Phase II Trial of Erlotinib and Docetaxel in Advanced and Refractory Hepatocellular and Biliary Cancers: Hoosier Oncology Group GI06‐101

Background. Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti‐EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti‐EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers. Methods. Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2–7, 9–14, 16–28 of each 28‐day cycle. The primary endpoint was 16 weeks progression‐free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E‐cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two‐stage initial design of the study, combined PFS was considered. A Simon optimal two‐stage design tested the hypothesis that the 16‐week PFS is ≤ 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study). Results. Twenty‐five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7–56.3) for BTC, and 17.6 weeks (95% CI 8.1–49.8) for HCC. The 16‐week PFS was 64% for BTC (95% CI 29.7–84.5), and 38% for HCC (95% CI 14.1–62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs 4.2 months). HCC patients with negative/low E‐cadherin expression had higher median PFS (6.7 vs 2.1 months) and OS (14.5 vs 4 months). Conclusion. Erlotinib with docetaxel met the 16‐week PFS ≥ 30% endpoint,but overall survival was comparable to that seen with single‐agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E‐cadherin expressi