Approval Summary: Cetuximab in Combination With Cisplatin or Carboplatin and 5-Fluorouracil for the First-Line Treatment of Patients With Recurrent Locoregional or Metastatic Squamous Cell Head and Neck Cancer

Cohen, Martin H.; Chen, Huanyu; Shord, Stacy S.; Fuchs, Chana; He, Kun; Zhao, Hong; Sickafuse, Sharon; Keegan, Patricia; Pazdur, Richard

doi:10.1634/theoncologist.2012-0458

Cited by 47 publications

(40 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To test this premise, ABT-806 in combination with different chemotherapy agents was assessed in both wild-type EGFR and EGFRvIII-expressing tumor models. Cetuximab is FDA-approved for use in combination with cisplatin and 5-FU in recurrent or metastatic HNSCC, so these combinations with ABT-806 were evaluated in the wild-type EGFR-expressing HNSCC tumor model SCC15 (23). Because ABT-806 was highly potent as monotherapy in this model (Fig.…”

Section: Abt-806 Combinations With Chemotherapymentioning

confidence: 99%

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Reilly

Phillips

Buchanan

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indiumlabeled version of ABT-806, [ 111 In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIIIexpressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity.

show abstract

Section: Abt-806 Combinations With Chemotherapymentioning

confidence: 99%

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Reilly

Phillips

Buchanan

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Early stage cSCC can be effectively treated with surgical removal, whereas early stage HNSCC may require radiation due to anatomical reasons, making HNSCC one of the most difficult to treat cancers [1]. Advanced stage cancers require combination therapies involving surgery, radiation and chemotherapies such as cisplatin, a DNA alkylating agent, as well cetuximab, a monoclonal antibody against EGFR [2, 3]. These combination treatments have yielded over 50% 5-year relative survival for HNSCC [4, 5].…”

Section: Introductionmentioning

confidence: 99%

FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms

Luo

Lechler

et al. 2016

Oncotarget

View full text Add to dashboard Cite

FRA1 (Fos-like antigen 1) is highly expressed in many epithelial cancers including squamous cell carcinoma of the skin (cSCC) and head and neck (HNSCC). However, the functional importance and the mechanisms mediating FRA1 function in these cancers are not fully understood. Here, we demonstrate that FRA1 gene silencing in HNSCC and cSCC cells resulted in two consequences – impaired cell proliferation and migration. FRA1 regulation of cell growth was distinct from that of c-Jun, a prominent Jun group AP-1 factor. While c-Jun was required for the expression of the G1/S phase cell cycle promoter CDK4, FRA1 was essential for AKT activation and AKT-dependent expression of CyclinB1, a molecule required for G2-M progression. Exogenous expression of a constitutively active form of AKT rescued cancer cell growth defect caused by FRA1-loss. Additionally, FRA1 knockdown markedly slowed cell adhesion and migration, and conversely expression of an active FRA1 mutant (FRA1DD) expedited these processes in a JNK/c-Jun-dependent manner. Through protein and ChIP-PCR analyses, we identified KIND1, a cytoskeletal regulator of the cell adhesion molecule β1-integrin, as a novel FRA1 transcriptional target. Restoring KIND1 expression rescued migratory defects induced by FRA1 loss. In agreement with these in vitro data, HNSCC cells with FRA1 loss displayed markedly reduced rates of subcutaneous tumor growth and pulmonary metastasis. Together, these results indicate that FRA1 promotes cancer growth through AKT, and enhances cancer cell migration through JNK/c-Jun, pinpointing FRA1 as a key integrator of JNK and AKT signaling pathways and a potential therapeutic target for cSCC and HNSCC.

show abstract

“…We therefore evaluated the prevalence of the EGFR ligands across four cancer indications in which EGFR-targeting agents have shown clinical benefitcolorectal cancer, HNSCC, lung adenocarcinoma, and lung squamous cell carcinoma (LUSC; refs. [45][46][47]. To this end, mRNA expression data for the seven EGFR ligands were obtained from TCGA for 1,792 treatment-na€ ve primary tumors and 178 matched normal tissue samples (Supplementary Tables S5 and S6).…”

Section: Primary Tumors Express Mixtures Of Low-and High-affinity Egfmentioning

confidence: 99%

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Kearns

Bukhalid

Sevecka

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest the need for improved therapeutics. Here, we demonstrate that signal amplification driven by highaffinity EGFR ligands limits the capacity of monoclonal anti-EGFR antibodies to block pathway signaling and cell proliferation and that these ligands are commonly coexpressed with low-affinity EGFR ligands in epithelial tumors. To develop an improved antibody therapeutic capable of overcoming high-affinity ligand-mediated signal amplification, we used a network biology approach comprised of signaling studies and computational modeling of receptor-antagonist interactions. Model simulations suggested that an oligoclonal antibody combination may overcome signal amplification within the EGFR:ERK pathway driven by all EGFR ligands. Based on this, we designed MM-151, a combination of three fully human IgG1 monoclonal antibodies that can simultaneously engage distinct, nonoverlapping epitopes on EGFR with subnanomolar affinities. In signaling studies, MM-151 antagonized high-affinity EGFR ligands more effectively than cetuximab, leading to an approximately 65-fold greater decrease in signal amplification to ERK. In cell viability studies, MM-151 demonstrated antiproliferative activity against high-affinity EGFR ligands, either singly or in combination, while cetuximab activity was largely abrogated under these conditions. We confirmed this finding both in vitro and in vivo in a cell line model of autocrine high-affinity ligand expression. Together, these preclinical studies provide rationale for the clinical study of MM-151 and suggest that high-affinity EGFR ligand expression may be a predictive response marker that distinguishes MM-151 from other anti-EGFR therapeutics.

show abstract

Approval Summary: Cetuximab in Combination With Cisplatin or Carboplatin and 5-Fluorouracil for the First-Line Treatment of Patients With Recurrent Locoregional or Metastatic Squamous Cell Head and Neck Cancer

Cited by 47 publications

References 14 publications

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms

Enhanced Targeting of the EGFR Network with MM-151, an Oligoclonal Anti-EGFR Antibody Therapeutic

Contact Info

Product

Resources

About