Trial Information

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

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.