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Abstract This study aims to monitor and identify adverse events (AEs) associated with cetuximab, a drug used to treat various late-stage (metastatic) tumors, to improve patient safety and guide drug use. This study retrospectively analyzed the cases reported in the FDA adverse event reporting system (FAERS) related to the application of cetuximab from 2013 Q1 to 2022 Q4. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the empirical Bayesian geometric mean (EBGM) algorithms, were employed to quantify the signals of cetuximab-associated AEs. A total of 8364225 reports were contained in the FAERS database, of which 5186 reports of cetuximab were identified as ‘primary suspected (PS)’ AEs. The application of cetuximab resulted in AEs in 22 system organ classes (SOCs), which preserved 176 significant disproportionality preferred terms (PTs) through the computation of four algorithms. The main SOCs (Skin and subcutaneous tissue disorders, investigations, metabolism and nutrition disorders, and blood and lymphatic system disorders) accounted for 58.63%. Some AEs were not on the drug label: speech disorder, intervertebral discitis, glomerulonephritis rapidly progressive and disseminated intravascular coagulation. This study identified new signals of adverse drug reactions (ADRs) other than those mentioned in the specification associated with cetuximab, providing valuable insights into the relationship between ADRs and cetuximab use. The findings highlight the importance of continuous surveillance to detect and manage AEs effectively, ultimately improving patient safety during treatment with cetuximab.

Abstract Background Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and treatment options for advanced CRC are limited. The regulatory mechanisms of aberrant NAT10-mediated N4-acetylcytidine (ac4C) modifications in cancer progression remains poorly understood. Consequently, an integrated transcriptomic analysis is necessary to fully elucidate the role of NAT10-mediated ac4C modifications in CRC progression. Methods NAT10 expression levels were analyzed in CRC samples and compared with those in corresponding normal tissues. The potential mechanisms of NAT10 in CRC were investigated using RNA sequencing, RNA immunoprecipitation sequencing, and acetylated RNA immunoprecipitation sequencing. Additional in vivo and in vitro experiments, including CCK-8 assays, colony formation and mouse xenograft models, were conducted to explore the biological role of NAT10-mediated ac4C modifications. We also evaluated and optimized a potential treatment strategy targeting NAT10. Results We found that NAT10 is highly expressed in CRC samples and plays a pro-oncogenic role. NAT10 knockdown led to PI3K-AKT pathway inactivation, thereby inhibiting CRC progression. However, treatment with the NAT10 inhibitor Remodelin induced only a limited and reversible growth arrest in CRC cells. Further epigenetic and transcriptomic analysis revealed that NAT10 enhances the stability of ERRFI1 mRNA by binding to its coding sequence region in an ac4C-dependent manner. NAT10 knockdown decreased ERRFI1 expression, which subsequently activated the EGFR pathway and counteracted the inhibitory effects on CRC. Based on these findings, we demonstrated that dual inhibition of NAT10 and EGFR using Remodelin and the EGFR-specific monoclonal antibody cetuximab resulted in improved therapeutic efficacy compared to either drug alone. Moreover, we observed that 5-Fluorouracil promoted the interaction between NAT10 and UBR5, which increased the ubiquitin-mediated degradation of NAT10, leading to ERRFI1 downregulation and EGFR reactivation. Triple therapy with Remodelin, cetuximab, and 5-Fluorouracil enhanced tumor regression in xenograft mouse models of CRC with wild-type KRAS, NRAS and BRAF. Conclusions Our study elucidated the mechanism underlying 5-Fu-induced NAT10 downregulation, revealing that NAT10 inhibition destabilizes ERRFI1 mRNA through ac4C modifications, subsequently resulting in EGFR reactivation. A triple therapy regimen of Remodelin, cetuximab, and 5-Fu showed potential as a treatment strategy for CRC with wild-type KRAS, NRAS and BRAF.

The randomized FIRE‐4.5 (AIO KRK0116) trial compared first‐line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) V600E‐mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell‐free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE‐4.5 included mCRC patients with BRAF V600E mutation detected by tissue‐based analyses. Liquid biopsies (LBs) were collected at baseline (pre‐treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)‐certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression‐free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild‐type patients. Follow‐up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild‐type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P

Abstract Antibody-drug conjugates (ADCs) are an emerging strategy in cancer therapy, enhancing precision and efficacy by linking targeted antibodies to potent cytotoxic agents. This study introduces a novel ADC that combines ribonuclease A (RNase A) with cetuximab (Cet), an anti-EGFR monoclonal antibody, through a polyethylene glycol (PEG) linker (RN-PEG-Cet), aimed to induce apoptosis in KRAS mutant colorectal cancer (CRC) via a ROS-mediated pathway. RN-PEG-Cet was successfully synthesized and characterized for its physicochemical properties, retaining full enzymatic activity in RNA degradation and high binding affinity to EGFR. In KRAS mutant SW-480 cells, RN-PEG-Cet significantly reduced cell viability at lower doses, with an IC50 of 11.7 µg/mL at 72 h. Compared to free Cet, RN-PEG-Cet demonstrated a ~ 2-fold increase in apoptosis and a ~ 3.5-fold increase in ROS production. The conjugate also disrupted the Nrf2/Keap1 pathway, with a significant upregulation of Keap1 (FC = 3.7, p ≤ 0.01) and downregulation of Nrf2 (FC = 3.3, p

Abstract Cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, has been shown to improve survival in nasopharyngeal carcinoma (NPC) patients. However, a correlation between the expression of EGFR and the response to cetuximab has not been observed, indicating that the mechanism underlying the effects of cetuximab needs to be further elucidated. The antitumour response involves immunotherapeutic mechanisms that target tumour-associated antigens, including complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), act either alone or, more often, in combination. However, EBV infected NPC cells often develop resistance mechanisms that allow them to evade immune surveillance. Here, we found that overexpression of the complement-regulated protein CD55 in EBV-associated NPC cells mainly suppresses ADCC activity thus reduces the efficacy of cetuximab. Mechanistically, EBV latent membrane protein 1 (LMP1) mediated upregulation of CD55 through the NF-κB signalling pathway. The present study provides a rationale for the development of CD55 inhibitors to improve the clinical efficacy of cetuximab in NPC.

Epidermal growth factor receptor (EGFR) inhibition is crucial in treating RAS wild-type metastatic colorectal cancer, yet current testing methods may miss rare RAS variants affecting treatment efficacy. We analyzed 4122 colorectal cancer patients receiving anti-EGFR antibodies from the Center for Cancer Genomics and Advanced Therapeutics database, identifying 54 patients (1.3%) with rare RAS variants undetectable by standard testing. These patients showed significantly lower response rates to anti-EGFR therapy (28.3%) compared to RAS wild-type cases (44.6%, p = 0.003). Disease control rates were also lower in rare variant cases (60.9%) versus wild-type cases (80.0%). Most common rare variants included KRAS Q22K, A59E, and A11_G12insGA. Comprehensive genomic profiling revealed additional alterations in TP53 (90.7%), APC (87.0%), and non-V600E BRAF mutations (25.9%). Our findings suggest that rare RAS variants predict poor anti-EGFR therapy response, highlighting the potential benefit of comprehensive genomic profiling before treatment initiation. This study provides real-world evidence supporting the clinical relevance of rare RAS variants in treatment decision-making for colorectal cancer. Future studies should focus on developing cost-effective comprehensive testing strategies and evaluating alternative treatment approaches for patients with rare RAS variants.

Abstract Background The objective of this study is to investigate the potential association between change in body composition before and after cetuximab-based therapy and the prognostic outcomes among individuals diagnosed with advanced colorectal cancer. Methods A retrospective analysis was undertaken on a cohort of 81 patients diagnosed with RAS wild-type (WT) metastatic colorectal cancer (mCRC) who were treated with cetuximab-based first-line therapy. To assess relevant body composition parameters, quantitative computed tomography (QCT) scans were conducted both before and after cetuximab treatment. These parameters encompassed measurements of visceral fat area (VFA), subcutaneous fat area (SFA), total muscle area (TMA) at the third lumbar vertebra level (L3), and bone mineral density (BMD) at the first and second vertebrae levels (L1/2). The skeletal muscle index (SMI) was subsequently calculated, and changes in parameters (∆VFA, ∆SFA, ∆SMI, ∆BMD) were standardized. Results The cut-off values for ∆VFA, ∆SFA, ∆SMI, and ∆BMD were 0.28%, -2.76%, -2.97%, and -7.98%, respectively. CEA, ∆VFA, ∆SMI, and ∆BMD were associated with poor outcomes of cetuximab-based first-line chemotherapy (P

Abstract Present work aims to prepare Soluplus stabilized, phospholipid-modified, and cetuximab-conjugated paclitaxel nanocrystals (NCs) as stable nanocarriers for targeted drug delivery. The NCs, prepared using concurrent antisolvent precipitation cum cold crystallization method followed by probe sonication, were found to be monodispersed particles with sub-200 nm size. The microscopic analysis uncovered rod and spherical anisotropy for Soluplus stabilized (PTX-NCs) and phospholipid modified (Lipid/PTX-NCs) nanocrystals, respectively. The formation of amorphous PTX-NCs and subsequent coating with phospholipid was confirmed by solid-state characterization using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform Infrared Spectroscopy (FTIR). X-ray Photoelectron Spectroscopic (XPS) analysis, indicated successful conjugation of cetuximab on NCs surface. Lipid coating rendered a sustained drug release behaviour to NCs at physiological pH. In vitro cell line studies confirmed the improved cellular internalization and better apoptosis induction capability of NCs, consequently resulting in enhanced efficacy of PTX against A549 cancer cells. Moreover, in Benzo[a] pyrene-induced lung cancer model, Cmab/Lipid/PTX-NCs showed significant improvement in tumor inhibition potential in comparison to pure PTX. The prepared Cmab/Lipid/PTX-NCs also exhibited improved pharmacokinetics performance, avoided off-target distribution, and showed a reduction in systemic toxicity. The findings of this study indicate the promising potential of the prepared cetuximab-functionalized phospholipid-coated paclitaxel nanocrystals in lung cancer therapy.

Abstract The chloride channel transmembrane protein 16A (TMEM16A) possesses a calcium-activated property linked to tumor-promoting malignant phenotype and electrophysiological stability. Numerous studies have shown that TMEM16A exhibits aberrant amplification in various squamous cell carcinomas such as esophageal squamous cell carcinoma (ESCC) and is correlated with unfavorable outcomes of ESCC patients. Therefore, TMEM16A is considered as a promising therapeutic target for ESCC. Because of its intricate structure, the development of therapeutic antibodies directed against TMEM16A has not been documented. In this study, we produced a series of novel monoclonal antibodies targeting TMEM16A and identified mT16#5 as an antibody capable of inhibiting ESCC cells migration, invasion and TMEM16A ion channel activity. Additionally, based on the validation that TMEM16A was positively correlated with expression of EGFR and the interaction between them, the mT16#5 exhibited a synergistic inhibitory effect on ESCC metastasis and growth when administered in combination with Cetuximab in vivo. In terms of mechanism, we found that mT16A#5 inhibited the phosphorylation of PI3K, AKT and JNK. These results highlight the anti-growth and anti-metastasis capacity of the combination of mT16A#5 and Cetuximab in the treatment of ESCC by targeting TMEM16A and EGFR, and provide a reference for combinational antibody treatment in ESCC.

Abstract Background Near-infrared fluorescence (NIRF) imaging is an excellent choice for image-guided surgery due to its simple operation and non-invasiveness. Developing tumor-specific fluorescent molecular probes is key to fluorescence imaging-guided surgery. EGFR (epidermal growth factor receptor) is closely related to the proliferation and growth of tumor cells and is highly expressed in epithelial ovarian cancer (EOC). The study aims to construct a NIR fluorescent molecular probe using cetuximab (an EGFR monoclonal antibody) and investigate its feasibility for targeting EOC in vivo through fluorescence imaging. Methods We determined the expression of EGFR in EOC. NIR fluorescent molecular probe with cetuximab (cetuximab-Cy7) was chemically engineered and identified. The subcutaneous xenografted tumor model of EOC was induced using SKOV3-Luc cell line with positive expression of EGFR. Cetuximab-Cy7 was used for in vivo fluorescence imaging, and phosphate-buffered saline, free Cy7 dye and mouse isotype immunoglobulin G-Cy7 were used as controls. NIRF imaging system was performed to study the distribution and targeting of the probes. Tumors were imaged in situ and ex vivo, and fluorescent intensity was quantified. Resected specimens were analyzed to confirm diagnosis, and immunohistochemical (IHC) staining was used to identify EGFR expression. Results EGFR expression was increased in EOC tissues than fallopian tube tissues. The high expression of EGFR was significantly correlated with well-differentiation, residual lesions ≤ 1 cm, no recurrence and increased survival. NIRF imaging showed that the cetuximab-Cy7 enabled detection of tumor lesions in EOC-bearing mice with the optimal dose of 30 µg. The suitable imaging time window may be 24–96 h post-injection. Ex vivo fluorescence imaging indicated that fluorescent signal was mainly detected in the tumor and the lung. IHC results confirmed that xenografts were EGFR positive. Conclusion Cetuximab-Cy7 can specifically target the tumors of EOC xenografted nude mice. This research lays the foundation for future studies on EOC surgery navigation.

Context: Colorectal cancer (CRC) is a major global health concern as innovative therapeutic strategies to enhance treatment outcomes. This study investigates the therapeutic potential of the ethanol extract derived from Volvariella volvacea in combination with cetuximab for CRC. Aims: To evaluate the inhibition of topoisomerase II alpha (TOP2A) and include the peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of cell growth and differentiation. Methods: The method used computational modeling and molecular docking to assess the binding affinities and interactions between the bioactive components, cetuximab, TOP2A, and PPARγ. In vitro experiments were conducted using CRC cell lines. Cells were treated with cetuximab alone or in combination with V. volvacea extract. Cell viability and immunofluorescence were conducted to evaluate the effect of combination therapy on TOP2A and PPARγ. Results: The results unveiled compelling binding interactions, suggesting the potential for dual targeting of TOP2A and PPARγ. The results demonstrated a reduction in cell viability, downregulation of TOP2A, and modulation of PPARγ. These findings indicate the potential of V. volvacea extract as an adjuvant therapy to cetuximab in CRC. Targeting both TOP2A and PPARγ enhances the efficacy of CRC treatment. Conclusions: Moreover, it highlights the importance of harnessing natural compounds and molecular insights to develop innovative combinatorial therapies for complex diseases like CRC.

Abstract Background In recent years, the addition of cetuximab to chemotherapy has improved treatment outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In this study, we present the real-world survival data of R/M HNSCC patients who received cetuximab-containing regimens from thirteen medical centers in Taiwan, as well as a three-level risk stratification model for this patient population. Methods This study enrolled R/M HNSCC patients from thirteen medical centers in Taiwan who received cetuximab-containing regimens from January 1, 2017 to June 6, 2022. The cases were divided into a training cohort and a validation cohort based on the start of treatment. Overall survival (OS) was evaluated in both cohorts and exploratory analysis was performed to identify associated adverse clinical and laboratory factors. The results of the exploratory analysis were used to construct a three-level risk stratification prediction model for OS. Results A total of 1434 patients with R/M HNSCC were enrolled in this study and received cetuximab-containing regimens. The overall population had a median OS of 8.57 months (95% CI: 8.07 – 9.08). Multivariate analysis of the training cohort identified poor ECOG performance status, heavy alcohol consumption, and prior adjuvant CCRT or lack of prior RT as adverse prognostic factors. Comparison of laboratory data between patients with OS≦6 and OS > 6 also revealed unfavorable factors, including increased white blood cell count, decreased hemoglobin level, increased platelet count, increased absolute neutrophil count, decreased absolute lymphocyte count, and increased neutrophil-to-lymphocyte ratio. Using forward prediction, a three-level risk stratification prediction model was constructed using the variables of ECOG performance status, alcohol consumption, skin metastasis, modality of radiation therapy, hemoglobin level, and neutrophil-to-lymphocyte ratio. The median OS in the low-risk, intermediate-risk, and high-risk groups were 12.02 months (95% CI 10.44–13.61), 7.5 months (95% CI 7.33–8.17), and 4.01 months (95% CI 3.94–4.08), respectively, with a log-rank test p-value

Abstract Introduction Cetuximab, used to treat head and neck squamous cell carcinoma and metastatic colorectal cancer, can cause severe infusion reactions. Case presentation We report an 87-year-old East Asian woman with stage IV ileocecal signet ring cell carcinoma who experienced severe allergic reactions to cetuximab despite pre-treatment. A dose escalation method, involving weekly incremental doses with comprehensive pre-treatment and close monitoring, was employed, successfully reducing allergic reactions and allowing safe administration. Conclusion This approach demonstrates a viable alternative for patients with hypersensitivity to cetuximab, warranting further research for personalized treatment optimization.

Objective: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Engineeredbiomolecules can be used as a targeted tool to deliver drugs directly to tumors that reduce the adverse effects of conventionaltreatments. We aimed to prepare non-targeted oxaliplatin-loaded chitosan nanoparticles (OXPT-CS NPs) and targetedOXPT-CS NPs decorated with cetuximab single-chain variable fragment (scFv) to send both NPs to epidermal growth factorreceptor (EGFR) overexpressing HCT 116 cells, a human colorectal carcinoma cell line, for comparing their cytotoxicity.Materials and Methods: In this experimental study, OXPT-CS NPs were synthesized using a fluid system. Encapsulationefficiency percentage (EE%) and oxaliplatin release rate were evaluated. Western blot and cell-based ELISA confirmed scFvproduction and its binding ability to EGFR, respectively. The Fourier transform infrared spectroscopy (FTIR) determinedthe conjugation of scFv to OXPT-CS NPs. The NPs were characterized, and their toxicity against the HCT 116 cells wasevaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and flow cytometry assays.Results: The EE% of OXPT-CS NPs was 93%, and the average diameters were 75.85 ± 8.81 nm and 92.48 ± 9.51before and after scFv conjugation, respectively. The scFv was purified via affinity chromatography. The western blotmethod and cell-based ELISA revealed successful purification of scFv and its attachment to EGFR on HCT 116 cells.The FTIR analysis determined the interactions between the scFv and OXPT-CS NPs. According to MTT and flowcytometry results, the targeted delivery system significantly reduced HCT 116 cancer cell viability and increasedapoptosis induction up to 99.8%.Conclusion: The scFv-OXPT-CS NPs demonstrated an increased cytotoxic function due to the presence of scFv in itsformulation. This delivery system offers a promising method for delivering chemotherapy drugs to cancer cells. Moreresearch is needed on the best strategies for improving treatment efficacy by targeting cancer cells.

The epidermal growth factor receptor (EGFR) plays a critical role in regulating essential cellular processes that are frequently hijacked to promote cancer. In colorectal cancer (CRC) in particular, the EGFR signaling pathway is frequently hyperactivated via receptor and/or ligand overexpression and downstream oncogenic mutations. Current EGFR-targeted therapies for metastatic CRC (mCRC) include the mAbs cetuximab and panitumumab. However, intrinsic and acquired resistance to EGFR-targeted mAbs are commonly observed. Thus, additional biomarkers are necessary to better understand patient sensitivity to EGFR-targeted therapies. Furthermore, therapeutic targeting of alternative EGFR pathway components may serve as one mechanism to overcome EGFR-targeted mAb resistance. In this review, we discuss the mounting evidence supporting EGFR ligands epiregulin (EREG) and amphiregulin (AREG), which are overexpressed in CRC with potential key roles in tumor progression, as predictive biomarkers for EGFR-targeted therapy sensitivity, as well as mediators of therapy resistance, though further studies are necessary to validate the prognostic roles and mechanisms by which these ligands contribute to resistance. Additionally, we review recent advances towards therapeutic targeting of EREG and AREG in cancer through the development and use of EREG- and AREG-targeted mAbs as well as antibody–drug conjugates (ADCs). We conclude with a discussion on the roadblocks to clinical implementation of EREG and AREG as biomarkers, as well as approaches to enhance the efficacy of current EREG- and AREG-targeted strategies.

Fang Fang,1,* Yun Yan Chen,1,* Xin-Ming Zhang,2 Jin Tang,1 Yu-Hao Liu,1 Chen-Shuo Peng,1 Yu Sun1,3 1School of Pharmacy, Wannan Medical College, Wuhu, 241002, People’s Republic of China; 2School of Chemistry and Materials Science, Anhui Normal University, Wuhu, 241002, People’s Republic of China; 3Institute of Synthesis and Application of Medical Materials, Wannan Medical College, Wuhu, 241002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu Sun, School of Pharmacy, Wannan Medical College, Wuhu, 241002, People’s Republic of China, Tel +86 553 3932026, Email whsunyu@163.comBackground: Epidermal growth factor receptor (EGFR) is a major target for the treatment of colorectal cancer. Thus, anti-EGFR antibody conjugated lipid-polymer hybrid nanoparticles can offer a potential means of enhancing the efficacy of chemotherapeutics in EGFR overexpressing cancers. In addition, the combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. Hence, it is highly desirable to develop a safe and effective delivery system for colorectal tumor therapy.Methods: In this study, EGFR-targeted and NIR-triggered lipid-polymer hybrid nanoparticles (abbreviated as Cet-Iri-NPs) were prepared with copolymer PPG-PEG, lipids DSPE-PEG-Mal and lecithin as carriers, CPT-11 as an anticancer chemotherapeutic agent, indocyanine green (ICG) as a photothermal agent, and cetuximab as a surface-targeting ligand.Results: In vitro analyses revealed that Cet-Iri-NPs were spherical with size of 99.88 nm, charge of 29.17 mV, drug entrapment efficiency of 51.72%, and antibody conjugation efficiency of 41.70%. Meanwhile, Cet-Iri-NPs exhibited a remarkable photothermal effect, and pH/NIR-triggered faster release of CPT-11 with near infrared (NIR) laser irradiation, which induced enhanced cytotoxicity against SW480 cells. Furthermore, the promoted tumor-growth suppression effect of Cet-Iri-NPs on SW480 tumor xenograft nude mice was achieved under NIR laser irradiation.Conclusion: These results indicate that the well-defined Cet-Iri-NPs are a promising platform for targeted colorectal cancer treatment with chemo-photothermal therapy. Keywords: Chemo-photothermal therapy, Targeted cancer therapy, Nanoparticles, Cetuximab, Indocyanine green

Aim: To estimate the cost–effectiveness of cetuximab in combination with radiotherapy compared with radiotherapy alone, for the treatment of locally advanced head and neck cancer patients in Spain. Methods: A probabilistic Markov model (second-order Monte Carlo simulation) with a five-year time horizon and quarterly Markov cycles was performed from the perspective of the Spanish National Health System (NHS). Results: The additional cost and quality-adjusted life-year (QALY) gain per patient receiving radiotherapy in combination with cetuximab compared with radiotherapy alone was €4356 (95% CI: €4350–4362) and 0.2380 (95% CI: 0.2370–0.2391) QALY, respectively. The incremental cost per QALY gain was €18,303 (95% CI: €18,243–18,354) with a probability of cost–effectiveness of 65.4% for a willingness to pay of €30,000 per QALY gained. Conclusion: According to the results of this analysis, the addition of cetuximab to radiotherapy would be a cost-effective alternative to radiotherapy alone in the treatment of locally advanced head and neck cancer in Spain.

This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB.

Despite advances in targeted therapies, primary and acquired resistance make the treatment of colorectal cancer (CRC) a pressing issue to be resolved. According to reports, the development of CRC is linked to miRNA dysregulation. Multiple studies have demonstrated that miR-135b-5p has an aberrant expression level between CRC tissues and adjacent tissues. However, it is unclear whether there is a correlation between miR-135b-5p and cetuximab (CTx) resistance in CRC. Use the GEO database to measure miR-135b-5p expression in CRC. Additionally, RT-qPCR was applied to ascertain the production level of miR-135b-5p in three human CRC cells and NCM460 cells. The capacity of cells to migrate and invade was examined utilizing the wound-healing and transwell assays, while the CCK-8 assay served for evaluating cell viability, as well as colony formation assays for proliferation. The expected target protein of miR-135b-5p in CRC cell cetuximab resistance has been investigated using western blot. Suppression of miR-135b-5p could increase the CTx sensitivity of CTx-resistant CRC cells, as manifested by the attenuation of proliferation, migration, and invasion ability. Mechanistic studies revealed miR-135b-5p regulates the epithelial-to-mesenchymal transition (EMT) process and Wnt/β-catenin signaling pathway through downgulating FOXN3. In short, knockdowning miR-135b-5p could increase FOXN3 expression in CRC cells, promote the EMT process, and simultaneously activate the Wnt/β-catenin signaling pathway to elevate CTx resistance in CRC cells.

The article discusses the ionic gelation of cationic chitosan (CS) with anionic hyaluronic acid (HA) sodium salt to form nanoparticles in the range of 125 nm. The particles were further functionalized with cetuximab to endow it with the ability to spatially target the tumor over-expressing EGFR. Solid-state characterization of the particles using XRD, FTIR, and DSC revealed the formation of stable nanoparticles with Cabazitaxel loaded in the amorphous nanostructure. XPS study used to assess the surface characteristics indicated that the cetuximab was successfully anchored on the surface of the particle. The prepared CS-HA-Cmab-NP elicited a pH-responsive drug release behavior due to the presence of CS in the matrix. In vitro performance of the nanoparticles was evaluated on MDA-MB-231 breast cancer cell lines showed overall increase in efficacy. In vivo pharmacokinetic and anti-tumor effect evaluated in female Sprague Dawley rats indicated that the Cmab-conjugated nanoparticles improved half-life of cabazitaxel and tumor reduction capability with higher survival rate and lower reduction in body weight. The results indicate that CS/HA nanoparticles anchored with cetuximab show enhanced efficacy in reducing the breast cancer tumor in DMBA-induced breast tumor model through spatial targeting, consequently reducing the systemic toxicity.

Squamous cell carcinoma of the head and neck is the sixth most common cancer worldwide. However, malignant tumors of the middle ear are extremely rare. Squamous cell carcinoma is the most common histologic type of tumor in this area, accounting for more than 50% of cases. Complex anatomical and topographic features of the inner ear and inapparent clinical symptoms result in delayed diagnosis of this disease. A case of a patient with highly differentiated middle ear squamous cell carcinoma is presented. The patient received complex treatment, including drug antitumor therapy according to the TPEx protocol: docetaxel + cisplatin + cetuximab. Being highly effective, this protocol requires a multidisciplinary approach in order to ensure maximum safety of therapy. The case illustrates the classic “portrait” of a patient with recurrent or metastatic squamous cell carcinoma of the head and neck and also provides a comprehensive description of the spectrum of adverse events faced by such patients and their oncologists. Based on this clinical case, the features of management of such adverse events are analyzed.

Abstract Background Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. Methods KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. Results Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%–49%) for pembrolizumab plus epacadostat, 21% (6%–46%) for pembrolizumab monotherapy, and 34% (19%–52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3–4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. Conclusions Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. Trial registration NCT03358472. Date of trial registration: November 30, 2017.

Introduction. Chemotherapy in combination with targeted therapy (CT + TT) using a monoclonal antibody against epidermal growth factor receptor (EGFR) cetuximab and subsequent maintenance targeted therapy (CT + TT/TT) is the leading 1st line therapy of recurrent/metastatic head and neck squamous cell carcinoma to achieve objective response irrespective of programmed cell death-ligand 1 (pD-L1) expression level. However, often in clinical practice patient profile does not match characteristics of patients included in registration studies. Therapy selection is based on massive advancement of the tumor, low performance status of the patient, use of various chemotherapy regimes which often decreases therapy effectiveness. This creates a necessity of identification of clinical markers of effectiveness based on the drug's pharmacodynamics and mechanism of action.Aim. To analyze the effect of clinical characteristics, peripheral blood markers, and systemic inflammation on long-term results of CT + TT/TT with cetuximab in cancer of the mucosa of the head and neck.Materials and methods. The prospective observational study performed at the Oncology Department with a course on thoracic surgery of the Kuban State Medical University, included 52 patients with head and neck squamous cell carcinoma receiving CT + TT/TT between 2020 and 2023. Clinical characteristics and results of peripheral blood tests were retrospectively analyzed, indices of inflammatory reaction prior to treatment and 12-16 weeks after CT + TT/TT with cetuximab were calculated. Statistical analysis was performed using the med Calc ver. 20.218 and IBM SPSS Statistics 22 software.Results. CT + TT/TT with cetuximab significantly increased red blood cell count (RBC), lymphocyte-monocyte ratio (LMR), and decreased systemic inflammatory markers (SIM) (p 3.27 after 12-16 weeks of therapy (AUC = 0.685; 95 % CI 0.486-0.885; p = 0.0691). median survival of patients after the start of CT + TT/TT with cetuximab was 28 months (95 % CI 17-48), progression-free survival was 8 months (95 % CI 5-36). For RBC count >3.8 x 1012/L 12-16 weeks after the start of therapy, risk of progression decreased by 79 % (hazard ratio 0.21; 95 % CI 0.07-0.62; p = 0.0047). Partial response after 12-16 weeks of CT + TT/TT decreased progression risk more than 4-fold (p

El cáncer anal primario representa del 1% al 3% de los cánceres gastrointestinales. La histología más común es el carcinoma escamocelular, con una incidencia de 0,5 a 2 por cada 100.000 personas. El principal factor de riesgo es la infección por el virus del papiloma humano, especialmente los subtipos 16 y 18, que representan del 85% al 93% de los casos. El tratamiento y el pronóstico dependen del estadio del tumor. Los tumores localizados se pueden tratar con cirugía curativa, pero las etapas localmente avanzadas requieren una combinación de quimioterapia y radiación. Los tumores en estadio avanzado (IIIC y IV) tienen un mal pronóstico incluso con quimioterapia. En los últimos años, la inmunoterapia y las terapias dirigidas son prometedoras para mejorar la supervivencia de los pacientes con enfermedad avanzada, recurrente o difícil de tratar. Se presenta el caso de una mujer de 69 años con carcinoma escamocelular moderadamente diferenciado (T2N1M0, estadio IIIA) del canal anal que, después del tratamiento con quimiorradioterapia e inhibidores de punto de chequeo y luego de la progresión de la enfermedad, recibió tratamiento con terapia blanco (cetuximab) y logró la remisión completa de la enfermedad y una respuesta mantenida por más de 18 meses. Este caso destaca los desafíos del tratamiento del cáncer anal avanzado y los beneficios potenciales de la terapia dirigida, especialmente cetuximab, para lograr respuestas a largo plazo. Se necesitan más investigaciones a gran escala para determinar el papel de la terapia blanco y la inmunoterapia en el tratamiento de este cáncer.

Abstract Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.

Abstract Colorectal cancer (CRC) often necessitates cetuximab (an EGFR-targeting monoclonal antibody) for treatment. Despite its clinical utility, the specific operative mechanism of cetuximab remains elusive. This research investigated the influence of PLCB3, a potential CRC oncogene, on cetuximab treatment. We extracted differentially expressed genes from the GSE140973, the overlapping genes combined with 151 Wnt/β-Catenin signaling pathway-related genes were identified. Then, we conducted bioinformatics analysis to pinpoint the hub gene. Subsequently, we investigated the clinical expression characteristics of this hub gene, through cell experimental, scrutinized the impact of cetuximab and PLCB3 on CRC cellular progression. The study identified 26 overlapping genes. High expression of PLCB3, correlated with poorer prognosis. PLCB3 emerged as a significant oncogene associated with patient prognosis. In vitro tests revealed that cetuximab exerted a cytotoxic effect on CRC cells, with PLCB3 knockdown inhibiting CRC cell progression. Furthermore, cetuximab treatment led to a reduction in both β-catenin and PLCB3 expression, while simultaneously augmenting E-cadherin expression. These findings revealed PLCB3 promoted cetuximab inhibition on Wnt/β-catenin signaling. Finally, simultaneous application of cetuximab with a Wnt activator (IM12) and PLCB3 demonstrated inhibited CRC proliferation, migration, and invasion. The study emphasized the pivotal role of PLCB3 in CRC and its potential to enhance the efficacy of cetuximab treatment. Furthermore, cetuximab suppressed Wnt/β-catenin pathway to modulate PLCB3 expression, thus inhibiting colorectal cancer progression. This study offered fresh perspectives on cetuximab mechanism in CRC.

Introduction: The development of new and changing melanocytic lesions has been increasingly reported as an adverse dermatologic toxicity of BRAF inhibitor therapy. Melanocytic lesions and melanomas induced by BRAF inhibitor therapy that lack BRAF V600E expression have been less commonly described. One mechanism that has been proposed for the development of BRAF inhibitor-induced melanocytic lesions, including those lacking BRAF V600E expression, is the paradoxical activation of the MAPK signaling pathway in BRAF wild-type (BRAFWT) cells. Case Presentation: Herein, we report a rare case of a 39-year-old woman who developed numerous BRAF V600E-negative eruptive melanocytic nevi following encorafenib, cetuximab, and binimetinib combination therapy, the current standard of care for the treatment of BRAF-mutant metastatic colorectal cancer. Conclusion: Patients treated with BRAF inhibitors, with or without related combination therapies, who develop BRAFWT melanocytic lesions are at risk for developing both dysplastic nevi and melanoma, thereby warranting baseline dermatoscopic evaluation prior to the initiation of therapy as well as regular follow-up during and after treatment.

Cetuximab (CET), a human murine chimeric IgG monoclonal antibody and an inhibitor of epidermal growth factor receptor (EGFR), has been shown to be effective in treating various types of cancer. However, its use is hindered by limitations such as resistance development, variability in patient response, side effects, and challenges in biomarker identification. Therefore, CET is often combined with other targeted therapies or chemotherapies to enhance its effectiveness. In this study, we investigate the anticancer effects and underlying mechanisms of the combination of CET, an EGFR inhibitor, and STA9090, an inhibitor of heat shock protein 90 (Hsp90), in both in vitro and in vivo models of non-small cell lung cancer (NSCLC). The results demonstrate significantly stronger effects on NSCLC cells in response to combination therapy than to treatment with either agent alone, indicating that the combination of CET and STA9090 has potential synergistic effects. Additionally, the combination therapy inhibits tumor growth in a xenograft nude mouse model more effectively than treatment with either agent alone, suggesting improved efficacy when used together. Furthermore, the synergistic effects of the combination therapy are likely due to inactivation of the receptor tyrosine kinase (RTK) pathway, which is overly activated in cancer and contributes to tumor growth, angiogenesis, and metastasis. Consequently, our findings suggest that STA9090 has potent direct antitumor activity and synergizes with CET against NSCLC tumors. It is highly likely that these synergistic effects are mediated through RTK pathway inactivation caused by the combination. Therefore, our findings strongly and consistently support the potential synergistic effect of STA9090, an RTK inhibitor, in combination with EGFR-targeting agents.

Abstract Background This study evaluates the association of diuresis and hydration through a new monitoring indicator called $${U}_{sen}$$ U sen and the risk of acute kidney injury in patients treated with cisplatin based-EXTREME regimen. Methods We retrospectively reviewed all the cycles of patients with recurrent and/or metastatic head and neck cancer who received cisplatin based-EXTREME regimen from June 2008 to July 2022. Hydration regimen, urine output and concomitant treatments data were collected on the day of cisplatin infusion and the following day of each course received. Results Of the 110 courses received by 46 patients, 38 (34.5%) results in AKI. No patient characteristics showed a significant difference between AKI (70%) and non-AKI (30%) group. In univariate analysis, dose reduction of cisplatin (odds ratio = 0.166 [0.04; 0.75], p = 0.01)) and $${U}_{sen}$$ U sen >8 (odds ratio = 0.316 [0.133; 0.755], p = 0.015) and cardiac treatments (odds ratio = 3.24 [1.26; 8.52], p = 0.02) were significantly associated with AKI risk. In multivariate analysis, cisplatin dose reduction (odds ratio = 0.129 [0.0241; 0.687], p = 0.016) and $${U}_{sen}$$ U sen >8 (odds ratio = 0.184 [0.0648; 0.523], p = 0.0015) were associated with a risk reduction of cisplatin-related AKI. Concomitant administration of cardiac treatments (odds ratio = 3.18 [1.1; 9.22], p = 0.033) showed an increased risk of cisplatin-related AKI. Conclusion The combination of diuresis and i.v. hydration through the $${U}_{sen}$$ U sen composite score was shown to be associated with cisplatin-induced AKI risk in patients treated with cisplatin based EXTREME regimen. It could be used as a practical indicator to trigger specific clinical management to limit the risk of cisplatin induced AKI.

Tiantian Xuan,1 Zhanmei Wang,1 Sibo Meng,1 Jiaxin Li,1 Jisheng Li,2 Fangli Cao,1,* Linli Qu1,* 1Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, People’s Republic of China; 2Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangli Cao; Linli Qu, Department of Medical Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong, 266035, People’s Republic of China, Tel +86-18561811936 ; +86-18561811457, Email caofangliqilu@163.com; qulinli2021@163.comPurpose: Cetuximab (CET) combined with chemotherapy significantly improved the survival in RAS and RAF wild-type metastatic colorectal cancer (mCRC) patients, while clinical evidence was lacking on the use of maintenance therapy (MT). The study aimed to explore the role of maintenance therapy following Cetuximab + chemotherapy and the optimal Cetuximab-based maintenance therapy regimen.Patients and Methods: We retrospectively reviewed data on the efficacy and safety of CET-based MT in patients with mCRC who achieved disease control after induction therapy.Results: Eighty-one patients with mCRC who achieved disease control after CET + chemotherapy induction were enrolled. Overall median progression-free survival (PFS) was 10.5 (95% CI = 8.8– 12.2) months and median maintenance/observation PFS (mnPFS) was 6.0 (95% CI = 5.0– 7.0) months. Among these 81 patients, 61 patients were prescribed MT (CET alone for 21 patients and CET + chemotherapy for 40 patients). Median PFS and mnPFS in the MT group were significantly longer than those for the non-MT group. Different MT regimens did not affect PFS and mnPFS significantly. Univariate and multivariate analysis demonstrated MT, complete response/partial response during induction therapy, and absence of peritoneal metastasis to be positively associated with longer PFS and mnPFS. Treatment-related adverse events (AEs) were tolerable during MT, and AE-related deaths were not observed.Conclusion: MT with CET or CET + chemotherapy was an appropriate option following initial induction chemotherapy for patients with RAS and RAF wild-type mCRC. This strategy endowed survival benefits and a tolerable safety profile.Keywords: colorectal cancer, maintenance therapy, cetuximab, RAS and RAF wild-type, targeted therapy

Abstract In the CheckMate 651 study, nivolumab plus ipilimumab versus EXTREME (cisplatin/carboplatin + cetuximab + fluorouracil) regimen was compared for effectiveness. It is not known whether these immunotherapy agents are cost-effective for recurrent or metastatic squamous cell carcinomas of the head and neck (R/M SCCHN). The purpose of this study was to compare the cost-effectiveness of nivolumab plus ipilimumab with EXTREME in the first-line setting from the standpoint of third-party payers in the United States. The projecting of costs and outcomes over 15 years was done using a three-state partitioned survival model discounted by 3% per year. Long-term extrapolation of CheckMate 651 was used to model progression-free survival and overall survival (OS). The incremental net health benefit (INHB), incremental net monetary benefit (INMB), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated. The uncertainty and stability of the model were accounted for via one-way and probabilistic sensitivity analyses. As compared with nivolumab plus ipilimumab, EXTREME was associated with an increase of 0.154 life-years and 0.076 QALYs, as well as a cost increase of $572 per patient. The corresponding ICERs were $7545/QALY along with the values of INMB and INHB were $113,267 and 0.076 QALYs, respectively, at a willingness to pay (WTP) threshold of $150,000/QALY. The probability of nivolumab plus ipilimumab being cost-effective was > 99% in patients with combined positive score (CPS) ≥ 1, CPS 1–19, or CPS ≥ 20. Moreover, hazard ratio for OS and body weight were the most sensitive parameters for the model. According to sensitivity analyses, these results were generally robust. In overall populations with R/M SCCHN, the EXTREME regimen is cost-effective compared with nivolumab plus ipilimumab. Given a WTP threshold of $150,000 per QALY, the probability of the EXTREME regiment being cost-effective compared with nivolumab and ipilimumab, was 64%. Importantly, there was heterogeneity in the cost-effectiveness probabilities, based on primary sites and expression levels of PD-L1. Therefore, tailored treatment based on individual patient and clinical characteristics, remains important, and may impact the cost-effectiveness of the regimens under study.

Introduction: Reexposure to anti-EGFR antibodies, such as a reintroduction or rechallenge with anti-EGFR antibodies, has attracted much attention in the field of metastatic colorectal cancer. A reintroduction of anti-EGFR antibodies often shows good therapeutic outcomes, as most patients eligible for such reintroduction discontinued treatment due to adverse events despite a good treatment response during front-line treatment. We herein report a case demonstrating an improvement in exertional dyspnea after the reintroduction of anti-EGFR antibody in a patient with metastatic rectal cancer who developed cancerous lymphangiopathy. Case Presentation: A 68-year-old man who had undergone curative surgery for stage IIIB rectal cancer was diagnosed with multiple lung metastases. During the late-line treatment, respiratory failure developed because of multiple lung metastases and cancerous lymphangiopathy. Two months after the initiation of irinotecan + cetuximab, which had been discontinued due to acneiform eruptions despite a good treatment response as a first-line treatment, his dyspnea and performance status dramatically improved. Conclusion: This case indicates that the reintroduction of anti-EGFR antibody to patients who have discontinued anti-EGFR antibody due to skin toxicity despite a good treatment response is a very useful treatment option for metastatic colorectal cancer.

Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells is a key mechanism in anti-cancer therapies with monoclonal antibodies, including cetuximab (EGFR-targeting) and avelumab (PDL1-targeting). Fc gamma receptor IIIa (FcγRIIIa) polymorphisms impact ADCC, yet their clinical relevance in NK cell functionality remains debated. We developed two complementary flow cytometry assays: one to predict the FcγRIIIa-V158F polymorphism using a machine learning model, and a 15-color flow cytometry panel to assess antibody-induced NK cell functionality and cancer-immune cell interactions. Samples were collected from healthy donors and metastatic colorectal cancer (mCRC) patients from the FIRE-6-Avelumab phase II study. The machine learning model accurately predicted the FcγRIIIa-V158F polymorphism in 94% of samples. FF homozygous patients showed diminished cetuximab-mediated ADCC compared to VF or VV carriers. In mCRC patients, NK cell dysfunctions were evident as impaired ADCC, decreased CD16 downregulation, and reduced CD137/CD107a induction. Elevated PD1+ NK cell levels, reduced lysis of PDL1-expressing CRC cells and improved NK cell activation in combination with the PDL1-targeting avelumab indicate that the PD1-PDL1 axis contributes to impaired cetuximab-induced NK cell function. Together, these optimized assays effectively identify NK cell dysfunctions in mCRC patients and offer potential for broader application in evaluating NK cell functionality across cancers and therapeutic settings.

IntroductionN-glycosylation is a post-translational modification that is highly important for the development of monoclonal antibodies (mAbs), as it regulates their biological activity, particularly in terms of immune effector functions. While typically added at the Fc level, approximately 15-25% of circulating antibodies exhibit glycosylation in the Fab domains as well. To the best of our knowledge, cetuximab (Erbitux®) is the only therapeutic antibody presenting Fab glycosylation approved world-wide targeting the epidermal growth factor receptor for the treatment of metastatic-colorectal and head and neck cancers. Additionally, it can trigger antibody-dependent cell cytotoxicity (ADCC), a response that typically is influenced by N-glycosylation at Fc level. However, the role of Fab glycosylation in cetuximab remains poorly understood. Hence, this study aims to investigate the structural role of Fab glycosylation on the conformational behavior of cetuximab.MethodsThe study was performed in silico via accelerated molecular dynamics simulations. The commercial cetuximab was compared to its form without Fab glycosylation and structural descriptors were evaluated to establish conformational differences.ResultsThe results clearly show a correlation between the Fab glycosylation and structural descriptors that may modulate the conformational freedom of the antibody, potentially affecting Fc effector functions, and suggesting a negative role of Fab glycosylation on the interaction with FcγRIIIa.ConclusionFab glycosylation of cetuximab is the most critical challenge for biosimilar development, but the differences highlighted in this work with respect to its aglycosylated form can improve the knowledge and represent also a great opportunity to develop novel strategies of biotherapeutics.

The interplay between immune components and the epithelium plays a crucial role in the development and progression of head and neck squamous cell carcinoma (HNSCC). Natural killer (NK) cells, one of the main tumor-killing immune cell populations, have received increasing attention in HNSCC immunotherapy. In this review, we explore the mechanism underlying the interplay between NK cells and HNSCC. A series of immune evasion strategies utilized by cancer cells restrict HNSCC infiltration of NK cells. Overcoming these limitations can fully exploit the antineoplastic potential of NK cells. We also investigated the tumor-killing efficacy of NK cell-based immunotherapies, immunotherapeutic strategies, and new results from clinical trials. Notably, cetuximab, the most essential component of NK cell-based immunotherapy, inhibits the epidermal growth factor receptor (EGFR) signaling pathway and activates the immune system in conjunction with NK cells, inducing innate effector functions and improving patient prognosis. In addition, we compiled information on other areas for the improvement of patient prognosis using anti-EGFR receptor-based monoclonal antibody drugs and the underlying mechanisms and prognoses of new immunotherapeutic strategies for the treatment of HNSCC.

Liver fibrosis, developed in almost all chronic liver injuries. Epidermal growth factor receptors (EGFR) have been thought to contribute to cirrhosis and liver fibrosis. Therefore, using a rat model of carbon tetrachloride (CCl4)-induced liver fibrogenesis, we investigated the preventive effects of cetuximab, an inhibitor of the EGF receptor (EGFR). Ameliorative effects of cetuximab were examined in rats, brought on by biweekly doses of 50 mg/kg of carbon tetrachloride (CCl4). There were a total of 24 male Long Evans rats split up into four distinct groups such as control, CCl4, control+cetuximab and CCl4+cetuximab. After two weeks of treatment with cetuximab (100 μg/kg), samples of tissue and blood were taken after all the rats had been sacrificed. Plasma samples were examined for the biochemical indicators of inflammation and oxidative stress. Histological staining on liver sections was performed for morphologic pathologies, and related genes expressions analysis were done with RT-PCR in liver tissue. The findings showed that cetuximab could raise the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) and considerably lower the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA), and nitric oxide (NO). Sirius red staining and hematoxylin-eosin (H&E) displayed that cetuximab therapy reduced the inflammatory cells infiltration and enhanced fibrotic lesions. In the meantime, cetuximab therapy also dramatically reduces the expression of genes linked to inflammation in the liver tissue, including NF-кB, iNOS, IL-6, TNF-α, and TGF-β. To sum up, the anti-inflammatory, antifibrotic, and antioxidant properties of cetuximab confer curative efficacy against liver fibrosis.

Background: Radiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20–25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab. Methods: A 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx. Results: The phase I study established the following recommended doses: weekly cetuximab (400 mg/m2 one week before, and 250 mg/m2 during radiotherapy); 5FU (500 mg/m2/day, d1-d4) plus cisplatin (40 mg/m2, d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached. Conclusions: Adding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity. Trial registration: This trial was registered with EudraCT number 2006-004770-27.

BackgroundThe significance of induction chemotherapy (IC) in the treatment of squamous cell carcinoma of the head and neck (SCCHN) with unresectable locoregional recurrence after curative surgery has not been clarified. The aim of this study was to evaluate the efficacy of IC followed by chemoradiotherapy (CRT) in these patients.MethodsAmong patients with unresectable locoregional recurrent SCCHN who had not undergone prior irradiation and were eligible for cisplatin, we conducted a retrospective analysis of patients who received CRT following IC with paclitaxel, carboplatin, or cetuximab (IC-PCE group) and those who received CRT without prior IC (CRT group) between June 2013 and August 2021.ResultForty-two patients were included. The CRT group and IC-PCE group consisted of 15 and 27 patients, respectively. Primary site was the oral cavity (n=25), oropharynx (n=3), hypopharynx (n=13) and larynx (n=1). Objective response rate (ORR) with IC-PCE was 55.6%; 24 patients (88.9%) subsequently received CRT. ORR after completion of CRT was significantly better in the IC-PCE group (95.8% in the IC-PCE group vs. 66.7% in the CRT group, p=0.024). Progression-free survival (PFS) of the total population on median follow-up of 2.4 years (range: 0.8-7.3) tended to be better in the IC-PCE group (2-year PFS: 55.6% in the IC-PCE group vs. 33.3% in the CRT group, log-rank p=0.176), especially in oral cancer (2-year PFS: 37.5% in the IC-PCE group vs. 0% in the CRT group, log-rank p=0.015).ConclusionTherapeutic strategies including IC-PCE in patients with unresectable locoregional recurrent SCCHN after curative surgery may contribute to improved prognosis, especially in oral cancer.

Abstract Over the past decades, red meat allergy, also known as mammalian meat allergy, which manifests differently from classic food allergies, has been reported in different countries and regions, including China. The allergen of this disease is not a protein but an oligosaccharide: galactose‐α‐1,3‐galactose, i.e., alpha‐gal or α‐gal. Therefore, this clinical syndrome is also called α‐gal syndrome (AGS). It clinically manifests as delayed anaphylaxis, i.e., patients generally develop allergic symptoms 2–6 h after ingesting red meat. This clinical manifestation is believed to be related to sensitization to α‐gal after tick bites. Sensitized individuals may also develop anaphylaxis after ingesting food and medicine or being exposed to medical equipment containing α‐gal, such as cetuximab and gelatin. Here, the literature on AGS is reviewed for a better understanding of its pathogenesis, clinical diagnosis, and treatment.

BackgroundTo investigate the effectiveness and safety of maintenance regimens based on cetuximab, we conducted a real-world, single-arm, retrospective study at a single center.MethodsIn Fujian Medical University Union Hospital, patients with unresectable metastatic colorectal cancer (mCRC) who received cetuximab-based maintenance therapy between December 2020 and December 2021 were included. All patients had RAS and BRAF wild-type. The maintenance regimen consisted of 6–12 cycles of cetuximab plus irinotecan (Phase 1) and cetuximab (Phase 2). Patients could receive reintroduction therapy in case of disease progression during Phase 2. Progression-free survival (PFS), overall survival (OS), and safety data were collected.ResultsAccording to the inclusion and exclusion criteria of the study, a total of 108 subjects who received maintenance therapy were included— 51 experienced disease progression during Phase 1, with PFS (1) of 7.3 months. Among the 52 patients who entered Phase 2, 17 were still in this phase at the end of follow-up, with PFS (2) of 10.1 months. In Phase 2, 35 patients experienced disease progression, of whom 24 received reintroduction therapy, with PFS (3) of 6.7 months. The overall PFS (total) during the maintenance period was 11.9 months, and the OS was 39.2 months. Grade III or higher adverse events were 4.6% during Phase 1 and 0% during Phase 2.ConclusionInnovative cetuximab-based maintenance therapy showed a trend toward improving the prognosis of mCRC patients with RAS and BRAF wild-type, while the toxic side effects of maintenance therapy were manageable.Clinical trial registrationhttps://www.chictr.org.cn, identifier ChiCTR2000040940.

Sinonasal NUT carcinoma (NC) is an exceptionally rare and fatal form of cancer, and the literature on this pathology is scarce. In this article, we report a case of ethmoidal NUT carcinoma, initially locally advanced then metastatic. Our case is the first to test immunotherapy and anti-EGFR in metastatic sinonasal NUT carcinoma.This is a 47-year-old man diagnosed with ethmoidal NUT carcinoma cT4N0M0. Neoadjuvant chemotherapy (CT) was started with 5 cycles of TCF (Docetaxel 40 mg/m2 CDDP 40mg/m2 and 5FU 2000mg/m2), resulting in a discrete partial metabolic response, followed by radiotherapy (RT) (total dose, 70 Gy; 2 Gy × 35 Fractions). The PET scan re-evaluated at 2 months showed no tumor response and metastatic bone progression. In view of the epidermoid component of the histology, treatment with Nivolumab was introduced, but failed after 6 cycles, followed by Carboplatin (AUC 2), Paclitaxel (80mg/m2) 3 weeks out of 4 and Cetuximab (500mg/m2) twice monthly, but failed after 3 cycles, and finally Vinorebline (30mg) 3 times weekly, stopped early due to deterioration in general condition. The patient died 17 months after initial diagnosis.

Abstract Exosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G‐protein Rab11a. These vesicles, termed Rab11a‐exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a‐exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non‐genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG‐carrying Rab11a‐exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a‐exosomes from cetuximab‐resistant KRAS‐mutant HCT116 cells, can suppress the effects of cetuximab on KRAS‐wild type Caco‐2 CRC cells. Using neutralising anti‐AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a‐exosomes affects its ability to compete with cetuximab. We propose that this Rab11a‐exosome‐mediated mechanism contributes to the establishment of resistance in cetuximab‐sensitive cells and may explain why in cetuximab‐resistant tumours only some cells carry mutant KRAS.

Background: While the triplet combination of encorafenib (ENCO), binimetinib (BINI), plus cetuximab (CET) yielded a higher response rate compared with the doublet combination of ENCO plus CET, no significant survival benefits of the triplet combination were observed in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC), according to the BEACON CRC study. Although ENCO plus CET is the standard second-line therapy, poor prognoses are expected after disease progression. Trial design: BAYONET is a single-arm multicenter phase II trial designed to evaluate the efficacy and safety of staged combination with ENCO, BINI, plus CET for patients with BRAF V600E-mutant mCRC refractory to ENCO plus CET. The main inclusion criteria are as follows: RAS wild-type/BRAF V600E-mutant mCRC;

Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths globally. The most extensive treatment is Tyrosine Kinase Inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) overexpression. Osimertinib, a third-generation TKI is approved to target EGFR exon 19 deletions or exon 21 L858R mutations. However, resistance is inevitable due to emergence of triple mutations (sensitizing mutations, T790M and C797S). To overcome this challenge, a combinatorial approach was used wherein Osimertinib liposomes were conjugated with cetuximab (CTX), an anti-EGFR monoclonal antibody, to improve drug efficacy and delivery. Additionally, pulmonary administration was employed to minimize systemic toxicity and achieve high lung concentrations. Methods: Osimertinib liposomes (OB-LPs) were prepared using thin film hydration method and immunoliposomes (CTX-OB-LPs) were prepared by conjugating the OB-LPs surface with CTX. Liposomes were characterized for particle size, zeta-potential, drug loading, antibody conjugation efficiency, in vitro drug release, and aerosolization performance. Further, the in vitro efficacy of immunoliposomes was evaluated in H1975 cell line. Results: Immunoliposomes exhibited a particle size of 150 nm, high antibody conjugation efficiency (87%), efficient drug release, and excellent aerosolization properties with an aerodynamic diameter of 3 μm and fine particle fraction of 88%. Furthermore, in vitro studies in H1975 cells showed enhanced cytotoxicity with CTX-OB-LPs displaying 1.7-fold reduction and 1.2-fold reduction in IC50 compared to Osimertinib and OB-LPs, respectively. The CTX-OB-LPs also significantly reduced tumor cell migration and colonization compared to Osimertinib and OB-LPs. Conclusions: These successful results for EGFR-targeting inhalable immunoliposomes exhibited potential for contributing to greater anti-tumor efficacy for the treatment of non-small cell lung cancer.

This paper summarized the Traditional Chinese Medicine(TCM) characteristic nursing of a case of cetuximab-induced facial rash. Based on the syndrome differentiation, TCM characteristic nursing interventions including TCM medication, auricular acupoint pressing, TCM spray, TCM aerosols were carried out, in combination of skin care, sleep guidance, nutrition support and emotion care, in order to relieve the skin rash and pain, improve the healing of skin damage and ensure the smooth progress of chemotherapy. (本文总结1例西妥昔单抗致颜面部皮疹患者的中医特色护理经验。基于辨证分型, 给予患者中药内服、耳穴压豆、中药外洗、中药喷雾疗法等中医特色疗法, 并配合皮肤护理、睡眠指导、饮食干预、情志护理等常规护理措施, 减轻患者皮肤瘙痒和疼痛, 促进皮损恢复, 确保后续化疗的顺利进行。)

Abstract Background Adding anti-epidermal growth factor receptor (anti-EGFR) target agents to conversion therapy may improve the resection rates and survival of patients with potentially resectable metastatic colorectal cancer (mCRC). This study aims to analyze the efficacy and safety of additional anti-EGFR target agents. Methods A systematic search was conducted on PubMed, Web of Science, Embase, and Cochrane Library. And all relevant studies published in English before January 2023 were collected to explore the impact of additional anti-EGFR targeted agent on the efficacy and safety of patients with potentially resectable mCRC (PROSPERO: CRD42022340523, https://www.crd.york.ac.uk/PROSPERO/ ). Results This study included a total of 8 articles, including 2618 patients. The overall response rate (ORR) and R0 resection rates of the experimental group were higher than those of the control group, while there was no significant difference in progression-free survival (PFS) and overall survival (OS) between the two groups. In RAS/KRAS wild-type patients, the ORR (RR: 1.20, 95% Cl: 1.02–1.41, p = 0.03), R0 resection rate (RR: 1.60, 95% Cl: 1.17–2.20, p = 0.003), PFS (HR: 0.80, 95% Cl: 0.68–0.93, p = 0.003), and OS (HR: 0.87, 95% Cl: 0.76–0.99, p = 0.031) of the experimental group were higher than those of the control group. While in KRAS mutant patients, there was no statistical difference between the two groups in ORR, R0 resection rate, PFS, and OS. Conclusion The addition of anti-EGFR targeted agents can improve the prognosis of RAS/KRAS wild-type patients with potentially resectable mCRC, while KRAS mutant patients may not benefit. In addition, the overall safety factor was controllable.

Abstract Background Treatment options for advanced colon cancer are mainly combinations of chemotherapy and targeted drugs. However, poor physical health and medication intolerance limit the choice of anticancer drugs. Colon cancer with cirrhosis is a particular patient group that poses a challenge to clinical treatment. Case presentation This article presents a case of a patient in the decompensated stage of cirrhosis who was diagnosed with advanced colon cancer. The initial presentation was a nodule on his navel named the Sister Mary Joseph’s nodule, which was later confirmed by biopsy and PET-CT as one of the metastases of colon cancer. The patient was treated with cetuximab and 5-fluorouracil at a below-guideline dose; however, portal vein thrombosis developed and led to death. This entire process, from diagnosis to death, occurred within a span of three months. Conclusion Cancers with cirrhosis are a special group that deserves more attention. There is no unified treatment guideline for these patients, especially those with extrahepatic primary tumors. We should be more cautious when choosing treatment for such patients in the future. Both chemotherapy and targeted treatment may potentially induce portal vein thrombosis, which appears to have a higher incidence and worse prognosis than cancers without cirrhosis.

Antibody-based radiopharmaceuticals are of increasing interest today in cancer imaging and radiotherapy. The cetuximab monoclonal antibody binds to the epidermal growth factor receptor (EGFR) and thus provides therapeutic and diagnostic protocols against this receptor. Following purification and conjugation with freshly prepared DOTA-NHS, the cetuximab antibody was labeled with lutetium 177 and samarium chloride-153. Labeling efficiency and in vitro stability were measured using thin-layer chromatography. Cellular tests were performed to determine radioimmunoactivity in cancer cells. The results showed that the labeling efficiencies of 177Lu-DOTA-cetuximab and 153Sm-DOTA-cetuximab were more than 97±1% and 96±2%, respectively. Also, the in vitro stability of the labeled products in fresh human serum after 96 hours was 83± 22% and 78%, respectively. Immunoreactivity was 91% for 177Lu-DOTA-cetuximab and 66±1% for 153Sm-DOTA-cetuximab. With different intensities based on time and beta energy, both products inhibited the growth of HT29 colon cancer cells. The results showed that the immunoconjugate complexes of 177Lu-DOTA-cetuximab and 153Sm-DOTA-cetuximab can be considered a novel radiopharmaceutical for cancer radioimmunotherapy.

Immunotherapy is the first-line option for treating advanced cutaneous squamous cell carcinoma (cSCC). However, up to half of patients experience no benefit and treatment resistance, warranting newer therapeutic approaches. Combinatory approaches, including cetuximab, may help overcome immunotherapy resistance and improve response rates in advanced cSCC. We report three cases of metastatic cSCC that achieved significant clinical responses after cetuximab therapy following initial progression on pembrolizumab. We have retrospectively reviewed these cases at a single academic center between 2018 and 2023. All patients initially progressed on pembrolizumab, after which cetuximab (mono- or combination therapy) was added with two complete responses and one partial response. Initial responses were noted within 2 to 7 months of starting cetuximab. While the benefit of cetuximab and immunotherapy in head-and-neck squamous cell carcinoma has growing evidence, information regarding cSCC remains limited. This study adds three cases to the underreported literature on treating advanced cSCC with cetuximab after initially failing immunotherapy.