IGF-Receptor Inhibitor and Sunitinib Show Activity in Stage IV Pancreatic Cancer

March 18, 2010

A novel IGF-receptor inhibitor stabilized disease in a majority of pancreatic cancer patients, according to a report at the 2010 GI Cancers Symposium.

ORLANDO-A novel IGF-receptor inhibitor stabilized disease in a majority of pancreatic cancer patients, according to a report at the 2010 GI Cancers Symposium. "We observed sustained partial responses with two different regimens of this agent," said Milind Javle, MD, associate professor of oncology at Houston's M.D. Anderson Cancer Center.

The phase I/II study evaluated MK-0646, a humanized monoclonal antibody that binds to the IGF-1 receptor. The IGF-1 receptor is associated with aggressive disease and with acquired resistance to drugs targeting EGFR. Preclinically, synergy is observed when an IGF-1 receptor antagonist and an EGFR antagonist are combined. This study evaluated MK-0646 paired with gemcitabine (Gemzar) and erlotinib (Tarceva).

Twenty-eight stage IV pancreatic adenocarcinoma patients were treated with weekly MK-0646 in combination with weekly gemcitabine or with weekly gemcitabine plus erlotinib. Of 24 evaluable patients, six (25%) had a partial response and eight (33%) achieved stable disease. The response duration ranged from 14 to 44-plus weeks, but time to progression did not differ between the arms, Dr. Javle said. Response to treatment occurred equally among patients receiving gemcitabine only or gemcitabine plus erlotinib (abstract 131).

Most patients (82%) required dose reductions of gemcitabine and erlotinib, but no patients withdrew due to adverse events. A randomized phase II study of 80 patients is planned, he said.

This MK-0646 study has a strong scientific rationale and the findings demonstrate some activity of the agent, but more data are needed before beginning phase III studies for any other anti-IGFR agent, said Philip A. Philip, MD, of the Karmanos Cancer Center in Detroit.

Sunitinib improves survival in advanced pancreatic NET

The final analysis of an international phase III trial found that sunitinib (Sutent) significantly prolonged both overall survival (OS) and progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumors (NET).

In fact, the study was stopped early because the number of events in the placebo arm, especially deaths, was much higher than that in the treatment arm, said lead author Eric Raymond, MD, PhD, a professor of medical oncology at Beaujon University Hospital in Clichy, France.

The study included 171 patients with advanced pancreatic NETs who were randomly assigned to continuous sunitinib (37.5 mg/d) or placebo. Median PFS, the study's primary endpoint, was 11.4 months in the sunitinib arm vs 5.5 months in the placebo arm, for a 58% reduction in risk (P < .001).

"With sunitinib, we improved PFS by doubling it to 11.4 months, with a highly significant P-value," Dr. Raymond said. "Events occurred in 34.9% on the sunitinib arm vs 60% of the placebo arm."

Sunitinib also offered an OS probability of 92.6% vs 85.2% with placebo for a 59% statistically significant reduction in risk (P = .0204).

The overall response rate was 9.3% with sunitinib and 0% with placebo. Median duration of response was 8.1 months with the drug. Stable disease rates were 34.9% and 24.7%, respectively. "Stable disease was a common feature of sunitinib treatment. Some of the patients are still stable after 2.5 years," Dr. Raymond said.

Adverse events were similar to those observed in other studies of sunitinib, and were manageable with dose interruption, dose reduction, and/or standard medical therapy (abstract 127).

Jordan Berlin, MD, clinical director of GI Oncology at Vanderbilt's Ingram Cancer Center in Nashville, said that along with showing an encouraging clinical benefit, the study demonstrated an important proof of principle: A targeted agent has a major effect in NET.