A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck

Seiwert, Tanguy Y.; Fayette, Jérôme; Cupissol, Didier; Campo, J. M. Del; Clément, Paul M.; Hitt, Ricardo; Degardin, M.; Zhang, W.; Blackman, Alice; Ehrnrooth, Eva; Cohen, Ezra E.W.

doi:10.1093/annonc/mdu216

Cited by 168 publications

(127 citation statements)

References 23 publications

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“…Afatinib activity has been seen in cetuximab refractory patients in clinical trials, suggesting a lack of cross-resistance in some instances (21,41). Similarly, our present study has shown that afatinib is effective for cetuximabresistant cell lines.…”

Section: Discussionsupporting

confidence: 81%

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Nakamura

Togashi

Nakahara

et al. 2016

Molecular Cancer Therapeutics

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The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib.

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Section: Discussionsupporting

confidence: 81%

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Nakamura

Togashi

Nakahara

et al. 2016

Molecular Cancer Therapeutics

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“…Other trials can also be interrogated with regard to EGFR inhibitor response and HPV status, even though these results have to be viewed with caution because of the small sample size. In a small cohort of patients treated with afatinib or cetuximab, similar response rates were found [18]. Preliminary results from the PARTNER study also showed responses to panitumumab treatment in p16-positive and -negative tumors [51].…”

Section: Predictive Biomarkersmentioning

confidence: 54%

“…Afatinib also did not improve OS in comparison with methotrexate but conferred a small benefit in terms of progression-free survival (PFS) [17]. In a phase II trial, afatinib showed antitumor activity comparable to cetuximab [18]. …”

Section: Targeted Therapies In Head and Neck Cancermentioning

confidence: 99%

Targeted Therapy of Head and Neck Cancer

2016

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Head and neck squamous cell carcinoma (HNSCC) is one of the most common solid cancers worldwide. It is mainly caused by exposure to tobacco smoke and alcohol as well as infection with the human papilloma virus (HPV). The prognosis is poor, especially once it recurs or metastasizes. Current therapeutic options include surgery, radio- and chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors are so far the only targeted agents that have been approved in head and neck cancer. Primary or secondary resistance is frequent or will eventually develop. Several driver mutations and other genomic aberrations have been described in HNSCC including EGFR overexpression and amplification. Yet, no predictive biomarkers for the application of EGFR inhibitors have been identified. Further targeted agents are in development for HNSCC, of which inhibitors of the PI3K pathway are the closest to clinical application. In recent years, the incidence of HPV-driven HNSCC has risen in Western countries. HPV-positive and -negative HNSCC are distinct molecular tumor entities, and consequences for targeted therapies have been discussed. This review looks at approved and investigational targeted treatment strategies as well as potential predictive biomarkers such as the HPV status to guide treatment.

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“…There was no statistically significant difference in ORR (2.7%, 7.6%, and 3.9%, respectively) or median OS (5.6, 6.0, and 6.7 months, respectively). A randomized phase II comparison of afatinib 50 mg/day versus standard-dose cetuximab demonstrated a similar DCR (50% vs. 57%), with an increase in grade $3 AEs with afatinib, including diarrhea (15% vs. 0%), rash (18% vs. 8%), and mucositis (12% vs. 0%) [55]. This study's design allowed crossover, and tumor shrinkage was observed in 40% and 31% of patients who crossed over to afatinib or cetuximab, respectively.…”

Section: Chemotherapy In Recurrent or Metastatic Diseasementioning

confidence: 91%

Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck

Iberri

Colevas

2015

The Oncologist

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The epidermal growth factor receptor (EGFR) is overexpressed in more than 80% of squamous cell cancers of the head and neck (SCCHN). An evolving understanding of the role of EGFR in tumorigenesis has made the receptor an important therapeutic target in SCCHN. Several EGFR inhibitors (EGFRIs) are active in SCCHN, and their use is associated with improvement in progression-free survival and overall survival in various treatment settings. Nevertheless, EGFR inhibition is associated with significant mucocutaneous toxicity that must be balanced against its anticipated efficacy. This review summarizes the relevant clinical trial experience with EGFRIs, with attention to efficacy, toxicity, and methods of selecting patients most likely to benefit from therapy.

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A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck

Cited by 168 publications

References 23 publications

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Targeted Therapy of Head and Neck Cancer

Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck

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