(ChemotherapyAdvisor) – Sequential delivery of the new targeted therapy vismodegib (GDC-0449; Erivedge) as monotherapy followed by combination treatment with gemcitabine provides clinical benefit to a subset of patients with metastatic pancreatic cancer, according to results presented June 19 at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges conference, Lake Tahoe, NV.
“We believe that GDC-0449 has the potential to change the approach to treating pancreatic cancer,” said Edward J. Kim, MD, PhD, of the University of Michigan Comprehensive Cancer Center in Ann Arbor, MI. CD44+/CD24+/ESA+ pancreatic cancer stem cells express significantly elevated levels of sonic hedgehog and this study found the best biologic correlate predictor of benefit with this regimen to be pretreatment sonic hedgehog expression level.
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Vismodegib (Genentech, South San Francisco, CA), an orally delivered small molecule inhibitor that targets the Smoothened (SMO) protein in the hedgehog signaling pathway, was approved by the Food and Drug Administration on January 30, 2012 for basal cell carcinoma.
To evaluate the effects of vismodegib on pancreatic cancer stem cells, patients with previously untreated metastatic pancreatic cancer received vismodegib, initiated as daily monotherapy for a four-week cycle followed by the combination of daily vismodegib with intravenous gemcitabine days 1, 8, and 15 of each subsequent cycle. Each patient had two sets of three core biopsies performed, one set prior to vismodegib therapy and second set three weeks after beginning vismodegib. Gemcitabine was added to vismodegib following the second biopsy.
Of a planned 25-patient enrollment, 20 have undergone paired biopsies and 18 of 20 were assessable for response after three cycles of therapy. Per RECIST, a subset of patients had evidence of disease progression on vismodegib monotherapy; however, continuation of vismodegib plus gemcitabine resulted in confirmed partial responses in five patients (28%); an additional four patients had stable disease, yielding a 50% progression-free survival rate of 50% at three months. Three patients received treatment for ≥12 cycles.
Percentage of pancreatic cancer stem cells were found to decrease in 56% of patients; of these, mean relative decrease was 60% ±22% (range, 16 to 87%). Proliferative index decreased in 54% of the patients (range, -11% to +28%). Sonic hedgehog expression was more highly expressed in patients achieving a partial response or stable disease vs. those with disease progression (mean H-score 285 vs. 168; P=0.016).
“Ongoing analysis of the effect of GDC-0449 on hedgehog pathway target genes is being conducted, Dr. Kim noted, and “ongoing correlative studies are underway to further refine the best predictor of who will benefit from this combination therapy.”
