Panitumumab in Combination With Cisplatin/Gemcitabine Chemotherapy in Patients With Cholangiocarcinomas - a Randomized Clinical Phase II Study
The rationale of the study is the assessment of the clinical activity of Panitumumab in
conjunction with standard Cisplatin/Gemcitabine chemotherapy in patients with
cholangiocarcinomas and gall bladder carcinomas in 1st-line therapy.
Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with
features of cholangiocyte differentiation. CCA is the second most common primary hepatic
malignancy, and epidemiologic studies suggest its incidence is increasing in Western
countries. Hepatobiliary malignancies account for 13% of the 7.6 million annual
cancer-related deaths worldwide and CCA accounts for approximately 20% of the deaths from
hepatobiliary malignancies (Kubicka and Manns 2000; Kubicka 2004; Blechacz and Gores 2008;
Malek et al. 2007).
The only curative option for patients with gallbladder- or bile duct cancer is surgical
resection. Advanced CCA has a devastating prognosis. There are only limited numbers of
studies about the systemic treatment options for biliary cancers. Gallbladder and bile duct
carcinomas are moderately chemotherapy-sensitive tumors. The objective response rates in
phase II studies with 5-FU or gemcitabine monochemotherapy are between 10 - 30 % (Kubicka et
al. 2001b). Higher response rates between 20 - 50 % have been observed in phase II studies
with combination chemotherapy, in particular with the combination of gemcitabine/cisplatin
(Kubicka 2004; Malek et al. 2007).
Recently for the first time an improvement of overall survival has been demonstrated in a
large randomized phase III trial with chemotherapy combination of cisplatin and gemcitabine
(n=206) compared to gemcitabine mono-chemotherapy (n=204) (Valle et al. 2009). Median
overall survival was 8,2 month in the monotherapy arm versus 11,7 month in the combination
arm (p=0.002). As a consequence of this study the combination of Cisplatin (25mg/m² d1,8)
and Gemcitabine (1000mg/m² d1,8) should be considered as the standard first line
chemotherapy for patients with irresectable cholangio- or gallbladder carcinomas.
The growing understanding of the molecular pathogenesis of CCA opens new therapeutic options
for molecular targeting (Blechacz and Gores 2008). In particular EGFR signaling appears to
be important for tumor growth of CCA. Inhibition of EGFR signaling has been shown to
significantly suppress CCA cell growth (Blechacz and Gores 2008). In addition EGFR can
directly be activated by bile acids and promote CCA cell proliferation, a potential
explanation for the tropism exerted by CCA for the biliary tree. It has been shown that EGFR
activation is sustained in CCA by failure to internalize the ligand-receptor complex, a
homeostatic mechanism essential for receptor inactivation. EGFR phosphorylation results in
activation of the downstream kinases p42/44 MAPK and p38 MAPK, which in turn increase
cyclooxygenase 2 expression in CCA cells.
Further evidence for the essential contribution of EGFR-signalling comes from studies with
IL-6 (Blechacz and Gores 2008). IL-6 is a key cytokine in the pathogenesis of CCA. IL-6 is
produced at high levels by CCA cells, and elevated IL-6 serum concentrations have been
reported in CCA patients. It has been shown that there is a cross-communication between IL-6
and EGFR resulting in IL-6 mediated overexpression of EGFR.
Recently the first results of a randomized phase II study of gemcitabine and oxaliplatin
(GEMOX) alone or in combination with cetuximab in patients with advanced biliary cancer have
been reported (Malka et al. 2009). The primary objective of the study was a 4-month PFS rate
of more than 60% in the experimental arm with cetuximab. The included patients were not
monitored for RAS or B-RAF mutations. However compared to GEMOX chemotherapy (n=51),
GEMOX+cetuximab (n=50) showed an increased 4-month PFS-rate (50% versus 61%) and an improved
median PFS (5 versus 7 months). This is the first evidence from a randomized trial that
anti-EGFR therapy may be effective for patients with cholangiocarcinomas and gallbladder
KRAS is a downstream molecule in the EGFR-pathway. Recently it has been shown that oncogenic
RAS mutations are predictive for poor efficacy of an anti-EGFR-therapy in colorectal cancer.
Conversely patients with colorectal cancers harbouring KRAS wild-type showed frequently
dramatic tumor responses upon anti-EGFR-treatment, indicating that colorectal cancers with
KRAS wild type are highly susceptible for an anti-EGFR-therapy. Although dysregulation of
KRAS is commonly observed in malignancies, mutations of KRAS have only been described in 12%
to 54% of intrahepatic CCA (Kubicka et al. 2001a; Blechacz and Gores 2008, Gruenberger et al
2009). This is in sharp contrast to pancreatic ductal carcinoma where KRAS mutations are
present in approximately 90% of cancers. Thus, despite shared developmental ontology between
the pancreatic ducts and the biliary tree, their adult cancers are different and may explain
the negative result of a phase III studies in pancreatic cancer with Cetuximab
Very preliminary and sparse data from a recent small phase II study with cetuximab do not
allow to speculate whether the RAS status does predict the response in cholangiocarcinomas
similarly to colorectal cancers (Gruenberger et al. 2009). However, due to the clear
evidence of absence of efficacy in mutant KRAS colorectal cancer, the presumptive population
"enrichment" should be applied in this first trial on biliary duct cancer, which is to focus
on KRAS wild type patients.
Since most of the patients with CCA are treated in large centers a chemotherapy protocol
with limited numbers of intravenous infusions appears to be very comfortable for patients
with CCA. A further argument for the investigation of Cisplatin/Gemcitabine/Panitumumab in a
randomized phase II study is the fact that the 3-week interval of the Cis/Gem protocol fits
very well into the 3-week interval of the Panitumumab schedule.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
progression-free survival rate
The progression-free survival rate at six months (primary endpoint) is defined as the number of patients recorded to be free of progression (according to RECIST) at this time point, divided by the number of patients randomized to the respective arm.
Arndt Vogel, PD Dr. MD
Hannover Medical School