Vismodegib Blocks Hedgehog-Expressing Pancreatic Cancer



Early results from a small clinical trial suggest the new oral skin cancer drug vismodegib may be therapeutic in patients receiving chemotherapy for metastatic pancreatic cancer.

Half of 20 patients treated with vismodegib (Erivedge, GDC-0449) and gemcitabine (Gemzar) were progression free at 3 months, investigators reported during a pancreatic cancer conference sponsored by the American Association for Cancer Research. Five patients had partial responses, and five had stable disease.

Dr. Daniel D. Von Hoff

The study found pretreatment sonic hedgehog expression level was the biological correlate most predictive of therapeutic benefit. Vismodegib, a small molecule drug from Genentech, blocks the Smoothened (SMO) protein in the hedgehog signaling pathway

If validated in additional studies, the combination of vismodegib and gemcitabine "has the potential to change the way we treat pancreatic cancer" lead author Dr. Edward Kim of the University of Michigan Comprehensive Cancer Center in Ann Arbor, said in a press briefing at the meeting in Lake Tahoe, Nev.

In previous research, the investigators determined that specific pancreatic cancer stem cells express significantly elevated levels of sonic hedgehog (Cancer Res. 2007;67:1030-7), which led to successful phase I studies, Dr. Kim said in an interview. Building on that foundation, for the current clinical trial, the researchers incorporated pair core tumor biopsies to prospectively compare the inhibition of the hedgehog pathway in pancreatic cancer before and after vismodegib treatment.

To date, 21 of the study’s planned 25 patients with advanced pancreatic cancer have been enrolled. Data from 20 of the patients with paired biopsies who had completed three treatment cycles were reported at the meeting.

All of the patients had previously untreated metastatic pancreatic cancer, for which the protocol initiated daily monotherapy with vismodegib for 4 weeks, followed by combination treatment with vismodegib and gemcitabine on days 1, 8, and 15 of each month in a 3-month cycle, Dr. Kim reported. Each patient underwent two sets of three core biopsies – one set prior to treatment and another set 3 weeks after treatment initiation.

To evaluate the effects of the experimental drug on pancreatic cancer stem cells, the investigators used immunohistochemistry to evaluate expression of sonic hedgehog and Ki-67, a static marker of tumor proliferation.

"After three cycles of therapy, five patients showed evidence of partial disease response [defined as a minimum 30% decrease in the sum of the longest-diameter target lesions relative to baseline, based on RECIST criteria] and five patients had stable disease, yielding 3-month progression-free survival rate of 50%," Dr. Kim stated. Additionally, half of the evaluable patients demonstrated an average 60% reduction in pancreatic cancer stem cells and a 54% decrease in the proliferation index.

Importantly, Dr. Kim noted, "sonic hedgehog expression was more highly expressed in patients who had a partial response or stable disease compared with patients whose disease progressed." Specifically, the mean pretreatment hedgehog expression H-score (intensity times the percentage of positive cells) was 285 in patients with partial response or stable disease compared with 168 in those with progression.

"We are currently conducting further correlative studies to determine the best predictors of which patients stand to benefit from this treatment regimen," he said. The researchers also are continuing to investigate the effect that vismodegib has on hedgehog pathway target genes.

The response rate observed in this study exceeded expectations, according to session moderator Dr. Daniel Von Hoff, chief scientific officer for the Scottsdale Healthcare Research Institute and physician-in-chief at TGen (Translational Genomics Research Institute) in Phoenix. "We usually see about a 5%-9% change of response to gemcitabine by itself, but here it was 25%. The good news is that this drug doesn’t add any toxicities."

The Food and Drug Administration approved vismodegib Jan. 30 for locally advanced or metastatic basal cell carcinoma that cannot be treated with surgery or radiation. It has not been considered for an indication in pancreatic cancer.

Dr. Kim and Dr. Von Hoff disclosed having no relevant financial conflicts of interest.

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