Single-agent gemcitabine is currently still regarded as one international standard of care
for patients with advanced pancreatic cancer (Burris 1997 ). The oral EGFR tyrosine kinase
inhibitor erlotinib received EMEA-approval for the treatment of patients with metastatic
pancreatic cancer in January 2007.
In the pivotal phase III trial, the combination of gemcitabine plus erlotinib was associated
with a statistically significant prolongation of OS (compared to single-agent gemcitabine),
however, the absolute survival benefit was - for the overall study population - clinically
moderate (median OS: 6.24 vs 5.91 months, 1-year OS rate: 23% vs 17%; HR = 0.82, p=0.038)
(Moore 2007 ).
The recently presented FOLFIRINOX regimen shows enhanced activity in metastatic pancreatic
cancer patients. This regimen is, however, limited to patients with good performance status
(ECOG 0-1), no major comorbidity, age <75 years, and bilirubin <1.5 ULN (Conroy 2011 ).
The majority of pancreatic cancer patients will therefore not be treated with this regimen.
Accordingly, novel treatment concepts are urgently needed in pancreatic cancer and
pre-clinical data indicate an important role of the EGFR1/erbB2 receptor signalling in the
pathogenesis of pancreatic adenocarcinoma (Yeh 2007 ). A recent publication (Larbouret
2010 ) indicates that the combination of cetuximab and trastuzumab induced superior
antitumour activity in human pancreatic carcinoma xenografts compared to gemcitabine alone
(see also Larbouret 2007 ). Furthermore, synergistic antitumour activity was observed
when monoclonal antibodies directed against the EGFR1 and erbB2 were combined (Ben-Kasus 2009
). Based on these data, there is a good rationale to further investigate the combined
inhibition of the erbB family in pancreatic cancer patients.
Afatinib (BIBW 2992) is a novel irreversible EGFR1- and HER2 and HER4 inhibitor that is
applied orally. The purpose of the present trial is to investigate the erbB family inhibition
by afatinib in patients with metastatic pancreatic cancer.
In the planned trial, afatinib will be applied at the dose (40 mg/day) that was chosen for
the randomised phase III trial (LUX 5 study) that investigates afatinib plus weekly
Presently there is also a phase I study ongoing that investigates the combination of afatinib
with gemcitabine (ClinicalTrials.gov Identifier: NCT01251653 U10-2249-02 ). Possibly the data
will be available once the study is ready to start. Otherwise a modification of the regimen
will be planned once the respective data will be available.
In this trial, we integrate a translational project which may allow the identification of
patients that primarily benefit from this novel treatment approach. The availability of
tumour tissue- and blood samples from each patient is therefore an important inclusion
A 2:1 randomisation is chosen favouring the experimental arm since a large body of data is
available on gemcitabine alone and since sufficient efficacy and toxicity data shall be
gained in the experimental arm. In addition, the patients' motivation to take part in the
trial will be greatly enhanced by a greater chance to receive the experimental agent.