S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma

Abstract

Background:Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers.Methods:Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively.Results:Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1–20%), with a median progression-free survival of 2 months (95% CI: 2–3), and median overall survival of 6 months (95% CI: 3–8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash.Conclusions:Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…While early studies investigating novel agents targeting relevant signaling pathways demonstrated interesting antitumor activity in a small proportion of patients, the overall results have been disappointing, with outcomes largely similar to chemotherapy agents in the refractory setting ( Table 2) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). This may be in part due to the utilization of non-selected trials, where patients are eligible for enrollment regardless of their tumor genomic alterations.…”

Nab-paclitaxel as alternative treatment regimen in advanced cholangiocellular carcinoma

“…In adenocarcinoma of the biliary tract, overexpression of the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor receptor (VEGFR) have been found in approximately 27% and 59%, respectively (16). Clinical phase II trials of sorafenib (400 mg BID) or erlotinib (100 mg daily) in patients with advanced biliary cancer, however, failed to show a meaningful benefit (18). The addition of cetuximab to standard chemotherapy in the BINGO trial also failed to reveal benefit when compared to chemotherapy only (19).…”

FBXW7 Pathway Functions as a Promising Therapeutic Target of Cholangiocarcinoma

“…Breakthroughs of immunologic therapies with antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have been made in a variety of malignancies [16][17][18][19][20][21]. Recent clinical trials of CCAs have focused on the agents targeted to specific genes such as EGFR and VEGFR, but promising clinical activity was not observed to date [22][23][24]. Further elucidation on tumor biology and molecular markers of CCAs is essential for future evaluation of targeted therapies.…”