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Hedgehog Inhibitor Regimen Active in Advanced Pancreatic Cancer

Published: Monday, Jan 20, 2014

Dr. Ana De Jesus-Acosta

Ana De Jesus-Acosta, MD

Add-on treatment with the hedgehog pathway inhibitor vismodegib demonstrated encouraging activity in patients with untreated metastatic pancreatic ductal adenocarcinoma, according to preliminary data from an ongoing trial.

More than 80% of 59 patients had stable disease or better response—including one complete response and 20 partial responses—to treatment with vismodegib in combination with gemcitabine and nab-paclitaxel (Abraxane). Interim data analysis showed a median progression-free survival (PFS) of 5.5 months and overall survival (OS) of 10 months, as reported at the 2014 Gastrointestinal Cancers Symposium held January 16-18, 2014 in San Francisco.

"This was a single-arm study, not a randomized trial, so we did not have a control group," explained Ana De Jesus-Acosta, MD, an assistant professor of oncology at Johns Hopkins' Sidney Kimmel Cancer Center in Baltimore, Maryland. "Nonetheless, we found these results very encouraging because they surpassed what we would have expected on the basis of historical data."

Hedgehog pathway signaling is increased in pancreatic ductal carcinoma, and preclinical studies have shown that hedgehog pathway inhibition reduces the population of cancer stem cells and stroma, De Jesus-Acosta and colleagues noted in a poster presentation. Previous studies demonstrated that vismodegib can be combined safely with gemcitabine, standard therapy for pancreatic ductal adenocarcinoma (PDAC).

Available evidence led to the organization of a phase II trial of combination therapy with vismodegib, gemcitabine, and nab-paclitaxel in patients with previously untreated metastatic PDAC. The trial has an accrual goal of 80 patients, and De Jesus-Acosta reported interim data from the trial.

Patients received treatment in 28-day cycles, consisting of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, and 15. Investigators initiated oral vismodegib therapy during the second cycle at a dose of 150 mg/day. Treatment continued until disease progression or until lack of clinical benefit was determined.

The primary endpoint of the ongoing study is PFS. Secondary endpoints include safety and toxicity, estimated OS, and tumor response.

The 59 patients enrolled thus far had a median age of 60; 54% of the patients were male, and ECOG performance status was 0 in 40% or patients and 1 in 60%. De Jesus-Acosta reported that 40 of the 54 patients had three or more metastatic sites, and in 45 of 54 cases, the liver was the primary disease site.

Of 57 patients evaluable for the primary endpoint, the median PFS was 5.5 months. On the basis of the experience to date, the patients had a median OS of 10 months.

The regimen led to an overall response rate of 43%, consisting of one complete response and 20 partial responses. An additional 21 patients had stable disease, resulting in a clinical benefit rate of 86%.

"All of the partial responses occurred within the patients' primary pancreatic tumors," said De Jesus-Acosta. "More than half of the patients (57%) had decreases in the CA 19-9 antigen exceeding 70% compared to baseline."

Combining vismodegib with gemcitabine and nab-paclitaxel did not result in any unexpected adverse events. The most common grade 3 or worse adverse events consisted of neutropenia (37.5%), anemia (21.4%), neuropathy (16.1%), and thrombocytopenia (12.5%). Grade ≥3 febrile neutropenia occurred in four patients (7%).

"We will continue to enroll patients until the goal of 80 has been reached, and then evaluate the overall results before deciding the next step in evaluation," De Jesus-Acosta said. "On the basis of what we have observed thus far, I would expect the regimen to be evaluated in a randomized trial."

As patient accrual continues, tissue analysis is ongoing and includes stem cells, hedgehog pathway signaling, and stromal activity.


De Jesus-Acosta A, O’Dwyer PJ, Ramanathan DD, et al. A phase II study of vismodegib, a hedgehog pathway inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated pancreatic ductal adenocarcinoma. J Clin Oncol. 201432(suppl 3; abstr 257).

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