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Cetuximab (Erbitux)

Web Resources: Cetuximab (Erbitux)
Latest Research Publications

Web Resources: Cetuximab (Erbitux) (6 links)

Latest Research Publications

Pinette A, McMichael E, Courtney NB, et al.
An IL-15-based superagonist ALT-803 enhances the NK cell response to cetuximab-treated squamous cell carcinoma of the head and neck.
Cancer Immunol Immunother. 2019; 68(8):1379-1389 [PubMed] Related Publications
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide and epidermal growth factor receptor (EGFR) is overexpressed in greater than 90% of patient tumors. Cetuximab is a monoclonal antibody that binds to EGFR and can activate immune cells, such as natural killer (NK) cells, that express receptors for the Fc (constant region) of immunoglobulin G. IL-15 (interleukin-15) is a critical factor for the development, proliferation and activation of effector NK cells. A novel IL-15 compound known as ALT-803 that consists of genetically modified IL-15 plus the IL-15 receptor alpha protein (IL15Rα) fused to the Fc portion of IgG1 has recently been developed. We hypothesized that treatment with ALT-803 would increase NK cell-mediated cytotoxicity of cetuximab-coated head and neck squamous cells. CD56

Addeo R, Caraglia M, Vincenzi B, et al.
Efficacy and Safety of Cetuximab plus Radiotherapy in Cisplatin-Unfit Elderly Patients with Advanced Squamous Cell Head and Neck Carcinoma: A Retrospective Study.
Chemotherapy. 2019; 64(1):48-56 [PubMed] Related Publications
INTRODUCTION: Concurrent platinum-based chemoradiation currently represents the standard treatment for advanced head and neck cancer (HNC), but it induces a significant toxicity, in particular among elderly patients. Elderly and unfit patients have been underrepresented in clinical trials and there is a need for tailored guidelines.
METHODS: A retrospective review of clinical data of HNC patients treated at the Operative Oncology Unit of the San Giovanni di Dio Hospital in Frattamaggiore (Naples, Italy) was performed. At study entry, a comprehensive assessment including absolute contraindications for cisplatin use, as well as comorbidities, socioeconomic status, BMI, and weight loss, was performed. The treatment included high-dose radiotherapy plus weekly cetuximab (initially at a dose of 400 mg/m2of body surface area and thereafter at 250 mg weekly during the whole radiotherapy). The aim of this study was to evaluate the activity and toxicity of this schedule in a series of patients aged older than 69 years.
RESULTS: Between May 30, 2013, and March 30, 2015, sixty-four patients (age range, 69-87 years; median age, 73.7 years; male/female ratio, 46/18) were treated. The overall response rate was 67% in this series of patients. The disease control rate was 76%. Disease progression was recorded in 25% of the patients. The median duration of loco-regional control was 17 months (range, 15.8-17.7 months). PFS was 14.8 months (range, 13.9-15.5 months). The overall survival was 34 months, with a median follow-up of 41.0 months (range, 31.1-36.8 months). The main grade 3/4 adverse events were acne rash in 52% and radiation dermatitis in 32% of the cases.
CONCLUSION: Cetuximab plus radiotherapy appears to be feasible and active in elderly patients unsuitable for cisplatin treatment. The treatment was supported by a favorable toxicity profile.

Marques RP, Heudtlass P, Pais HL, et al.
Patient-reported outcomes and health-related quality of life for cetuximab versus bevacizumab in metastatic colorectal cancer: a prospective cohort study.
J Cancer Res Clin Oncol. 2019; 145(7):1719-1728 [PubMed] Related Publications
PURPOSE: Uncertainty exists regarding Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQoL) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab or bevacizumab. We conducted a prospective cohort study comparing PROs and HRQoL from both therapies.
METHODS: We assessed PROs and HRQoL from patients treated with cetuximab or bevacizumab using QLQ-C30 and QLQ-CR29 questionnaires at three sequential time points, including baseline. Global Health Status (GHS), functional and symptom scales, and Overall Treatment Utility (derived from clinical and patient-reported outcomes) were compared for the two treatment strategies.
RESULTS: Between January 2017 and April 2018, 44 patients were allocated to cetuximab (n = 19) or bevacizumab (n = 25). Except for RAS mutation status, patient baseline characteristics were generally well balanced across treatment groups. A higher proportion of patients experienced a deterioration in GHS (≥ 10%) in cetuximab arm - 53.8% (95% CI 25.1-80.8%) at 6 weeks and 66.7% (95% CI 29.9-92.5%) at 12 weeks-comparing to bevacizumab cohort: 18.2% (95% CI 5.2-40.3%) at 6 weeks and 12.5% (95% CI:1.6-38.3%) at 12 weeks. Treatment utility rates at 6 and 12 weeks were, respectively, 88.6% and 69.8% for bevacizumab, compared to 49% and 19.1% for cetuximab (p = 0.004), a difference confirmed in subset analyses.
CONCLUSIONS: In patients with mCRC, cetuximab-containing regimens led to a progressive negative impact on PROs and global HRQoL, when compared to baseline and bevacizumab. Future research is needed to confirm these results. Our findings demonstrate the value of PROs when assessing comparative effectiveness of different treatment regimens.

Larsen FO, Jensen BV, Nørgaard HH, et al.
Intrahepatic Oxaliplatin and Systemic 5-FU +/- Cetuximab in Chemo-Naïve Patients with Liver Metastases from Colorectal Cancer.
Oncology. 2019; 96(6):299-308 [PubMed] Related Publications
BACKGROUND: In case of response to chemotherapy, unresectable liver metastases from colorectal cancer can be converted to resectable and thereby obtain a chance of cure. The primary aim of this trial was to evaluate the response rate with intrahepatic oxaliplatin in combination with systemic 5-FU +/- cetuximab. Secondary aims were to evaluate the conversion rate from unresectable to resectable liver metastases, median progression-free survival, median overall survival, and toxicity.
METHODS: Forty-five chemo-naïve patients with liver metastases from colorectal cancer were treated in a prospective phase II trial. Calcium folinate and 5-FU were delivered systemically while oxaliplatin was delivered alternating between systemic and intrahepatic administration. When oxaliplatin was delivered intrahepatic-ally, infusion time was reduced to 10 min followed by embolic material. In patients with KRAS wild-type tumors, cetuximab was added.
RESULTS: The treatment was well tolerated and only pain in the liver and a mild increase in liver enzymes were observed after intrahepatic oxaliplatin. The patients obtained a response rate of 82%. Further, 58% converted from having unresectable to resectable liver metastases. The median overall survival and progression-free survival were 38.7 months (95% confidence interval [CI] 33.0-44.3) and 12.9 months (95% CI 10.2-15.6), respectively.
CONCLUSIONS: Intrahepatic infusion of oxaliplatin in 10 min with systemic 5-FU to patients with chemo-naïve colorectal cancer is feasible and with low toxicity. A high response rate and long median overall survival were obtained.

Zheng B, Wang X, Wei M, et al.
First-line cetuximab versus bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a systematic review and meta-analysis.
BMC Cancer. 2019; 19(1):280 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A first-line biologic treatment for metastatic colorectal cancer (mCRC) is still controversial. We, therefore, performed a meta-analysis to determine the efficacy of first-line cetuximab versus bevacizumab for RAS and BRAF wild-type mCRC.
METHODS: In March 2018, an electronic search of the following biomedical databases was performed: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov and Web of Knowledge. Randomized controlled trials (RCTs) and prospective or observational cohort studies (OCSs) were included. Subgroup analyses of all RCTs were performed in all outcomes. All statistical analyses were performed using RevMan software 5.3.
RESULTS: Two RCTs and three OCSs, involving a total 2576 patients, were included. The meta-analysis reported that cetuximab was associated with a longer overall survival (OS) [HR 0.89, 95% CI (0.81-0.98); p = 0.02], a higher ORR [RR 1.11, 95% CI (1.03-1.19); p = 0.006], higher complete response [RR 3.21, 95% CI (1.27-8.12); p = 0.01] and a greater median depth of response than bevacizumab. However, no significant difference was observed between cetuximab and bevacizumab groups for PFS, DCR, partial response, progressive disease, curative intent metastasectomy, EORR and incidence of grade 3 or higher adverse events. In the subgroup meta-analyses of the RCTs, inconsistent results compared to the main analysis, however, were found, in the ORR, DCR and curative intent metastasectomy.
CONCLUSIONS: The current evidence indicates that compared to bevacizumab treatment, cetuximab provides a clinically relevant effect in first-line treatment against mCRC, at the cost of having lower stable disease.

Suton P, Skelin M, Rakusic Z, et al.
Cisplatin-based chemoradiotherapy vs. cetuximab-based bioradiotherapy for p16-positive oropharyngeal cancer: an updated meta-analysis including trials RTOG 1016 and De-ESCALaTE.
Eur Arch Otorhinolaryngol. 2019; 276(5):1275-1281 [PubMed] Related Publications
PURPOSE: Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is a special entity among head and neck squamous cell carcinomas (HNSCCs). Given its favorable prognosis, one of the de-escalating strategies in the treatment of OPC includes the introduction of cetuximab (C225) instead of cisplatin (CDDP) in conjunction with radiotherapy. An updated meta-analysis of published studies has been performed, which directly compared the efficacy of CDDP vs. C225 given concurrently with radiotherapy as definitive treatment of p16-positive OPC.
METHODS: A systematic literature search was performed for studies published between 2006 and 2018. A total of 1490 citations were obtained and 8 studies met inclusion criteria, with a total of 1665 patients.
RESULTS: The data from seven studies were available for the analysis of 2-year overall survival (OS). Calculated pooled OR for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy, was 0.45 (P < 0.0001). The data from eight studies were available for the analysis of 2-year locoregional recurrence (LRR). Calculated pooled OR for CDDP-based chemoradiotherapy vs. C225-based bioradiotherapy was 0.35 (P < 0.0001). Patients receiving CDDP with irradiation had 2.2- and 2.9-fold decreased risk for death from any cause and LRR, respectively.
CONCLUSIONS: For patients with HPV-positive OPC, radiotherapy plus C225 showed inferior OS and higher LRR rates compared with radiotherapy plus CDDP. CDDP-based chemoradiotherapy should remain standard of definitive treatment of p16-positive OPC.

Nakamura H, Tamaki S, Yagyuu T, et al.
Relationship Between EGFR Expression in Oral Cancer Cell Lines and Cetuximab Antibody-dependent Cell-mediated Cytotoxicity.
Anticancer Res. 2019; 39(3):1275-1282 [PubMed] Related Publications
BACKGROUND/AIM: Cetuximab treatment targets the epidermal growth factor receptor (EGFR) overexpressed in oral cancer. This study aimed to investigate the anti-tumour activity of cetuximab against oral cancer cell lines with respect to antibody-dependent cell-mediated cytotoxicity (ADCC), and determine the correlation between ADCC and EGFR expression.
MATERIALS AND METHODS: EGFR expression in oral cancer cells was measured by quantitative flow cytometric analysis and immunohistochemistry. ADCC activity was measured by 4-h calcein release assays.
RESULTS: Cetuximab-mediated ADCC against oral cancer cells was detectable at a concentration of 0.1 μg/ml. A high correlation was observed between the number of EGFR molecules on the surface of oral cancer cells and ADCC (correlation coefficient: 0.847; p=0.032).
CONCLUSION: ADCC is an important mechanism underlying the therapeutic effect of cetuximab, and EGFR expression in tumour cells might serve as a predictive marker to evaluate the effect of cetuximab treatment.

Jia J, Zhang P, Gou M, et al.
The Role of Serum CEA and CA19-9 in Efficacy Evaluations and Progression-Free Survival Predictions for Patients Treated with Cetuximab Combined with FOLFOX4 or FOLFIRI as a First-Line Treatment for Advanced Colorectal Cancer.
Dis Markers. 2019; 2019:6812045 [PubMed] Free Access to Full Article Related Publications
Background: Previously, it was demonstrated that serum levels of tumor markers, CEA and CA19-9, correlated with chemotherapy. Consequently, it has been hypothesized that dynamic monitoring of changes in these markers may predict the shrinkage or growth of colorectal cancers. To test this hypothesis, we analyzed CEA and CA19-9 serum levels in patients with advanced colorectal cancer who received cetuximab in combination with chemotherapy. These levels were evaluated at various time points to identify their potential to serve as early efficacy predictors during treatment and early predictors of disease progression.
Patients and Methods: Measurements of tumor markers, CEA and CA 19-9, in patients with metastatic colorectal cancer (
Results: After completing three cycles of treatment, the best diagnosis of cetuximab resistance was achieved when CEA increased by 35% (efficacy, 83.33%; sensitivity, 75.41%) and when CA19-9 increased by 28% (efficacy, 80.00%; sensitivity, 84.31%). Next, the efficacy of cetuximab at the time of diagnosis (at the first imaging examination/after three cycles of treatment) was evaluated after the first cycle of chemotherapy. When CEA decreased by 60% from its baseline level, the best effective rate and sensitivity were observed (63.64% and 80.95%, respectively). Similarly, when CA19-9 was 45% lower than its baseline level, the best effective rate and sensitivity were observed (84.21% and 93.18%, respectively). To evaluate progression-free survival (PFS), levels of both CEA and CA19-9 were evaluated after the third cycle of chemotherapy. Increases of 35% and 28%, respectively, resulted in a shorter PFS period compared with the other patients (3.15 months vs. 9.10 months, respectively;
Conclusions: CEA and CA19-9 are useful indicators of therapeutic curative effect from cetuximab combined with first-line chemotherapy. These markers also helped assess cetuximab resistance and served as early predictors of initial treatment effectiveness. Furthermore, a simultaneous increase or decrease in the levels of both indicators was consistent with the observed differences in PFS.

Zhang X, Li Y, Wei M, et al.
Cetuximab-modified silica nanoparticle loaded with ICG for tumor-targeted combinational therapy of breast cancer.
Drug Deliv. 2019; 26(1):129-136 [PubMed] Free Access to Full Article Related Publications
Combinational therapy is usually considered as a preferable approach for effective cancer therapy. Especially, combinational chemo and photothermal therapy is of particular interest due to its high flexibility as well as efficiency. In this article, we the silica nanoparticles (SLN) were surface conjugated with Cetuximab (Cet-SLN) to target epidermal growth factor receptor (EGFR), a common receptor that usually observed to overexpress in multiple breast cancers. Moreover, the high drug loading capacity of Cet-SLN was employed to encapsulate photothermal agent indocyanine green (ICG) to finally fabricate a versatile drug delivery system (DDS) able to co-deliver Cet and ICG (Cet-SLN/ICG) for combinational chemo-photothermal therapy of breast cancer. The obtained results clearly demonstrated that Cet-SLN/ICG was well-dispersed nanoparticles with preferable stability under physiological condition. Furthermore, due to the conjugation of Cet, Cet-SLN/ICG could target EGFR which overexpress in MCF-7 cells. Most importantly, both in vitro and in vivo results suggested that compared with Cet or ICG alone, the Cet-SLN/ICG showed superior anticancer efficacy. In conclusion, Cet-SLN/ICG could be a potential platform for effective combinational chemo-photothermal therapy for breast cancer.

Muro K, Itabashi M, Hashida H, et al.
Observational study of first-line chemotherapy including cetuximab in patients with metastatic colorectal cancer: CORAL trial.
Jpn J Clin Oncol. 2019; 49(4):339-346 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: We aimed to clarify the clinical practice and outcomes of first-line cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Efficacy and safety were evaluated in each group classified by the European Society for Medical Oncology Guidelines 2012.
METHODS: This prospective observational study included patients with previously untreated metastatic colorectal cancer from 158 centers in Japan who started first-line cetuximab-containing chemotherapy from January 2012 to June 2013 and were followed for up to 3 years. The resection rates after chemotherapy were calculated and the overall survival was estimated using the Kaplan-Meier method for Group 1 (G1, potentially resectable), Group 2 (G2, not resectable and tumor-related symptoms) and Group 3 (G3, not resectable and asymptomatic).
RESULTS: Of 578 patients, 562 were classified into G1 (n = 165), G2 (n = 224) or G3 (n = 173). The resection rate of any site was higher in G1 (57.0%) than in G2 (11.2%) and G3 (11.6%). G1, G2 and G3 showed median overall survivals (95% confidence interval) of 45.9 (38.1-not available), 16.7 (14.5-18.8) and 30.6 (23.2-34.8) months, respectively (P < 0.0001). The common tumor-related symptoms in G2 were pain, fatigue and anorexia, from which 31.7, 22.2 and 14.8% of the patients suffered at baseline.
CONCLUSIONS: The expected efficacy and safety of first-line cetuximab-containing chemotherapy were demonstrated in patients with metastatic colorectal cancer under clinical practice in Japan.

Lu X, Liu S, Han M, et al.
Afatinib-loaded immunoliposomes functionalized with cetuximab: A novel strategy targeting the epidermal growth factor receptor for treatment of non-small-cell lung cancer.
Int J Pharm. 2019; 560:126-135 [PubMed] Related Publications
Afatinib, a selective and irreversible inhibitor of tyrosine kinase, was approved for the treatment of advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) overexpression in 2013. Cetuximab (CTX), an anti-EGFR monoclonal antibody, is co-administered with afatinib to improve efficacy. Unfortunately, dose-related adverse reactions caused by combination therapy have affected patient compliance, and have resulted in treatment discontinuation in severe cases. In the present study, afatinib was encapsulated in "liposomes" (LPs) to achieve longer circulation in the blood and an enhanced permeability-and-retention effect in tumors. Concomitantly, CTX was designed to bind to drug-loaded LPs to form "immuno-LPs" for tumor-cell selectivity and therapeutic activity. In vitro, the cellular internalization rate of immuno-LPs was significantly higher than that of LPs (p < 0.05). In vivo, a markedly increased area under the curve and prolonged terminal half-life were detected in rats injected with the two LP formulations, indicating that LP encapsulation protected afatinib from binding to hemoglobin to control the risk of idiosyncratic drug reactions. Compared with free afatinib and LPs, immuno-LPs exhibited strongly enhanced drug delivery and antitumor efficacy in an NSCLC xenograft model, with stronger tumor selectivity and potentially fewer side-effects. Hence, EGFR-targeting immuno-LPs appear to be promising for NSCLC treatment.

Qiu W, Zhang C, Wang S, et al.
A Novel Anti-EGFR mAb Ame55 with Lower Toxicity and Better Efficacy than Cetuximab When Combined with Irinotecan.
J Immunol Res. 2019; 2019:3017360 [PubMed] Free Access to Full Article Related Publications
To improve efficacy and minimize toxicity of EGFR inhibition treatment, we developed Ame55, a novel anti-EGFR IgG1 with lower affinity to EGFR than cetuximab (C225) from a human phage library. Ame55 had lower bioactivity than cetuximab

Gurdal H, Tuglu MM, Bostanabad SY, Dalkiliç B
Partial agonistic effect of cetuximab on epidermal growth factor receptor and Src kinase activation in triple‑negative breast cancer cell lines.
Int J Oncol. 2019; 54(4):1345-1356 [PubMed] Related Publications
Cetuximab is a monoclonal antibody developed to inhibit the binding of growth factors and the subsequent activation of epidermal growth factor receptor (EGFR). Triple‑negative breast cancer (TNBC) is resistant to cetuximab treatment. The aim of the present study was to examine the partial agonistic properties of cetuximab, which not only blocks ligand binding, but also partially triggers EGFR activation, which may lead to cetuximab resistance in TNBC. The phosphorylation of growth factor receptors and their signalling pathways were evaluated by determining the phosphorylation of EGFR, insulin‑like growth factor receptor (IGF‑1R), vascular endothelial growth factor receptor (VEGFR)‑2, Src kinase, phosphoinositide‑3‑kinase (PI3K), extracellular signal‑regulated kinase (ERK1/2) and serine/threonine‑specific protein kinase (Akt) and the degradation of EGFR, and by assessing the morphology and proliferation of MDA‑MB‑231 and MDA‑MB‑468 cells. Cetuximab treatment led to the phosphorylation of EGFR, VEGFR‑2, IGF‑1R and downstream signalling molecules, Src kinase and PI3K in these cells, as well as Akt in the MDA‑MB‑231 cells. The cetuximab‑mediated phosphorylation of IGF‑1R, VEGFR‑2 and Akt was inhibited by the EGFR kinase inhibitor, AG1478, and the Src kinase inhibitor, PP2. Cetuximab treatment led to the degradation of EGFR. The cetuximab‑induced phosphorylation and EGFR degradation were less prominent compared with those induced by EGF. Cetuximab partially inhibited EGF‑mediated responses. Cetuximab, similar with EGF, altered cellular morphology in a serum‑free medium. In both cell lines, the Src kinase inhibitor enhanced the cetuximab‑induced anti‑proliferative response. These results indicate that cetuximab exerts a partial agonistic effect on EGFR, which activates Src kinase and subsequently transactivates IGF‑1R and VEGFR‑2. This partial agonistic property is likely one of the mechanisms underlying the resistance of TNBC to cetuximab.

Agarwal V, Subash A, Nayar RC, Rao V
Is EGFR really a therapeutic target in head and neck cancers?
J Surg Oncol. 2019; 119(6):685-686 [PubMed] Related Publications
Epidermal growth factor receptor (EGFR) is overexpressed in 90% to 100% of squamous cell carcinoma of the head and neck (SCCHN). The overexpression of EGFR and its ligand transforming growth factor is associated with poorer survival. EGFR inhibitors such as Cetuximab (Erbitux) have shown a significant antitumoral effect in SCCHN and has improved locoregional control and as well as survival. Even though there was some success with Cetuximab, work with other EGFR inhibition has not been very fruitful and not really shown any promise. Mechanism of action of Cetuximab could be immune-mediated rather than EGFR inhibition and EGFR may not necessarily be a therapeutic target in SCCHN.

Yu Y, Ying J, Zhang W, et al.
Outcome of chemotherapy with or without targeted agents in metastatic colorectal cancer patients with deficient DNA mismatch repair: A single center, cohort study.
Asia Pac J Clin Oncol. 2019; 15(3):128-135 [PubMed] Related Publications
AIMS: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) is a rare disease accounting only for 4-5% of the whole mCRC and its optimal treatment still remains unclear. We conducted a retrospective study to evaluate the outcome of chemotherapy with or without bevacizumab or cetuximab in this setting.
METHODS: A total of 729 colorectal cancer patients with dMMR status were screened for eligibility. The Kaplan-Meier method, the log-rank test and Cox analysis were utilized for survival analyses.
RESULTS: A total of 43 patients met the inclusion criteria and enrolled in the study. The median overall survival (OS) of entire cohort was 21.7 months. Chemotherapy plus bevacizumab group exhibited a tendency of substantially higher overall response rate (ORR) than chemotherapy alone group (63.6% vs. 23.8%, P = 0.053), whereas the ORR between chemotherapy plus cetuximab group and chemotherapy alone group were similar (28.6% vs. 23.8%, P = 1.000). Compared with chemotherapy alone group, bevacizumab combined group achieved a significantly longer progression-free survival (10.0 months vs. 4.8 months, P = 0.028), whereas cetuximab combined group was not (6.8 months vs. 4.8 months, P = 0.158). Although the median OS seemed to favor bevacizumab combined group, no significant differences were detected between the three arms (33.7, 21.7 and 15.3 months, respectively; P = 0.345). Prognostic analysis showed that primary tumor resection was the positive prognostic factor of OS (hazards ratio: 0.438; P = 0.041).
CONCLUSION: dMMR mCRC seems resistant to chemotherapy and cetuximab. Bevacizumab combined therapy shows a sign of potentially favorable outcome in this subtype.

Yao Z, Peng P, Xu D, et al.
EGFR inhibitor C225 Increases the Radio-Sensitivity of Human Breast Cancer Cells
Asian Pac J Cancer Prev. 2019; 20(1):311-319 [PubMed] Free Access to Full Article Related Publications
Objective: This study was undertaken to investigate the effect of C225 on the radio-sensitivity of MDA-MB-231 cells line and to disclosure underlying mechanism. Methods: CCK8 assay was used to measure the proliferation inhibition of C225 on MDA-MB-231 cells. The combined effects of C225 plus radiation on the proliferation of MDA-MB-231 cells were also evaluated by CCK-8 assay. The clonogenic assay was performed to evaluate the cell surviving fractions and to determine the radio-sensitizing effect of C225 on MDA-MB-231 cells. The apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blot analysis was used to detect the expression of p-EGFR, p-Akt, p-P38, and caspase-3. Results: C225 had an inhibiting effect on the proliferation of cells in a concentration-dependent manner. The cloning formation capacity was decreased in C225 plus radiation group. C225 increased radio-sensitivity of cells and led to cell cycle arrest in G0/G1 phase markedly. Cells treated with C225 and radiation predominantly exhibited G0/G1 phase arrest and significant decreased in the fraction of cells in the S phase. Moreover, C225 and radiation significantly increased the apoptosis rate of cells. Decreased cell proliferation was further supported by the down-regulation of p-EGFR and its downstream singling pathway proteins such as p-Akt and p-P38. The up-regulation of the Caspase-3 expression in C225 plus radiation group revealed that C225 could increase radiation-inducing cell apoptosis. Conclusion: C225 could increase the radio-sensitivity of cells, which may be due to the anti-proliferative synergistic effect between C225 and radiation as well as the down-regulation of the PI3K/Akt signaling pathway.

Trodello C, Higgins S, Ahadiat O, et al.
Cetuximab as a Component of Multimodality Treatment of High-Risk Cutaneous Squamous Cell Carcinoma: A Retrospective Analysis From a Single Tertiary Academic Medical Center.
Dermatol Surg. 2019; 45(2):254-267 [PubMed] Related Publications
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and has potential for regional or distant metastasis. Despite the standardization of features associated with high-risk cSCC, an advanced subset of cSCC, there is no established consensus regarding proper management of this tumor.
OBJECTIVE: To evaluate the efficacy of cetuximab, add to existing management options, and aid in the development of standardized treatment for this tumor.
MATERIALS AND METHODS: Medical records were searched using Current Procedural Terminology codes for cetuximab and cSCC. Demographic data and tumor characteristics, along with treatment regimens and follow-up times, were collected. A total of 20 cases were examined.
RESULTS: Of the 20 cases, 3 experienced a complete response and 7 experienced a partial response, yielding an overall response of 50% and a combined median disease-free survival of 6.35 months (range 1-46.8 months).
CONCLUSION: As most of the patients who experienced a response received cetuximab as part of a multimodality treatment approach, cetuximab may be most efficacious when administered with concurrent therapies such as surgery or radiation. Further larger prospective studies to determine the optimal dosing and frequency of cetuximab and the utility of concurrent therapies are warranted.

Hamauchi S, Yokota T, Mizumachi T, et al.
Safety and efficacy of concurrent carboplatin or cetuximab plus radiotherapy for locally advanced head and neck cancer patients ineligible for treatment with cisplatin.
Int J Clin Oncol. 2019; 24(5):468-475 [PubMed] Related Publications
BACKGROUND: Locally advanced squamous cell carcinoma of the head and neck (LASCCHN) is usually treated with cisplatin (CDDP)-based chemoradiotherapy, except when patients are elderly or have renal, cardiac, or neurogenic dysfunction. This study compared the safety and efficacy of concurrent carboplatin (CBDCA) to cetuximab (Cmab) plus radiotherapy (RT) in patients ineligible for CDDP treatment.
METHODS: We retrospectively analyzed LASCCHN patients who received CBDCA plus RT (n = 29) or Cmab plus RT (n = 18) due to ineligibility for CDDP treatment at two Japanese institutions between August 2006 and December 2015.
RESULTS: Patients characteristics for CBDCA plus RT and Cmab plus RT were: median age, 74 and 75 years; 0-1 performance status, 90% and 100%; main primary tumor site, hypopharynx 52% (n = 15) and oropharynx 39% (n = 7); and stage IV, 90% (n = 26) and 50% (n = 9), respectively. With a median follow-up time of 60.0 months for CBDCA plus RT and 53.6 months for Cmab plus RT, 3-year locoregional control rates were 56% versus 58%, and median progression-free survival was 42.7 versus 11.6 months. CBDCA plus RT was associated with more grade 3/4 hematologic toxicities, including neutropenia and thrombocytopenia, whereas Cmab plus RT was associated with more grade 3/4 oral mucositis and radiation dermatitis.
CONCLUSIONS: CBDCA or Cmab as a concurrent systemic therapy with RT is a possible treatment option for LASCCHN patients ineligible for CDDP treatment, although attention to hematological toxicity should be paid.

Groysbeck N, Stoessel A, Donzeau M, et al.
Synthesis and biological evaluation of 2.4 nm thiolate-protected gold nanoparticles conjugated to Cetuximab for targeting glioblastoma cancer cells via the EGFR.
Nanotechnology. 2019; 30(18):184005 [PubMed] Related Publications
Therapeutic monoclonal antibodies benefit to patients and the conjugation to gold nanoparticles (AuNPs) might bring additional activities to these macromolecules. However, the behavior of the conjugate will largely depend on the bulkiness of the AuNP and small sizes are moreover preferable for diffusion. Water-soluble thiolate-protected AuNPs having diameters of 2-3 nm can be synthesized with narrow polydispersity and can selectively react with incoming organic thiols via a S

Wang N, Wang K, Song F, Liu Y
Cetuximab in combination with chemoradiotherapy for nasopharyngeal carcinoma: A meta-analysis.
Indian J Cancer. 2018 Apr-Jun; 55(2):196-200 [PubMed] Related Publications
AIMS AND OBJECTIVES: The aims and objectives of this study are to investigate the efficacy and safety of chemoradiotherapy (CCRT) with or without cetuximab in nasopharyngeal carcinoma (NPC).
METHODS: We searched the Cochrane Library, PubMed, Embase, CNKI, VIP, Chinese biomedicine literature database, and WANFANG database for relevant articles. The methodological quality of included studies was evaluated, and data were analyzed using RevMan 5.0 software.
RESULTS: Ten relevant articles (783 patients) were identified. The results were complete response rate; the response rate was significantly better in the cetuximab plus CCRT (C225+CCRT) group than the CCRT group. The partial response and 3-year-overall survival rates were not significantly different between the two groups. Regarding adverse effects, myelosuppression was observed in the CRRT group and the C225+CCRT group; the main toxicity was mucositis and rash, but no significant statistical difference was observed.
CONCLUSION: The combination of cetuximab and CCRT was more effective for NPC than CCRT alone and had no serious side effects.

Wells JC, Tu D, Siu LL, et al.
Outcomes of Older Patients (≥ 70 Years) Treated With Targeted Therapy in Metastatic Chemorefractory Colorectal Cancer: Retrospective Analysis of NCIC CTG CO.17 and CO.20.
Clin Colorectal Cancer. 2019; 18(1):e140-e149 [PubMed] Related Publications
BACKGROUND: The safety and efficacy of targeted therapy in older patients (≥ 70 years) with metastatic colorectal cancer is not well evaluated.
PATIENTS AND METHODS: Outcomes of older patients (including overall survival [OS], progression-free survival [PFS], toxicity, and quality of life [QoL]) were compared to young patients using data from 2 large previously reported clinical trials, CO.17 (cetuximab vs. best supportive care) and CO.20 (cetuximab plus placebo vs. cetuximab plus brivanib). Only patients with wild-type KRAS tumors were included.
RESULTS: A total of 251 (26.3%) of 955 patients were ≥ 70 years old. No significant differences in OS, PFS, or grade 3/4 adverse events were observed between older and younger patients treated with cetuximab (or cetuximab with placebo) in either trial. Younger patients trended toward superior OS in both CO.17 (hazard ratio = 1.80; P = .16) and CO.20 (hazard ratio = 1.34; P = .07). QoL maintenance favored younger patients in CO.17 (3.6 vs. 5.7 months; P = .046) but no difference of QoL maintenance was observed in the larger CO.20 trial (1.7 vs. 1.8 months; P = .64). Combination therapy of cetuximab and brivanib was significantly more toxic in older adults (87% vs. 77%; P = .03).
CONCLUSION: OS, PFS, and toxicities were similar between older and younger patients with wild-type KRAS metastatic colorectal cancer when treated with cetuximab. Both age groups likely experience similar QoL maintenance with cetuximab. Dual targeted therapy was significantly more toxic in older patients.

Kuo WI, Cheng KH, Chang YJ, et al.
Radiolabeling, Characteristics and NanoSPECT/CT Imaging of 188Re-cetuximab in NCI-H292 Human Lung Cancer Xenografts.
Anticancer Res. 2019; 39(1):183-190 [PubMed] Related Publications
BACKGROUND/AIM: Cetuximab has exhibited high EGFR-targeting specificity and clinical promise in previous studies. In this study, we formulated unit dose kits for preparation of high specific activity

Baas J, Krens L, Bohringer S, et al.
Genome wide association study to identify predictors for severe skin toxicity in colorectal cancer patients treated with cetuximab.
PLoS One. 2018; 13(12):e0208080 [PubMed] Free Access to Full Article Related Publications
EGFR-antibodies are associated with significant skin toxicity, including acneiform rash and folliculitis. It remains impossible to predict the occurrence of severe skin toxicity due to the lack of predictive markers. Here, we present the first genome-wide association study (GWAS) to find single nucleotide polymorphisms (SNPs) associated with EGFR inhibitor-induced skin toxicity using data of the multicentre randomized phase III CAIRO2 trial (clinicaltrials.gov NCT00208546). In this study, advanced or metastatic colorectal cancer patients were treated with capecitabine, oxaliplatin and bevacizumab with or without cetuximab. Germline DNA was available in 282 of the 368 patients in the cetuximab arm. Mild skin toxicity occurred in 195 patients (i.e. CTC grade 1 or 2, respectively 91 and 104 patients) and severe skin toxicity (i.e. grade 3) in 36 patients. Grade 4 skin toxicity did not occur. None of the SNPs reached the formal genome wide threshold for significance of 5x10(-8), though SNPs of at least 8 loci did show moderate association (p-value between 5x10(-7) and 5x10(-5)) with the occurrence of grade 3 (severe) skin toxicity. These SNPs did not overlap with SNPs associated with cetuximab efficacy as found in a previous GWAS in the same CAIRO2 cohort. If formally proven by replication, the SNPs associated with severe EGFR induced skin toxicity may be helpful to predict the occurrence and severity of skin toxicity in patients that will receive cetuximab and allow for adequate information on the risk of skin toxicity and prophylactic measurements.

Joseph K, Alkaabi K, Warkentin H, et al.
Cetuximab-radiotherapy combination in the management of locally advanced cutaneous squamous cell carcinoma.
J Med Imaging Radiat Oncol. 2019; 63(2):257-263 [PubMed] Related Publications
INTRODUCTION: We report the outcomes of using a combination of cetuximab with radiation therapy (Cetux-RT) to treat a selected group of patients with locally advanced (unresectable) cutaneous squamous cell carcinoma (LA-cSCC). This study presents two-year efficacy and safety data for 8 patients with LA-cSCC treated within a single institution.
METHODS: Between 2014 and 2017 a total of eight patients (seven males, one female) with LA-cSCC received curative intent treatment with Cetux-RT. All patients received an initial loading dose of cetuximab at 400 mg/m
RESULTS: The median age was 81 years (range, 55-87). The ECOG performance status of all patients was between 0 and 2. With a median duration of follow-up of 25 months (range 10-48 months), five patients remain in a complete response. After a partial response, another patient has relapsed and is receiving palliative chemotherapy, while two patients have died during the period of follow up (one of whom died following progression of disease, the other of an unrelated cause). Treatment in this group of patients was well tolerated, with most toxicities ≤ grade 2, and no toxicities of grade 4/5 reported.
CONCLUSIONS: Cetux-RT was well tolerated and provided durable disease control within this patient sample. Our data support the use of the Cetux-RT regimen for selected patients with inoperable LA-cSCC and adequate performance status.

André P, Denis C, Soulas C, et al.
Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells.
Cell. 2018; 175(7):1731-1743.e13 [PubMed] Free Access to Full Article Related Publications
Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8

Nadler E, Joo S, Boyd M, et al.
Treatment patterns and outcomes among patients with recurrent/metastatic squamous cell carcinoma of the head and neck.
Future Oncol. 2019; 15(7):739-751 [PubMed] Related Publications
AIM: Cetuximab was approved in 2008 for treating recurrent/metastatic (R/M) head-and-neck squamous-cell carcinoma (HNSCC), and this study assessed the utilization of cetuximab for R/M-HNSCC in a real-world setting.
MATERIALS & METHODS: Adult patients with R/M-HNSCC, who initiated systemic therapy between 1 September 2011 and 31 December 2014 and followed through 31 December 2015, were identified from iKnowMed electronic-health-records database (McKesson Specialty Health) supplemented with manual chart-abstraction.
RESULTS: For 325 R/M-HNSCC patients; median age 62 years; 82% males, 67% had oropharyngeal cancer, most common first-line (1L) regimen was platinum-based combinations (76%), of whom only 8% received platinum + cetuximab +/- 5-fluorouracil.
CONCLUSION: Despite US FDA approval and National Comprehensive Cancer Network guidelines recommending use of cetuximab for palliative treatment of R/M-HNSCC, our study demonstrates low utilization in 1L and 2L settings, underscoring the need to understand reasons for low utilization.

Li B, Jiang Z, Xie D, et al.
Cetuximab-modified CuS nanoparticles integrating near-infrared-II-responsive photothermal therapy and anti-vessel treatment.
Int J Nanomedicine. 2018; 13:7289-7302 [PubMed] Free Access to Full Article Related Publications
Background: Photothermal therapy (PTT) has received extensive attention owing to its non-invasive nature and highly therapeutic outcomes. PTT agents and near-infrared (NIR) laser are essential elements in PTT. However, most PTT agents are composed of heavy metals, characterized by serious cytotoxicity and side effects, and NIR irradiation often damages normal tissue owing to the high dose, thus limiting the clinical application of PTT.
Purpose: In this regard, exploring new perspectives enabling more PTT agents to be enriched into the tumor and NIR laser irradiation decay in PTT is vital.
Methods: In this study, cetuximab (Ab), an anti-angiogenic antibody which targets the EGFR, was modified on CuS NPs (CuS-Ab NPs) to improve the aggregation of CuS NPs in the tumor.
Results: The cellular uptake data and the biodistribution results showed comparable accumulation of CuS-Ab NPs in tumor, thus decreasing the cytotoxicity and side effects in normal tissues. More importantly, the modification of Ab in CuS-Ab NPs impressively inhibited the formation and progression of tumor vessels, as demonstrated by immunohistochemistry staining. The introduction of anti-vessel treatment requires CuS-Ab NPs to provide weak PTT, which means that a small amount of laser energy is required, inevitably causing negligible damage to normal tissue.
Conclusion: Therefore, our tailor-made CuS-Ab NPs have promising potential in clinical applications.

Liu X, Lukowski JK, Flinders C, et al.
MALDI-MSI of Immunotherapy: Mapping the EGFR-Targeting Antibody Cetuximab in 3D Colon-Cancer Cell Cultures.
Anal Chem. 2018; 90(24):14156-14164 [PubMed] Related Publications
Immunotherapies are treatments that use a patient's immune system to combat disease. One important type of immunotherapy employed in cancer treatments is the delivery of monoclonal antibodies to block growth receptors. In this manuscript, we develop a methodology that enables accurate and simple evaluation of antibody-type drug delivery using MALDI-MSI. To overcome the mass-range limitation that prevents the detection of large therapeutic antibodies, we used in situ reduction and alkylation to break disulfide bonds to generate smaller fragments. These smaller fragments are more readily ionized and detected by MALDI-MSI without loss of spatial information on the parent drug. As a proof of concept study, we evaluated the distribution of cetuximab in 3D colon cell cultures. Cetuximab is a monoclonal antibody that binds to the extracellular domain of epidermal-growth-factor receptor (EGFR), which is often overexpressed in colorectal cancer (CRC) and mediates cell differentiation, proliferation, migration, and angiogenesis. Cetuximab directly inhibits tumor growth and metastasis and induces apoptosis. By performing on-tissue reduction followed by MALDI-MSI analysis, we successfully mapped the time-dependent penetration and distribution of cetuximab in spheroids derived from two different colon-cancer cell lines (HT-29 and DLD-1). The localization patterns were further confirmed with IF staining of the drug. Changes in other biomolecules following drug treatment were also observed, including the elevation of ATP in spheroids. The developed method has also been applied to map cetuximab distribution in patient-derived colorectal-tumor organoids (CTOs). Overall, we believe this powerful label-free approach will be useful for visualizing the heterogeneous distribution of antibody drugs in tissues and tumors and will help to monitor and optimize their use in the clinic.

da Costa AABA, Costa FD, Araújo DV, et al.
The roles of PTEN, cMET, and p16 in resistance to cetuximab in head and neck squamous cell carcinoma.
Med Oncol. 2018; 36(1):8 [PubMed] Related Publications
There is no established biomarker for cetuximab efficacy in recurrent head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to evaluate the prognostic and predictive impact of PTEN, cMET, and p16 expression in recurrent HNSCC. In this retrospective study, 112 patients with recurrent HNSCC received chemotherapy (CT) alone (n = 37) or chemotherapy with cetuximab (n = 75). PTEN, cMET, and p16 protein expression were evaluated by immunohistochemistry. The median overall survival (mOS) for the patients treated with cetuximab + CT versus CT alone was 11.4 months and 7.0 months, (p = 0.949). The median progression-free survival (mPFS) was 6.2 months versus 3.0 months (p = 0.154). Patients with PTEN loss exhibited a mOS of 5.8 months versus 10.5 months (p = 0.002) and a mPFS of 3.2 months versus 4.7 months (p = 0.019). A multivariate analysis identified an independent association between PTEN loss and OS (HR 2.27; 95% confidence 95% CI 1.27-4.08; p = 0.006) and with PFS (HR 1.85; 95% CI 1.09-2.99; p = 0.022). A negative prognostic impact of PTEN loss was observed in the patients treated with cetuximab + CT, and not in the CT only group. Expression of cMET and p16 showed no impact on OS or PFS. The present findings confirm that PTEN is a prognostic factor for metastatic HNSCC and they support further studies of PTEN expression to evaluate its predictive value to cetuximab response.

Huang ZH, Ma XW, Zhang J, et al.
Cetuximab for esophageal cancer: an updated meta-analysis of randomized controlled trials.
BMC Cancer. 2018; 18(1):1170 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Increasing evidence indicates that cetuximab (CET) combined with chemoradiotherapy may be effective for patients with esophageal cancer. However, the recent results are still contradictory and no consensus has yet been reached on this issue. To evaluate the clinical effects and safety of CET, we conducted an updated meta-analysis by retrieving published data up to June 2018.
METHODS: A comprehensive literature search was performed in several electronic databases, including PubMed, Embase, the Cochrane Library, CNKI database and Chinese Biomedicine Database using subject terms and free terms. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to determine the efficiency and safety of CET.
RESULTS: This meta-analysis included 10 randomized controlled trials (RCTs). Five RCTs reported localized esophageal cancer and other five RCTs reported metastatic esophageal cancer. For these patients with localized esophageal cancer, CET could not significantly improve the response rate, overall survival and progression-free survival (PFS, 1-5 years). But CET treatment might increase the incidences of diarrhea (OR = 2.07; CI = 1.01-4.25) and rash (OR = 16.91; CI = 3.20-89.42). For other patients with metastatic esophageal cancer, the addition of CET significantly increased the response rate (OR = 3.34; CI = 1.90-5.88), disease control rate (OR = 2.92; CI = 1.49-5.71) and 2-year overall survival (OR = 2.78; CI = 1.20-6.46) compared with the control group. However, CET could not improve the 1-year overall survival and might make patients with metastatic esophageal cancer more susceptible to rash (OR = 5.50; CI = 2.14-14.14). No significant differences in other adverse effects were found between the two groups.
CONCLUSIONS: Our findings suggested that adding CET to multimodal therapy significantly improved response rate and disease control rate for patients with metastatic esophageal cancer rather than patients with localized esophageal cancer. CET might be a safe therapeutic choice, but CET failed to significantly improve the overall survival and PFS for patients with localized or metastatic esophageal cancer.

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