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Clinical, Cosmetic and Investigational... 2024Panitumumab is a recombinant, fully humanized immunoglobulin G monoclonal antibody targeting the epidermal growth factor receptor (EGFR). It is approved for the first-...
Panitumumab is a recombinant, fully humanized immunoglobulin G monoclonal antibody targeting the epidermal growth factor receptor (EGFR). It is approved for the first- and second-line treatment of advanced wild-type KRAS colorectal cancer. Although common cutaneous side effects include acneiform dermatitis, folliculitis, and xerosis, ocular toxicities have occasionally been reported. Herein, we report the case of an 81-year-old Thai female with chemorefractory advanced stage sigmoid colon cancer who developed isolated periorbital dermatitis following treatment with panitumumab plus modified FOLFOX6. The cutaneous adverse reaction recurred after subsequent infusions; however, it was alleviated by topical therapy. To our knowledge, panitumumab-induced periorbital dermatitis is exceptionally rare. To raise awareness of potential periocular cutaneous side effects in patients taking EGFR inhibitors, the published literature regarding periorbital dermatitis induced by these agents has also been reviewed in this article. Periorbital dermatitis should be considered as a potential cutaneous reaction following panitumumab administration, and should be promptly treated.
PubMed: 38586180
DOI: 10.2147/CCID.S459067 -
International Journal of Molecular... Mar 2024Kirsten rat sarcoma virus oncogene homolog () is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), mutations are present in more than... (Review)
Review
Kirsten rat sarcoma virus oncogene homolog () is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), mutations are present in more than 50% of cases, and the glycine-to-cysteine mutation at codon 12 ( G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.
Topics: Humans; Cetuximab; Panitumumab; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins p21(ras); Tremor; Colorectal Neoplasms; Mutation; Lung Neoplasms
PubMed: 38542278
DOI: 10.3390/ijms25063304 -
Diseases (Basel, Switzerland) Feb 2024The correlation between cancer and venous thromboembolism (VTE) is solid, whereas the knowledge about cancer-related arterial thromboembolism (ATE) still needs a deeper...
The correlation between cancer and venous thromboembolism (VTE) is solid, whereas the knowledge about cancer-related arterial thromboembolism (ATE) still needs a deeper investigation to clarify its pathogenesis. We describe two cases that represent useful hints for a comprehensive review of the thrombotic issue. A 75-year-old man with advanced rectal cancer treated with fluoropyrimidines suffered two catheter-related VTE events managed according to current guidelines. There was no indication for "extended" anticoagulant therapy for him, but during antithrombotic wash-out and fluoropyrimidines plus panitumumab regimen, he suffered a massive right coronary artery (RCA) thrombosis. Another patient with no cardiovascular (CV) risk factors and affected by advanced bladder cancer was treated with a platinum-containing regimen and suffered an acute inferior myocardial infarction 2 days after chemotherapy administration. He was successfully treated with primary Percutaneous Transluminal Coronary Angioplasty of RCA, discontinuing platinum-based therapy. Our observations raise the issue of cancer-associated thrombosis (CAT) complexity and the potential correlation between arterial and venous thrombotic events. Moreover, physicians should be aware of the thrombotic risk associated with anticancer therapies, suggesting that an appropriate prophylaxis should be considered.
PubMed: 38534971
DOI: 10.3390/diseases12030047 -
Proceedings of the National Academy of... Mar 2024FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to...
FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different hotspot mutations in human colon organoids. Functionally, mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.
Topics: Humans; F-Box-WD Repeat-Containing Protein 7; Ubiquitin-Protein Ligases; Epidermal Growth Factor; Proteomics; ErbB Receptors; Neoplasms; F-Box Proteins
PubMed: 38483988
DOI: 10.1073/pnas.2309902121 -
Anti-cancer Drugs Jun 2024Colorectal cancer (CRC) ranks third in global cancer prevalence, with 40% presenting as metastatic colorectal cancer (mCRC). KRAS mutations in mCRC patients confer...
Colorectal cancer (CRC) ranks third in global cancer prevalence, with 40% presenting as metastatic colorectal cancer (mCRC). KRAS mutations in mCRC patients confer resistance to anti-EGFR treatments. Promising inhibitors such as sotorasib and adagrasib targeting KRASG12C mutations have demonstrated efficacy. Herein, we present a heavily pretreated mCRC case with a progression-free survival of 12 months with sotorasib and panitumumab. In 2017, a 27-year-old male presented with abdominal pain and received a diagnosis of stage IIIC KRAS G12C mutant CRC. Following surgery and adjuvant chemotherapy, he developed metastases in the liver and lungs in 2020. Treatment with FOLFIRINOX and bevacizumab, and later FOLFIRI and bevacizumab, with surgeries and local interventions resulted in partial responses. Upon disease progression, sotorasib and panitumumab were initiated, achieving a complete metabolic response. After 12 months of progression-free survival, oligoprogressive liver lesions were surgically resected. This case highlights the remarkable outcome of a heavily treated KRAS G12C mutant mCRC patient. The combination of sotorasib and panitumumab, along with multidisciplinary approaches including surgery and local interventions, played an important role in our patient's survival.
Topics: Male; Humans; Adult; Panitumumab; Bevacizumab; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras); Antibodies, Monoclonal; Progression-Free Survival; Camptothecin; Pancreatic Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Mutation; Piperazines; Pyridines; Pyrimidines
PubMed: 38451823
DOI: 10.1097/CAD.0000000000001587 -
European Journal of Cancer (Oxford,... May 2024The first-line treatment choice of EGFRIs plus doublet chemotherapy vs. bevacizumab plus doublet chemotherapy remains a topic of interest for patients with left-sided... (Meta-Analysis)
Meta-Analysis Review
A meta-analysis of efficacy and safety data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in adult patients with RAS wild-type metastatic colorectal cancer by sidedness.
The first-line treatment choice of EGFRIs plus doublet chemotherapy vs. bevacizumab plus doublet chemotherapy remains a topic of interest for patients with left-sided RAS WT mCRC. We conducted a systematic literature review and meta-analysis of clinical trial data published between 2015 and 2024. We evaluated the relative efficacy and safety of first-line EGFRIs plus doublet chemotherapy (FOLFIRI or FOLFOX) vs. bevacizumab plus doublet chemotherapy for patients with RAS WT left-sided mCRC, as well as in all- and right-sided tumors. We identified eight trials with 2624 patients. Five trials reported outcomes by tumor sidedness. In the left-sided population, overall survival (OS) (Hazard Ratio (HR) = 0.80, 95% Confidence Interval (CI): 0.71-0.90) and objective response rate (ORR) (Odds ratio [OR]=1.61, 95% CI: 1.30-1.99) favored EGFRI plus chemotherapy, while no statistically significant differences were observed for progression-free survival (PFS) (HR=0.93, 95% CI: 0.84-1.04) or resection rate (RR). Similar results were found in the all-sided population. In the right-sided population, PFS favored bevacizumab plus chemotherapy (HR=1.45, 95% CI: 1.19-1.78), while no statistically significant differences were observed for OS (HR=1.17, 95% CI: 0.95-1.44), ORR (OR=0.99, 95% CI: 0.69-1.41), and RR. Early tumor shrinkage in the all-sided population favored EGFRI plus chemotherapy (OR=1.72; 95% CI: 1.36-2.17); limited data precluded evaluation by sidedness. Safety was available in 6 trials for all-sided tumors and 1 trial for left-sided tumors, each demonstrating typical class-specific adverse events. This most comprehensive meta-analysis indicates a benefit for first-line EGFRI plus chemotherapy over bevacizumab plus chemotherapy in patients with left-sided RAS WT mCRC.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; ErbB Receptors
PubMed: 38442645
DOI: 10.1016/j.ejca.2024.113975 -
World Journal of Gastrointestinal... Feb 2024Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer (CRC). Effective drainage is often impossible...
BACKGROUND
Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer (CRC). Effective drainage is often impossible before initiating systemic chemotherapy, owing to the liver's diffuse metastatic involvement. Moreover, an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable.
CASE SUMMARY
The patient, a man in his 50s, presented with progressive fatigue and severe jaundice. Computed tomography revealed multiple hepatic masses with thickened walls in the sigmoid colon, which was pathologically confirmed as a well-differentiated adenocarcinoma. No or mutations were detected. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was 2. Biliary drainage was impossible due to the absence of a dilated bile duct, and panitumumab monotherapy was promptly initiated. Subsequently, the bilirubin level decreased and then normalized, and the patient's PS improved to zero ECOG score after four cycles of therapy without significant adverse events.
CONCLUSION
Anti-EGFR antibody monotherapy is a safe and effective treatment for wild-type CRC and hepatic metastases with severe hyperbilirubinemia.
PubMed: 38425406
DOI: 10.4251/wjgo.v16.i2.557 -
Cancer Treatment Reviews Apr 2024The last two decades have witnessed major breakthroughs in the development of targeted therapy for patients with metastatic colorectal cancer (mCRC), an achievement... (Review)
Review
The last two decades have witnessed major breakthroughs in the development of targeted therapy for patients with metastatic colorectal cancer (mCRC), an achievement which stems largely from advances in translational research. Precision medicine is now widely practiced in routine oncological care, where systemic therapy is individualized based on clinical factors such as primary tumor sidedness, location and number of metastases, as well as molecular factors such as the RAS and BRAF mutation status, mismatch repair / microsatellite status and presence of other actionable genomic alterations in the tumor. The optimal selection of patients with RAS and BRAF-wild type (WT), left-sided primary tumor for treatment with epidermal growth factor receptor (EGFR) and chemotherapy (chemo) has markedly improved survival in the first-line setting. The pivotal trials of cetuximab in combination with BRAF/ MEK inhibitor for BRAF V600E mutant mCRC, and panitumumab with KRAS G12C inhibitor in KRAS(G12C)-mutant mCRC have been practice-changing. Anti-HER2 small molecular inhibitor, antibodies and antibody-drug conjugates have significantly improved the treatment outcome of patients with HER2 amplified mCRC. Anti-angiogenesis agents are now used across all lines of treatment and novel combinations with immune-checkpoint inhibitors are under active investigation in MSS mCRC. The non-invasive monitoring of molecular resistance to targeted therapies using Next Generation Sequencing analysis of circulating tumor-derived DNA (ctDNA) and captured sequencing of tumors have improved patient selection for targeted therapies. This review will focus on how latest advances, challenges and future directions in the development of targeted therapies in mCRC.
Topics: Humans; Colorectal Neoplasms; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Panitumumab; Cetuximab; Colonic Neoplasms; Rectal Neoplasms
PubMed: 38422896
DOI: 10.1016/j.ctrv.2024.102700 -
Scientific Reports Feb 2024Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and hypoxia are associated with radioresistance. The goal of this study is to...
Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and hypoxia are associated with radioresistance. The goal of this study is to study the synergy of anti-HER2, trastuzumab, and anti-EGFR, cetuximab, and characterize the tumor microenvironment components that may lead to increased radiation sensitivity with dual anti-HER2/EGFR therapy in head and neck squamous cell carcinoma (HNSCC). Positron emission tomography (PET) imaging ([Zr]-panitumumab and [Zr]-pertuzumab) was used to characterize EGFR and HER2 in HNSCC cell line tumors. HNSCC cells were treated with trastuzumab, cetuximab, or combination followed by radiation to assess for viability and radiosensitivity (colony forming assay, immunofluorescence, and flow cytometry). In vivo, [F]-FMISO-PET imaging was used to quantify changes in oxygenation during treatment. Bliss Test of Synergy was used to identify combination treatment synergy. Quantifying EGFR and HER2 receptor expression revealed a 50% increase in heterogeneity of HER2 relative to EGFR. In vitro, dual trastuzumab-cetuximab therapy shows significant decreases in DNA damage response and increased response to radiation therapy (p < 0.05). In vivo, tumors treated with dual anti-HER2/EGFR demonstrated decreased tumor hypoxia, when compared to single agent therapies. Dual trastuzumab-cetuximab demonstrates synergy and can affect tumor oxygenation in HNSCC. Combination trastuzumab-cetuximab modulates the tumor microenvironment through reductions in tumor hypoxia and induces sustained treatment synergy.
Topics: Humans; Cetuximab; Squamous Cell Carcinoma of Head and Neck; Trastuzumab; Head and Neck Neoplasms; Cell Line, Tumor; Tumor Microenvironment; ErbB Receptors
PubMed: 38355949
DOI: 10.1038/s41598-024-52897-5 -
Nature Medicine Mar 2024Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic...
Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .
Topics: Humans; Panitumumab; Bevacizumab; Antibodies, Monoclonal; Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; ErbB Receptors; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras)
PubMed: 38347302
DOI: 10.1038/s41591-023-02791-w