Pancreatic Cancer (2014)

Dasatinib. DasatinibBARCELONA, Spain—In the first clinical trial of a targeted agent against locally advanced pancreatic cancer (as opposed to metastatic pancreatic cancer), dasatinib did not increase survival when combined with gemcitabine compared with gemcitabine alone. Jeff Evans, MD, Professor of Translational Research and Director of the Institute of Cancer Sciences at the University of Glasgow, reported the results of the Phase II double-blind placebo-controlled trial here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (Abstract 0-0001), noting that patients in sites in Europe, North America, and Australia with inoperable, untreated locally advanced pancreatic cancer were randomly selected to receive gemcitabine-dasatinib (100 patients) or dasatinib-placebo (102 patients). The primary endpoint was overall survival. “There was no difference in overall or progression-free survival between the groups,” Evans reported. Median progression-free survival was 166 days for gemcitabine-dasatinib and 167 days for gemcitabine-placebo; overall survival times were 375 and 393 days, respectively. Response rates were also similar. The gemcitabine-dasatinib combination was more toxic, he said, with more Grade 3/4 cytopenias, pain, fatigue, liver abnormalities, infections, and pleural effusion. The rationale for combining dasatinib with gemcitabine was dasatinib's inhibition of the tyrosine-kinase proton-oncogene c-Src in preclinical studies, as well as tumor cell invasion and metastasis. Gemcitabine nonresistance is known to be associated with elevated c-Src activity, Evans noted. Preclinical models also demonstrated synergy of gemcitabine and c-Src inhibition, and two Phase II studies showed that the gemcitabine-dasatinib combination was safe. But it was not effective, Evans said of this clinical study, and “further development of this combination in locally advanced pancreatic cancer is not being pursued.” However, he added that secondary and exploratory endpoints are being analyzed for objective response rates, freedom from distant metastases, pain and fatigue, and CA-19-9 levels when those data are mature. Inflammatory Status of Patients May Point to Subgroup BenefitFigureThe Discussant for the study asked a provocative question: “Using simple tools, could we turn this into a positive trial?” Stefano Cascinu, MD, Professor of Medicine at Clinica di Oncologia Medica at Universita Politecnica delle Marche in Italy, assessing the strengths and weaknesses of the dasatinib-gemcitabine study, said there was a strong preclinical rationale to conduct it, given that c-Src is linked to aggressive tumor biology and metastasis and that c-Src inhibition exhibits pre-clinical synergy with gemcitabine. But patients in the trial were unselected with respect to c-Src, he said. “We don't know anything about their c-Src levels,” and while Src may be the link between inflammation and cancer, there was no attempt in this trial to determine inflammation.JEFF EVANS, MD. JEFF EVANS, MDInflammation may be important factor to consider here, he said, pointing to the positive Phase II RECAP study of ruxolitinib plus capecitabine in the treatment of metastatic pancreatic cancer. Overall survival favored ruxolitinib-capecitabine versus capecitabine alone in a pre-specified subgroup of patients with elevated C-reactive protein (CRP), a marker of systemic inflammation. Ruxolitinib is a JAK-1/2 inhibitor, and JAKs mediate cytokine signaling by activating STAT transcription factors. STATs in turn can be tyrosine-phosphorylated directly by tyrosine kinases such as c-Src. “An assessment of STAT3 levels in patients in the dasatinib-gemcitabine trial and a re-analysis of their inflammatory status using simple tools such as CRP may help us to understand if there is a possibility to have positive results,” Cascinu said. Furthermore, he said the dasatinib-gemcitabine combination may ultimately prove beneficial if freedom from distant metastases is analyzed as an endpoint.