Combination Of Cetuximab Research Articles

Treatment Options in BRAF-mutant Metastatic Colorectal Cancer

Treatment of BRAF-mutant colorectal cancer (CRC) traditionally represents an unmet need, mainly due to its unfavourable prognostic outlook, limited options for targeted treatment and scarce benefit from epithelial growth-factor receptor (EGFR) inhibitors. Recently, the development of BRAF V600E inhibitors has expanded the therapeutic armamentarium, although exclusive targeting of BRAF has proved to be an unsuccessful strategy due to reactivation of the mitogen-activated protein kinase pathway through multiple escape mechanisms. Combination strategies that exploit simultaneous inhibition of BRAF, EGFR and/or mitogen-activated protein/extracellular signal-regulated kinase have achieved greater success, with the BEACON CRC trial providing the first evidence for an improvement in survival with a chemotherapy-free approach in pre-treated patients with CRC, leading to regulatory approval for the combination of encorafenib and cetuximab. Subsequent research efforts attempt to build on these foundations, exploring targeted maintenance strategies and conceivably moving the combination towards the first line of therapy soon, as well as laying the foundation for the use of liquid biopsy as a guidance tool in a precision oncology approach.

Abstract PO-131: The role of liver endothelium on pancreatic cancer growth

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among major cancers in the United States, and the 5-year survival rate for patients with metastatic PDAC (mPDAC) is only at 3%. Past studies have shown that the paracrine secretion of soluble factors by endothelial cells (ECs) created a unique niche and promoted the survival of cancer cells (cell growth or chemoresistance) in other types of cancer. The liver is the main site of distant metastases in mPDAC, but the influence of the liver EC microenvironment on mPDAC has not been elucidated. In this study, we determined the paracrine effects of liver ECs on the survival of PDAC and identify involved mechanism. Methods: Primary liver ECs were isolated from non-neoplastic liver tissues to mimic the liver EC microenvironment. Conditioned medium (CM) from liver ECs were collected and then applied to PDAC cells, with CM from PDAC as control CM. Effects of CM on PDAC cell proliferation were measured by the MTT assay. Changes in phosphorylation of receptor tyrosine kinases (RTK) between PDAC CM and EC CM treated PADC cells were determined by a Phospho-RTK Array kit and then validated by Western blotting. Involved RKTs were blocked by antibodies for determining their roles in mediating EC effects on PDAC cells. Lastly, A xenograft tumor model was used to establish PDAC tumors and then treated xenograft mice were subcutaneously injected by either PADC CM or EC CM, and tumors growth was monitored and recorded to evaluate the effect of ECs on PADCs. Results: Compared to PDAC CM, EC CM promoted proliferation in 4 different PDAC cells. We found that human epidermal growth factor receptor 3 (HER3 or ERBB3) was only expressed and activated in BxPC-3 cells (HER3+ve), in which the HER3-AKT signaling pathway was activated by EC CM. Furthermore, blocking HER3 activation with a humanized HER3 antibody, seribantumab, completely blocked EC CM-induced AKT activation and cell proliferation. Moreover, depletion of neuregulin (NRG) from EC CM attenuated HER3-AKT activation and indicated that EC-secreted NRG might play a role in promoting PDAC growth. It is interesting that ERK activation was also observed but was not affected by HER3 inhibition. It implied that EGFR signaling pathway might also be involved in EC CM induced PDAC cell growth. Moreover, the combination of cetuximab, trastuzumab and seribantumab yielded the best inhibitory ability on EC CM promoted cell growth as compared to antibody alone or the combination of two of them. Finally, EC CM promoted PDAC tumor growth was also observed in BxPC-3 derived xenograft mouse model. Conclusions: Our results demonstrated that liver EC-secreted factors promoted PDAC growth either in vitro or in vivo, and HER3 was expressed in a subset of PDAC cells and mediated EC-induced proliferation. Moreover, EGFR pathway may also play a role in EC induced cell growth and needs to be addressed in the future study. Our findings suggest a potential of using the combination of HER antibodies/inhibitors for treating patients with HER3+ve mPDACs. Citation Format: Wei Zhang, Michel’le Wright, Moeez Rathore, Ali Vaziri-Gohar, Jordan Winter, Rui Wang. The role of liver endothelium on pancreatic cancer growth [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-131.

Recent Research on Combination of Radiotherapy with Targeted Therapy or Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Review for Radiation Oncologists.

Simple SummaryRadiotherapy (RT) is an effective treatment for head and neck squamous cell carcinoma (HNSCC). Concurrent RT with high dose cisplatin (100 mg/m2, days 1, 22, and 42) is the standard of care (SOC) for non-operative HNSCC in curative settings, however, it is associated with both significant toxicities. In this review, we discussed the evidence of combination of anti-epidermal growth factor receptor, cetuximab, or immune checkpoint inhibitors (ICIs) with RT to compare with SOC. Cetuximab has been shown to be a less effective agent than cisplatin multiple recent trials, but it remains a reasonable alternative for those who are not fit for cisplatin. ICIs are active agents in recurrent and metastatic HNSCC. The role of ICIs with RT in the curative setting is yet to be defined. Multiple clinical trials are currently recruiting. Combining ICIs with stereotactic body radiotherapy (SBRT) is an attractive treatment in patients with oligometastatic or oligoprogressive HNSCC to boost the anti-tumor immune response.Radiotherapy plays an important role of managing head and neck squamous cell carcinoma (HNSCC). Concurrent radiotherapy with radiosensitizing cisplastin chemotherapy is the standard of care (SOC) for non-operable locally advanced HNSCC. Cetuximab, a monoclonal antibody of epidermal growth factor receptor, was the most extensively studied targeted therapy as a chemo-sparing agent that was used concurrently with radiotherapy. Immunotherapy is used in the treatment of metastatic HNSCC. There is evidence to support the synergistic effect when combining radiotherapy with immunotherapy to potentiate anti-tumor immune response. There has been increasing interest to incorporate immune checkpoint inhibitor (ICI) with radiotherapy in the curative setting for HNSCC. In this review, we discuss the latest evidence that supports concurrent radiotherapy with cisplatin which remains the SOC for locally advanced HNSCC (LA-HNSCC). Cetuximab is suitable for patients who are not fit for cisplatin. We then summarize the clinical trials that incorporate ICI with radiotherapy for LA-HNSCC in concurrent, neoadjuvant, and adjuvant settings. We also discuss the potential of combining immunotherapy with radiotherapy as a treatment de-escalating strategy in HPV-associated oropharyngeal carcinoma. Finally, the pre-clinical and clinical evidence of the abscopal effect when combining stereotactic body radiotherapy with ICIs is presented.

Skin Toxicity as Predictor of Survival in Refractory Patients with RAS Wild-Type Metastatic Colorectal Cancer Treated with Cetuximab and Avelumab (CAVE) as Rechallenge Strategy.

Simple SummaryAnti-EGFR-related skin toxicity has been described as a predictive biomarker of response in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). With the CAVE mCRC trial we previously provided the first evidence of the activity of cetuximab plus avelumab as rechallenge treatment in pretreated chemo-refractory RAS WT mCRC. Nowadays, skin toxicity remains the only confirmed clinical biomarker of response to anti-EGFR treatment in mCRC. The role of skin toxicity has not yet been explored in a rechallenge setting. In this paper we provide a post-hoc analysis of the CAVE mCRC trial that investigated the role of skin toxicity as a predictive biomarker of activity of cetuximab plus avelumab treatment and its correlation with different clinico-molecular variables on survival at the univariate and multivariate levels. High-grade skin toxicity, together to the circulating tumor DNA RAS/BRAF/EGFR wild-type status were the only variables with an impact on PFS and OS.The single-arm phase II CAVE mCRC trial evaluated the combination of cetuximab plus avelumab as rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients, with clinical response to first-line anti-EGFR-based chemotherapy, who progressed and received a subsequent line of therapy. The correlation of skin toxicity (ST) and different clinico-molecular variables with overall survival (OS), progression-free survival (PFS) and response rate (RR) was assessed at univariate and multivariate analysis. A total of 33/77 (42.9%) patients experienced grade 2–3 ST and displayed median OS (mOS) of 17.8 months (CI 95%, 14.9–20.6); whereas 44/77 (57.1%) patients with grade 0–1 ST exhibited mOS of 8.2 months (CI 95%, 5.5–10.9), (hazard ratio (HR), 0.51; CI 95%, 0.29–0.89; p = 0.019). Median PFS (mPFS) was 4.6 months (CI 95%, 3.4–5.7) in patients with grade 2–3 ST, compared to patients with grade 0–1 ST with mPFS of 3.4 months (CI 95%, 2.7–4.1; HR, 0.49; CI 95%, 0.3–0.8; p = 0.004). Grade 2–3 ST (HR, 0.51; CI 95%, 0.29–0.89; p = 0.019) and RAS/BRAF/EGFR WT circulating tumor DNA (ctDNA) (HR, 0.50; CI 95%, 0.27–0.9; p = 0.019) had a statistically significant effect on OS at univariate analysis. At the multivariate analysis, RAS/BRAF/EGFR WT ctDNA status maintained statistical significance (HR, 0.49; CI 95%, 0.27–0.9; p = 0.023), whereas there was a trend towards ST grade 2–3 (HR, 0.54; CI 95%, 0.29–1.01; p = 0.054). Skin toxicity is a promising biomarker to identify patients with mCRC that could benefit of anti-EGFR rechallenge.

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

Cetuximab is approved for the treatment of metastatic colorectal cancer (mCRC) with RAS wild-type. Nevertheless, the prognosis remains poor and the effectiveness of cetuximab is limited in KRAS mutant mCRC. Recently, emerging evidence has shown that ferroptosis, a newly discovered form of nonapoptotic cell death, is closely related to KRAS mutant cells. Here, we further investigated whether cetuximab-mediated regulation of p38/Nrf2/HO-1 promotes RSL3-induced ferroptosis and plays a pivotal role in overcoming drug resistance in KRAS mutant colorectal cancer (CRC). In our research, we used two KRAS mutant CRC cell lines, HCT116 and DLD-1, as models of intrinsic resistance to cetuximab. The viability of cells treated with the combination of RSL3 and cetuximab was assessed by the CCK-8 and colony formation assays. The effective of cetuximab to promote RSL3-induced ferroptosis was investigated by evaluating lipid reactive oxygen species accumulation and the expression of the malondialdehyde and the intracellular iron assay. Cetuximab therapy contributed to regulating the p38/Nrf2/HO-1 axis, as determined by western blotting and transfection with small interfering RNAs. Cetuximab promoted RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 in KRAS mutant CRC cells, and this was further demonstrated in a xenograft nude mouse model. Our work reveals that cetuximab enhances the cytotoxic effect of RSL3 on KRAS mutant CRC cells and that cetuximab enhances RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 axis through the activation of p38 MAPK.

Tipifarnib enhances anti-EGFR activity of cetuximab in non-HRas mutated head and neck squamous cell carcinoma cancer (HNSCC)

ObjectiveTo test the potential ability of tipifarnib to impair proliferation and to enhance the activity of the EGFR inhibitor cetuximab in wild-type H-Ras HNSCC, which accounts for the majority of HNSCC. Materials and MethodsCell growth, apoptosis and signaling changes in HNSCC cells following tipifarnib exposure in vitro were assessed by SRB, colony formation assay, annexin V staining and Western blot, respectively. A patient-derived xenograft (PDX) animal model was adopted to evaluate the efficacy of tipifarnib in vivo with and without cetuximab. ResultsTreatment of wild-type H-Ras HNSCC cell lines in vitro with tipifarnib reduced cell growth and increased levels of defarnesylated H-Ras in a dose-dependent manner. In a PDX mouse model, treatment with single-agent tipifarnib led to only near-significant growth inhibition. The addition of cetuximab resulted in increased anti-proliferative effect both in culture and in PDX models, which was also mirrored by Western blot and apoptosis assay results. ConclusionTipifarnib has only a moderate ability to slow tumor growth as a single agent in HNSCC with wild type H-Ras, despite specifically inhibiting the farnesyltransferase upon which the function of H-Ras depends. The combination of cetuximab and tipifarnib appears to enhance the anti-proliferative effect of single-agent tipifarnib and marginally enhance that of single agent cetuximab. These findings deserve further evaluation.

AMG-510 Plus Cetuximab Enhance Radiosensitivity in KRAS p.G12C Mutant Colorectal Carcinoma Cell Lines via Increasing Apoptosis and Inducing G1/S Arrest

<h3>Purpose/Objective(s)</h3> KRAS p.G12C mutation is rare (∼3%) but with a dismal prognosis in colorectal carcinoma (CRC). AMG-510 is a first-in-class KRAS p.G12C inhibitor, which shows clinical efficacy in KRAS p.G12C mutant solid tumors including non-small cell lung cancer and CRC. The addition of cetuximab could revert resistance to AMG-510 in CRC. Herein, we evaluate the anti-cancer effect of AMG-510 plus cetuximab in combination with radiation in CRC. <h3>Materials/Methods</h3> Two KRAS p.G12C mutant CRC cell lines were treated with AMG-510, AMG-510 plus cetuximab, irradiation (IR), and the combination of IR and AMG-510 plus cetuximab. Clonogenic assays were used to study the radiosensitizing effect of AMG-510 combined with cetuximab. Immunofluorescence staining of rH2AX was used to detect double-strand break (DSB) repair. Cell proliferation was performed using a cell counting kit. Then, we performed flow cytometry analysis to detect cell apoptosis rate and cell cycle distribution. <h3>Results</h3> First, we found that AMG-510 plus cetuximab enhanced the radiosensitivity of X-ray in the SW837 cell line (sensitization enhancement ratio: 1.32). The combination of AMG-510 and cetuximab reduced cell proliferation and increased cell apoptosis rate and DNA damage, with or without irradiation. The flow cytometry analysis of the cell cycle showed G1/S phase arrest after AMG-510 monotherapy and AMG-510 plus cetuximab treatment. Moreover, the P53/Rb/P21 pathway was activated after the addition of AMG-510 with or without cetuximab. <h3>Conclusion</h3> The combination of AMG-510 and cetuximab might be a potent treatment as a radiosensitizer. However, more studies in vivo and clinical trials should be performed to further evaluate this regimen in the future.

CETUXIMAB: A POTENTIALLY UNDER RECOGNIZED ETIOLOGY OF SUDDEN CARDIAC DEATH

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Certain medications have been linked to an increased risk of sudden cardiac death through varying mechanisms. Herein, we describe a case of a cardiac arrest where cetuximab was presumed the culprit. CASE PRESENTATION: A 58-year-old female with a history relevant for TxN3bM0 squamous cell carcinoma of the neck on chemoradiation therapy was transferred to the hospital after having a cardiac arrest while receiving cetuximab. She presented earlier to the cancer center with no complaints. During cetuximab infusion, she had a cardiac arrest (pulseless electrical activity). She was resuscitated per ACLS guidelines and had a return of spontaneous circulation (ROSC) within eight minutes. Post ROSC, she was hemodynamically stable, with appropriate oxygenation and ventilation. An electrocardiogram showed normal sinus rhythm with no signs of ischemia. Point of care ultrasonography (POCUS) showed a normal left ventricular ejection fraction, with no evidence of wall motion abnormalities, right ventricular strain, or pericardial effusion. POCUS also ruled out deep vein thrombosis and pneumothorax. Cardiac enzymes, brain natriuretic peptide, potassium, calcium, and magnesium, were normal. Post-cardiac arrest care was provided, including targeted temperature management. The next day, she was following commands and meeting extubation criteria. She was extubated and transferred to the floor one day after. Formal echocardiography confirmed POCUS findings. In the absence of another explanation for her cardiac arrest, cetuximab was to blame. DISCUSSION: Cetuximab is a monoclonal antibody that binds the epidermal growth factor receptor (EGFR), competitively inhibiting the binding of EGF and resulting in inhibition of cell growth and induction of apoptosis. Cetuximab is indicated for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) in combination with radiation therapy. The addition of cetuximab in this population increased median overall survival by 20 months1. In patients with SCCHN treated with cetuximab and radiation therapy, 2% had sudden death1. Cardiac arrest also occurred in 3% of SCCHN patients treated with cetuximab in combination with platinum-based therapy and fluorouracil2. As a result, cetuximab's package has "sudden death" as a black box warning. Of note, 50% of patients treated with cetuximab may develop hypomagnesemia, and weekly monitoring of electrolytes is recommended. In our patient, electrolytes were normal, and the exact mechanism of cetuximab-induced cardiac arrest remains unclear. CONCLUSIONS: Cetuximab-induced cardiac arrest occurs in 2%-3% of treated patients in controlled studies. Real-world incidence may be higher. We report this case to add to the literature what we believe is a case of cetuximab-related cardiac arrest. REFERENCE #1: 1. Bonner JA, et. al. New England Journal of Medicine. 2006 Feb 9;354(6):567-78. REFERENCE #2: 2. Vermorken JB, et al. New England Journal of Medicine. 2008 Sep 11;359(11):1116-27. DISCLOSURES: No relevant relationships by Tony Abdo, source=Web Response No relevant relationships by Ammaar Azeem, source=Web Response No relevant relationships by SYED HUSSAIN, source=Web Response

PD-L2 glycosylation promotes immune evasion and predicts anti-EGFR efficacy

BackgroundCombination therapy has been explored for advanced head and neck squamous cell carcinoma (HNSCC) owing to the limited efficacy of anti-epidermal growth factor receptor (EGFR) therapy. Increased expression and glycosylation...

Weekly vs. 3‑weekly paclitaxel, carboplatin, and cetuximab (PCC) in recurrent/metastatic head and neck cancer

The combination of paclitaxel, carboplatin and cetuximab (PCC) is efficacious in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). The current study assessed the incidence of grade 3/4 (G3/4) toxicity for patients receiving weekly or 3-weekly PCC for R/M SCCHN. The present single-institution, retrospective analysis included 74 patients who received weekly [paclitaxel 45 mg/m2 and carboplatin area under the curve (AUC), 1.5] or 3-weekly (paclitaxel 175 mg/m2 and carboplatin AUC, 5) PCC. For each regimen, cetuximab was administered at 400 mg/m2 for the first week, after which the dosage was reduced to 250 mg/m2 weekly until disease progression occurred. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v4.03, and response to therapy was determined using computed tomography every 12 weeks. The results revealed that 26 patients (35%) received weekly PCC and 48 patients (65%) received PCC every 3 weeks. A total of 6 (25%) patients receiving weekly PCC experienced G3/4 toxicity compared with 30 (66%) patients that received PCC every 3 weeks (odds ratio, 0.18; 95% confidence interval, 0.05-0.64; P=0.01). The most common G3/4 side effects were neutropenia (8 vs. 53%), anemia (15 vs. 32%) and fatigue (3 vs. 10%). The incidence of G3/4 toxicity or any grade toxicity requiring dose modification or discontinuation was 74 vs. 77%, respectively. The overall response rate was 39% with weekly PCC compared with 27% in those receiving PCC every 3 weeks. The 1-year progression-free and overall survival rates were 27 and 46% for patients receiving weekly PCC, and 13 and 44% for patients receiving PCC every 3 weeks. Weekly PCC had a reduced risk of G3/4 toxicity when compared with PCC administered every 3 weeks. Considering the improved tolerance of weekly PCC, this regimen should be considered for older patients and patients being treated with second-line chemotherapy.

Postoperative chemoradiotherapy with cisplatin is superior to radioimmunotherapy with cetuximab and radiotherapy alone : Analysis of the Austrian head and neck cancer registry of the AGMT.

BackgroundThe addition of cisplatin or cetuximab to radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) has significantly improved the outcome. While the superiority of cisplatin over cetuximab in combination with radiotherapy has been shown in a definitive setting, we set out to compare postoperative chemoradiotherapy with cisplatin to radioimmunotherapy with cetuximab and radiotherapy alone within the Austrian head and neck cancer registry of the Working Group on Pharmaceutical Tumor Treatment (AGMT) study group.Material and methodsIn the AGMT head and neck cancer registry, data of 557 patients with SCCHN from five Austrian cancer centers were prospectively collected between 2012 and 2017. Of these patients 120 received postoperative chemoradiotherapy with cisplatin, 26 patients received postoperative radioimmunotherapy with cetuximab and 56 patients were treated with adjuvant radiotherapy only. Patient characteristics, stage of disease, details on treatment as well as survival were analyzed by a chart-based review.ResultsIn patients treated with postoperative radiotherapy the addition of cisplatin significantly improved progression-free survival (PFS) and overall survival (OS) compared to cetuximab (PFS 84.2 months vs. 17.0 months, p = 0.04, OS not reached vs. 46.0 months, p = 0.02) and PFS compared to radiotherapy alone (PFS 84.2 months vs. 28.5 months, p < 0.01). Patients treated with cetuximab were significantly older and had a worse performance score than patients receiving cisplatin or radiotherapy alone.ConclusionThis study confirmed the importance of multimodal treatment concepts in patients with locally advanced SCCHN. Postoperative cetuximab might be an option in patients not eligible for high-dose cisplatin but cisplatin should remain the standard of care.

The Role of Akt in Acquired Cetuximab Resistant Head and Neck Squamous Cell Carcinoma: An In Vitro Study on a Novel Combination Strategy.

The epidermal growth factor receptor (EGFR) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). Resistance to EGFR-targeted therapies, such as cetuximab, poses a challenging problem. This study aims to characterize acquired cetuximab resistance mechanisms in HNSCC cell lines by protein phosphorylation profiling. Through this, promising combination treatments can be identified to possibly overcome acquired cetuximab resistance in HNSCC. Protein phosphorylation profiling showed increased phosphorylation of Akt1/2/3 after cetuximab treatment in acquired cetuximab resistant cells compared to cetuximab sensitive cells, which was confirmed by western blotting. Based on this protein phosphorylation profile, a novel combination treatment with cetuximab and the Akt1/2/3 inhibitor MK2206 was designed. Synergy between cetuximab and MK2206 was observed in two cetuximab sensitive HNSCC cell lines and one acquired cetuximab resistant variant in simultaneous treatment schedules. In conclusion, this study demonstrates that increased Akt1/2/3 phosphorylation seems to be characteristic for acquired cetuximab resistance in HNSCC cell lines. Our results also show an additive to synergistic interaction between cetuximab and MK2206 in simultaneous treatment schedules. These data support the hypothesis that the combination of cetuximab with PI3K/Akt pathway inhibition might be a promising novel therapeutic strategy to overcome acquired cetuximab resistance in HNSCC patients.

The Right Partner in Crime: Unlocking the Potential of the Anti-EGFR Antibody Cetuximab via Combination With Natural Killer Cell Chartering Immunotherapeutic Strategies.

Cetuximab has an established role in the treatment of patients with recurrent/metastatic colorectal cancer and head and neck squamous cell cancer (HNSCC). However, the long-term effectiveness of cetuximab has been limited by the development of acquired resistance, leading to tumor relapse. By contrast, immunotherapies can elicit long-term tumor regression, but the overall response rates are much more limited. In addition to epidermal growth factor (EGFR) inhibition, cetuximab can activate natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC). In view of the above, there is an unmet need for the majority of patients that are treated with both monotherapy cetuximab and immunotherapy. Accumulated evidence from (pre-)clinical studies suggests that targeted therapies can have synergistic antitumor effects through combination with immunotherapy. However, further optimizations, aimed towards illuminating the multifaceted interplay, are required to avoid toxicity and to achieve better therapeutic effectiveness. The current review summarizes existing (pre-)clinical evidence to provide a rationale supporting the use of combined cetuximab and immunotherapy approaches in patients with different types of cancer.

A randomized phase II study comparing the efficacy and safety of the glyco-optimized anti-EGFR antibody tomuzotuximab against cetuximab in patients with recurrent and/or metastatic squamous cell cancer of the head and neck – the RESGEX study

BackgroundThe aim of the RESGEX study was to compare the efficacy and safety of the anti-epidermal growth factor receptor (anti-EGFR) antibody tomuzotuximab against cetuximab both in combination with chemotherapy in patients with recurrent and/or metastatic squamous cell cancer of the head and neck in the first-line treatment.Patients and methodsIn this phase II trial 240 patients were equally randomized for six cycles to receive either tomuzotuximab (initial dose 990 mg then 720 mg) weekly and cisplatin 100 mg/m2 and fluorouracil (5-FU; 1000 mg/m2/day, days 1-4) every 3 weeks or cetuximab (400 mg/m2 subsequent 250 mg/m2) weekly with the same chemotherapeutic backbone followed by antibody maintenance treatment. The primary endpoint was progression-free survival.ResultsMedian progression-free survival was 6.5 months [95% confidence interval (CI) 5.9-7.9 months] in the tomuzotuximab group and 6.2 months (95% CI 5.8-7.3 months) in the cetuximab group (P = 0.86). The median overall survival (OS) estimate was 11.6 months (95% CI 9.5-17.2 months) in the tomuzotuximab group and 13.8 months (95% CI 12.3-16.4 months) in the cetuximab group (P = 0.96). In an exploratory analysis a small subgroup of p16-positive patients had a significantly longer OS compared with p16-negative patients (hazard ratio 1.860, 95% CI 1.09-3.16, P = 0.02).ConclusionsThe glyco-engineered antibody tomuzotuximab failed to demonstrate improved efficacy with a chemotherapeutic backbone in the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. It remains a so far unanswered question whether such antibody would partner better with different drugs such as checkpoint inhibitors.

441P A study of vemurafenib and cetuximab in combination with FOLFIRI for patients with BRAF V600E-mutated advanced colorectal cancer (NCT03727763): Preliminary results

The prevalence of BRAF V600E in colorectal cancer （CRC） was about 10%. Despite recent therapeutic advances, BRAF V600E mutant CRC is still a challenge with a low response rate and suboptimal survival. Here we reported the safety and preliminary anti-tumor activity of vemurafenib and cetuximab in combination with FOLFIRI for BRAF V600E-mutated advanced CRC patients.

511TiP A phase III, multicenter, open-label, randomized study to assess the efficacy and safety of cetuximab plus capecitabine versus cetuximab as maintenance treatment following first-line induction treatment with FOLFOX and cetuximab in Chinese patients with RAS and BRAF WT mCRC

Considering the efficacy and safety of capecitabine and cetuximab as potent agent for maintenance therapy from previous studies, evaluation on the efficacy of cetuximab in combination with capecitabine as a potential maintenance regimen for RAS and BRAF wild-type mCRC patients is warranted. This abstract describes the design of this study.

906P Simlukafusp α and cetuximab combination in patients with recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck

Simlukafusp alfa (SIM; FAP-IL2v) is an interleukin-2 variant moiety fused to a human antibody against fibroblast activation protein-α (FAP). High affinity binding of SIM to FAP, expressed on cancer-associated fibroblasts, mediates its accumulation in malignant lesions. SIM retains binding affinity to IL-2 receptor βγ without binding to IL-2Rα resulting in activation of immune effector NK and CD8 T cells but not regulatory T cells. This phase I study evaluated potential enhancement of ADCC-competent antibody cetuximab (CET) by SIM in patients (pts) with head and neck squamous cell carcinoma (HNSCC) with prior ≥1 lines of treatment.

415P Comparison of cetuximab every 2 weeks versus standard once-weekly administration for the first-line treatment of RAS wild-type metastatic colorectal cancer among patients with left- and right-sided primary tumor location

In patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) receiving first-line treatment with cetuximab (CET) in combination with chemotherapy, the noninferiority of the off-label schedule of CET 500 mg/m2 every 2 weeks (q2w) compared with the approved schedule of CET at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2 (q1w) was shown in a pooled analysis of patient-level data from 2 noninterventional studies (EREBUS, ERBITAG) and 3 clinical trials (CEBIFOX, CECOG/CORE 1.2.002, APEC).

Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors.

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high mortality rate owing to very few available oncological treatments. For many years, a combination of platinum-based chemotherapy and anti-EGFR antibody cetuximab has represented the only available option for first-line therapy. Recently, immunotherapy has been presented an alternative for positive PD-L1 HNSCC. However, the oncologists’ community foresees that a new therapeutic era is approaching. In fact, no-chemo options and some molecular targets are on the horizon. This narrative review addresses past, present, and future therapeutic options for HNSCC from a translational point of view.

Modern strategy for treatment of metastatic colorectal cancer as key to increasing life expectancy of patients with metastatic colorectal cancer without mutations in RAS genes

The review is devoted to the place of cetuximab in the treatment of metastatic colorectal cancer (mCRC) without mutations in the RAS (RAS wt) and BRAF (BRAF wt) genes, depending on the goals of therapy, as well as to the analysis of the inflence of various factors, including the localization of the primary tumor, on the effectiveness of treatment. Randomized clinical trials and meta-analyses conducted on their basis allow us to conclude that cetuximab in combination with an infusion doublet or triplet provides the maximum frequency of deep and early objective responses, regardless of the location of the primary tumor. The drug is superior in this parameter to both a single chemotherapy (CT) and a combination of CT with bevacizumab which is important in terms of achieving resectability in patients with potentially resectable metastases. For patients with left-sided localization of the primary tumor and RAS wt, cetuximab, prescribed in the 1st line, provides a reliable and clinically signifiant increase in life expectancy. Postponing the start of its use until 2–4 cycles of CT (until the result of a molecular genetic study is obtained) does not negatively affect the effectiveness of the 1st line of therapy for mCRC RAS wt, and with left-sided localization of the primary tumor, CT with delayed cetuximab exceeds the usage of CT with bevacizumab from the fist cycle for ORR, OS and PFS. The optimal duration of induction chemo-targeted therapy is 3–4 months (6–8 courses), after which it is advisable to switch to maintenance treatment with one cetuximab. The new mode of administration of cetuximab once every 2 weeks at a dosage of 500 mg/m 2 IV provides maximum convenience of its use.