Neoplasms

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Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

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Neoplasms, Squamous Cell

Head and Neck Neoplasms

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Afatinib

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Patients randomized to the arm A will take a single oral dose of Afatinib from Day 1, for 14 to 28 days, depending on the date of surgery. The number of dosing days will be chosen so that patients are off treatment for a maximum of 7 days before surgery.

Afatinib 40mg per os daily for 14 to 28 days, depending on the date of the surgery

Christophe Le Tourneau

The purpose of this study is to identify predictive and pharmacodynamic biomarkers of activity and efficacy of pre-operative Afatinib (BIBW2992) in untreated non-metastatic head and neck squamous cell carcinoma patients

More than 500,000 new patients with squamous cell carcinomas of the head and neck (SCCHN) are diagnosed each year around the world. Patients who relapse after primary therapy for locoregional disease and those who present with distant metastases have limited prognosis.

Drug therapy for cancer control and the palliation of patients with recurrent or metastatic SCCHN is currently suboptimal. In contemporary trials the most active cytotoxic drug combinations have response rates in the range of 30%, and are associated with frequent and severe toxicities and treatment-related mortality.

Molecular targeting has been demonstrated in oncology as a relevant strategy in cancer therapeutics. In March 2006, the FDA announced the approval of a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR), cetuximab, for use in combination with radiation therapy in patients with locally advanced SCCHN. Furthermore, the addition of cetuximab to cisplatin and 5FU as first-line therapy in patients with recurrent or metastatic SCCHN has significantly improved overall survival when compared to cisplatin and 5FU alone. Phase II data of cetuximab given as monotherapy in recurrent or metastatic SCCHN patients who have progressed on platinum-based therapy have demonstrated an overall response rate of 13% and a median survival of about 6 months. Small molecules tyrosine kinase inhibitors of EGFR, such as gefitinib and erlotinib, seem to be slightly less effective than cetuximab. Based on these results, FDA has also approved cetuximab monotherapy use for this indication in recurrent or metastatic SCCHN.

However, despite high expression of EGFR in SCCHN, EGFR inhibitor monotherapy has only had modest activity. Potential mechanisms of resistance to EGFR-targeted therapies involve EGFR and K-Ras mutations, epithelial-mesenchymal transition, and activation of alternative and downstream pathways. Strategies to optimize EGFR-targeted therapy in head and neck cancer involve the selection for patients most likely to benefit and the use of therapies to target the network of pathways involved in tumor growth, invasion, angiogenesis, and metastasis.

Afatinib is an irreversible dual inhibitor of EGFR and HER2 tyrosine kinase. Preclinical data suggest that Afatinib might have a larger spectrum antitumor activity than EGFR tyrosine kinase inhibitors. In vivo and in vitro studies indeed showed that Afatinib displays antitumor activity in erlotinib/gefitinib-resistant lung models. Afatinib compared favourably to cetuximab in platinum-resistant metastatic SCCHN. In addition, Afatinib has shown promising antitumor activity in HER2-overexpressing metastatic breast cancer after trastuzumab failure and in metastatic adenocarcinomas of the lung harbouring EGFR activating mutations.

To date, predictive and pharmacodynamic biomarkers studies have mostly been performed in pre-treated metastatic patients. Erlotinib has been the most studied EGFR-targeted agent in terms of biomarkers identification in SCCHN. In the metastatic setting, sequential biopsies allowed correlating potential predictive and pharmacodynamic biomarkers with the outcome of patients treated with erlotinib. The decrease of p-EGFR in tumor tissue was associated with increased time-to-progression (TTP) and overall survival (OS) in one study. In another study, elevated pre-treatment levels of p27 and p-STAT3 in tumor tissue predicted for prolonged TTP and OS, while a decrease in p-EGFR, p-NFkB and p27 correlated with increased TTP, OS or both. However, the lack of control arm precluded to draw any definitive conclusion. One study evaluated erlotinib in the neoadjuvant setting in untreated patients with operable SCCHN. Baseline p21 expression in tumor tissue correlated with clinical response to treatment. But again, the absence of control arm in this later study precluded drawing definitive conclusions regarding the potential predictive and pharmacodynamic value of the biomarkers under evaluation.

The main characteristics of our study are:

1. the pre-operative setting in untreated patients with the advantage of having untreated patients for whom it is easy to get pre- and post-treatment tumor specimen, during initial panendoscopy and surgery, respectively
2. the randomization versus no treatment which is the only way to be able to draw robust conclusions regarding the potential predictive and pharmacodynamic value of the biomarkers under evaluation. Single-arm phase II trials can only identify prognostic markers of activity, but not predictive biomarkers of activity.

Importantly, surgery will not be delayed in any case by the study. However, it is required that planning of surgery will enable patients to receive between 21 and 28 days of treatment to participate into the study given the planned date of surgery.

Research of Biomarkers of Activity and Efficacy of BIBW2992 in Untreated Non-metastatic HNSCC Patients

Multi-centric Randomized Phase II Study of Pre-operative Afatinib (BIBW2992) Aiming at Identifying Predictive and Pharmacodynamic Biomarkers of Biological Activity and Efficacy in Untreated Non-metastatic Head and Neck Squamous Cell Carcinoma Patients

Correlation between baseline potential biomarkers and

1. radiological response to Afatinib
2. FDG-PET response to Afatinib

To identify the predictive biomarkers, the following translational researches will be carried out on initial tumor biopsy

* IHC tumour characterization
* High throughput protein analysis
* Molecular analyses : FISH , Mutations by PCR , Quantitative RT-PCR

Correlation between down- or up-regulation of potential biomarkers (in pre-treatment biopsy and surgical specimen) and

1. radiological response to Afatinib
2. FDG-PET response to Afatinib

To identify the pharmacodynamic biomarkers, the following translational researches will be carried out on initial tumor biopsy and surgical specimen

* IHC tumour characterization
* High throughput protein analysis
* Molecular analyses : FISH , Mutations by PCR , Quantitative RT-PCR

- Efficacy will be defined as the tumour reduction between the baseline and the surgery (end of treatment). The radiological response will be assessed on CT/MRI of the head and neck. Tumour size will be the sum of 2 target lesions following the measurement rules from the RECIST 1.1. Noteworthy, a lymph node can be considered a target lesion only if its smallest diameter is ≥15 mm (according to RECIST 1.1). Measurement of a lymph node consists in measuring its smallest diameter (according to RECIST 1.1).

Toxicity will be assessed according to NCI CTC-AE v4.0 criteria

Complete pathological response is defined as the absence of invasive cancer cells on the surgical specimen in the primary tumor and in lymph nodes.

Spots Global Cancer Trial Database for pre operative treatment