Exceptional responses in patients with upper gastrointestinal malignancies enrolled in first-in-man studies: 2002-2012.

Abstract

311 Background: First-in-man (FIM) studies test the efficacy and safety of novel therapeutic agents with proven in vitro activity when used for the first time in humans. Patients with advanced upper gastrointestinal malignancies (UGIM) have limited systemic treatment options. We established a database of FIM studies published from 2002-2012 to identify exceptional responders in patients with UGIM. Methods: Using a Scopus search, we compiled a database of published FIM studies enrolling patients with UGIM between 2002 and 2012. We identified exceptional responders to therapy among these patients as a complete response or a partial response lasting at least 6 months. Results: We identified 84 FIM studies enrolling at least one patient with UGIM. In total 554 patients with UGIM were enrolled including 290 pancreatic adenocarcinomas (52.3%), 110 gastric adenocarcinomas (19.9%), 83 esophageal carcinomas (15.0%), 41 hepatocellular carcinomas (7.4%), and 30 cholangiocarcinomas/gallbladder carcinomas (5.4%). One patient with pancreatic cancer treated with bosutinib, a src kinase inhibitor, had a complete response with a progression-free survival (PFS) of 42 months. Four partial responses were reported including one pancreatic cancer patient treated with CHR-3996, a histone deacetylase inhibitor (PFS 12 mo); two pancreatic cancer patients treated with trametinib, a MEK inhibitor (10 and 11.75 mo); and one cholangiocarcinoma patient treated with SB-743921, a kinesin inhibitor (11 mo). Two additional partial responses were noted without available PFS data including one pancreatic cancer patient treated with KOS-1584, a second generation epothilone, and one gastric cancer patient treated with apatinib, a VEGFR-2 inhibitor. Conclusions: Exceptional responses are seen in patients with UGIM enrolled in FIM studies. Actionable genetic aberrations may be driving disease in these patients. Further studies are needed to understand these responses at the molecular level. These molecular studies could open new treatment opportunities for patients with advanced UGIM.