IGF Receptor Antagonist Shows Activity in Advanced Pancreatic Cancer

Orlando, FL—For patients with advanced pancreatic cancer, a novel inhibitor of the insulin-like growth factor (IGF) receptor led to response rates or stable disease in a majority of patients, according to a study reported at the 2010 Gastrointestinal Cancers Symposium.

“We observed sustained partial responses with two different regimens of this agent,” said Milind Javle, MD, professor of oncology at MD Anderson Cancer Center in Houston.

Activation of the IGF-1 receptor is associated with aggressive disease and acquired resistance to drugs that target the epidermal growth factor receptor (EGFR). Preclinical studies have shown that synergy can be obtained when an IGF-1 receptor antagonist and an EGFR antagonist are combined, Dr Javle said.

The novel agent is a humanized monoclonal antibody that binds to the IGF-1 receptor and blocks its interaction with IFG-1 and IGF-2 ligands. It enhances gemcitabine-induced apoptosis and inhibits multiple actions along the signaling pathway, he explained.

The phase I/II study enrolled 28 individuals with stage IV pancreatic adenocarcioma 6 months or more after completion of chemotherapy. MK-0646 was given in combination with gemcitabine (weekly gemcitabine plus weekly MK-0646 at 5 mg/kg or 10 mg/kg) or gemcitabine plus the EGFR inhibitor cetuximab. Along with determining maximum tolerated dose, the study assessed progression-free survival (PFS) of the two combination arms.

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Of 24 evaluable patients, 6 (25%) had a partial response and 8 (33%) experienced stable disease. The response duration ranged from 14 to 44 weeks, but time to progression did not differ between the arms ( = 0.4796), Dr Javle reported.

“What is important is that we believe these responses are sustained,” he commented. He said the responses occurred equally in the arms containing erlotinib, versus those with only gemcitabine.

Of the 28 patients, 23 (82%) required dose reductions of gemcitabine, and 7 required reductions in erlotinib. Five patients discontinued erlotinib because of toxicity but no patients withdrew from the study completely because of adverse events, he said. Hyperglycemia and fatigue were the most frequent toxicities, while elevated liver enzymes and hypermagnesemia also occurred. Grade 3-4 neutropenia was observed in about half the patients, but there were no cases of febrile neutropenia.

The investigators are moving into a randomized phase 2 study of 80 patients, “which should provide further stop-or-go information for a phase 3 trial,” he said. He added that biomarker studies are also being conducted, which might determine which patients will benefit from this compound.

Philip A. Philip, MD, of the Karmanos Cancer Center, Detroit, Michigan, said in a formal discussion of the study that the study has a strong “scientific rationale” and the findings demonstrate “some activity” of the agent, although “it is too early to make much of this.”

Other anti-IGF receptor agents are also in development and entering trials, he added, but suggested, “We need more data before designing phase III studies of anti-IGFR agents.”