3310/hta17140 -
BMC Cancer Aug 2021Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a...
MONARCC: a randomised phase II study of panitumumab monotherapy and panitumumab plus 5-fluorouracil as first-line therapy for RAS and BRAF wildtype metastatic colorectal cancer: a study by the Australasian Gastrointestinal Trials Group (AGITG).
BACKGROUND
Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a "lighter" treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population.
METHODS/DESIGN
MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies.
DISCUSSION
MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer.
TRIAL REGISTRATION
Australia New Zealand Clinical Trials Registry: ACTRN12618000233224 , prospectively registered 14 February 2018.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Male; Multicenter Studies as Topic; Mutation; Neoplasm Metastasis; Panitumumab; Prognosis; Prospective Studies; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; ras Proteins
PubMed: 34407800
DOI: 10.1186/s12885-021-08644-4 -
British Journal of Clinical Pharmacology Oct 2009
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Cell Proliferation; Colorectal Neoplasms; ErbB Receptors; Humans; Panitumumab
PubMed: 19843050
DOI: 10.1111/j.1365-2125.2009.03492.x -
The Oncologist Jul 2017Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor... (Review)
Review
UNLABELLED
Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat-Sarcoma () mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog () exon 2, cumulative evidence also shows that patients whose tumors harbor exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti-EGFR treatment.In line with the resistance of mutated (mt) tumors, treatment response in mt tumors may also be altered given their important role in the EGFR signaling pathway. However, is not recommended as predictive biomarker yet because the evidence for the impact of mutations on treatment outcome is considered insufficient.This article summarizes the evidence for the impact of mutations on treatment outcome of anti-EGFR mAbs. Based on a review of literature, eight meta-analyses were included that consistently show that patients with mutations have a lack of treatment benefit of anti-EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for is even higher than for extended as a biomarker. We therefore advise ESMO and ASCO to reconsider status as a predictive biomarker for response.
IMPLICATIONS FOR PRACTICE
In metastatic colorectal cancer (mCRC), therapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab is indicated in absence of mutations. Cumulative evidence shows that patients with mutations, who comprise 10% of the mCRC population, do not benefit from anti-EGFR-antibody treatment. Although guidelines state that evidence for as a predictive marker is insufficient, we highlight that the quality and quantity of evidence is higher than suggested. We therefore encourage the use of as a predictive marker in order to exclude patients from therapy for whom limited treatment benefit is expected.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Biomarkers, Tumor; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Humans; Mutation; Panitumumab; Proto-Oncogene Proteins B-raf; Treatment Outcome; ras Proteins
PubMed: 28576857
DOI: 10.1634/theoncologist.2017-0031 -
Clinical Cancer Research : An Official... Oct 2023High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in...
PURPOSE
High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis.
EXPERIMENTAL DESIGN
Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS).
RESULTS
A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection.
CONCLUSIONS
High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.
Topics: Humans; Amphiregulin; Epiregulin; Cetuximab; Panitumumab; Retrospective Studies; Colorectal Neoplasms; Artificial Intelligence; Intercellular Signaling Peptides and Proteins; Colonic Neoplasms; Rectal Neoplasms; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors
PubMed: 37363997
DOI: 10.1158/1078-0432.CCR-23-0859 -
The Oncologist Jul 2022This North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab,...
BACKGROUND
This North Central Cancer Treatment Group (NCCTG) N064A (Alliance) phase II trial evaluated upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer.
METHODS
The treatment consisted of fluoropyrimidine and panitumumab given concurrently with radiotherapy followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month overall survival (OS) rate and secondary endpoints included confirmed response rate (RR), OS, progression-free survival (PFS), and adverse events. Enrollment of 50 patients was planned and the study fully accrued.
RESULTS
Fifty-two patients were enrolled, but only 51 were treated and included in the analysis. The median age of patients was 65 years and 54.9% were women. Twenty-two patients received at least 1 cycle of systemic therapy following radiotherapy, but 29 patients received chemoradiotherapy only without receiving subsequent chemotherapy after completion of chemoradiotherapy. The overall RR was 5.9% (95% CI: 1.2%-16.2%). The 12-month OS rate was 50% (95% CI: 38%-67%) which fell short of the per-protocol goal for success (51.1%). The median PFS was 7.4 months (95% CI: 4.5-8.6) and the median OS was 12.1 months (95% CI 7.9-15.9). Grade 3 or higher adverse events were reported by 88%.
CONCLUSION
The combination of panitumumab, chemotherapy, and external beam radiation therapy was associated with very high rates of grades 3-4 toxicities and survival results did not meet the trial's goal for success. This regimen is not recommended for further study (ClinicalTrials.gov Identifier NCT00601627).
Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Pancreatic Neoplasms; Panitumumab
PubMed: 35285484
DOI: 10.1093/oncolo/oyac002 -
Cancer Biology & Therapy Dec 2013The epidermal growth factor receptor (EGFR) has been validated as a therapeutic target in several human tumors, including colorectal cancer (CRC).(1,2) Occupancy of the...
The epidermal growth factor receptor (EGFR) has been validated as a therapeutic target in several human tumors, including colorectal cancer (CRC).(1,2) Occupancy of the EGFR with ligand can activate the RAS/RAF/MAPK, STAT, and PI3K/AKT signaling pathways. These pathways modulate cellular proliferation, adhesion, angiogenesis, migration, and survival.(3) Anti-EGFR targeted antibodies, such as cetuximab and panitumumab, have shown response and disease stabilization rates of approximately 10% and 30%, respectively, when administered as monotherapy in CRC.(1,4) EGFR expression is used for patient selection for these studies. However, clinical results have suggested that the level of EGFR expression as measured by immunohistochemistry may not predict clinical benefit.(4,5)
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Female; Humans; Male; Panitumumab; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins
PubMed: 24317328
DOI: 10.4161/cbt.27395 -
Frontiers in Bioscience (Elite Edition) Jan 2012The epidermal growth factor receptor (EGFR) has become an important target in cancer treatment. In consequence, drugs directed at this and other molecular targets are an... (Review)
Review
The epidermal growth factor receptor (EGFR) has become an important target in cancer treatment. In consequence, drugs directed at this and other molecular targets are an increasingly important part of the treatment of numerous tumours. Cetuximab and panitumumab, two monoclonal antibodies that target EGFR, have proved to be effective in metastatic colorectal cancer treatment. However, some patients do not respond to treatment with EGFR inhibitors and, for this reason, interest in the identification of patients most likely to benefit from treatment with these agents has grown considerably. K-Ras, a member of the RAS family of signalling proteins plays an important role in EGFR- mediated regulation of cellular proliferation and survival. Patients with wild-type K-Ras were found to have significantly greater overall survival, progression-free survival and/or response rate compared with patients harbouring K-Ras mutations.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Humans; Panitumumab
PubMed: 22201852
DOI: 10.2741/357