Abstract
SummaryAdvanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study that enrolled adult patients with unresectable or metastatic biliary tract, pancreas, duodenal, or ampullary carcinomas that have not received any prior treatment for their disease. Dose escalation followed a standard 3 + 3 design, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity, except nausea/vomiting, or grade 4 hematologic toxicity. A dose expansion cohort in ABTC was treated at the MTD. Twenty-eight patients were enrolled and 4 dose levels were explored. The MTD was erlotinib 150 mg + GEM 800 mg/m2 + OX 85 mg/m2. DLTs were diarrhea and anemia. Most frequent toxicities were nausea (78 %), fatigue (71 %), neuropathy (68 %), and diarrhea (61 %), predominantly grade 1–2. In the ABTC patients, the objective response and disease control rates were 29 % and 94 %, respectively, and median overall survival was 18 months. Erlotinib plus GEMOX was well tolerated. Encouraging anti-tumor activity was seen as evidenced by a high disease control rate and longer median OS than standard chemotherapy in the patients with ABTC.
Highlights
7500 new cases of advanced biliary tract cancer (ABTC) will be diagnosed each year in the United States [1]
Several chemotherapy agents have been evaluated in biliary tract cancer patients, with a gemcitabine backbone emerging as a standard [2]
Given the evidence that patients with KRAS mutations have a poorer response to epidermal growth factor receptor (EGFR)-directed therapies [17, 18] and that biliary tract cancers have a spectrum of mutations in EGFR and its downstream signaling pathways, including KRAS and PIK3CA [19,20,21,22,23], we evaluated the potential relationship between mutational status and clinical outcome
Summary
7500 new cases of advanced biliary tract cancer (ABTC) will be diagnosed each year in the United States [1]. These are generally divided into intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and cancer of the gallbladder. Ampulla of Vater cancer is variably included with biliary cancers. These cancers frequently present in a stage too advanced for surgical resection, and a majority of the patients with operable disease will have recurrence after complete resection. Several chemotherapy agents have been evaluated in biliary tract cancer patients, with a gemcitabine backbone emerging as a standard [2].
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