Targeted therapy of advanced gallbladder cancer and cholangiocarcinoma with aggressive biology: eliciting early response signals from phase 1 trials

Abstract

Purpose: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease. methods: Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies.

Results: Of 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) > 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0), 3.0 months (95% CI 2.3, 4.6), and 3.0 months (95% CI 2.4, 3.9) for their first-, second-, and last-line FDA-approved therapy. In univariate analysis, >3 metastatic sites, elevated alanine aminotransferase (ALT) (>56IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL) were associated with a shorter PFS. Mutational analysis revealed mutation in the KRAS oncogene in 2 of 11 patients (18%). The SD >6 months/PR rate of 28% was seen with hepatic arterial infusion of oxaliplatin, and inhibitors of angiogenesis, HER-2/neu or MEK.

Conclusions: The PFS in phase I trials was similar to that of the first, second, and last-line therapy (P=0.95, 0.98, 0.76, respectively) with FDA-approved agents given in the advanced setting, emphasizing a role for targeted agents in a clinical trials setting as potentially valuable therapeutic options for these patients.

Figure 1. Waterfall plot of the best RECIST response to the best phase I trial of all 40 treated patients

Six patients who did not undergo restaging due to early disease progression are reflected as a 20% increase. Time (in months) reflects the duration of response.

Figure 2. Prolonged partial response for 12.1 months noted in the primary hepatic lesion of a patient with advanced cholangiocarcinoma treated with hepatic arterial infusion of a cytotoxic agent along with intravenous anti-angiogenic agent

CT scan of the abdomen showed liver metastases at baseline and after 12 months of treatment. White arrows show multiple areas of hypoattenuation secondary to splenic embolization.

Figure 3

(A) PFS of patients treated on phase I trials compared to their first-line, second-line and last systemic antitumor therapy given in the advanced setting prior to phase I referral. (B) Median overall survival after starting a phase I trial. Dotted lines represent 95% confidence intervals for the estimated survival probabilities.