Amgen pulled its monoclonal antibody ganitumab, an insulin-like growth factor-I receptor inhibitor, from a phase III trial for metastatic pancreatic cancer.

Drugs targeting the insulin-like growth factor-I receptor (IGF-IR) saw another failure in August in a clinical study that combined Amgen's monoclonal antibody ganitumab (AMG 479) with gemcitabine for treating metastatic pancreatic cancer. Amgen pulled the drug from its phase III trial after an interim review concluded that ganitumab wouldn't do better at improving overall survival than the chemotherapy would alone.

Ganitumab's demise follows other high-profile disappointments with IGF-IR drugs, once seen as a promising drug class in targeted therapy.

“IGF-IR looked like a great target, and we were all happy to jump on the bandwagon,” says Vuk Stambolik, PhD, an associate professor at the University of Toronto. However, Pfizer's monoclonal antibody for non–small cell lung cancer, figitumumab, worsened outcomes before it was pulled from a phase III trial in 2009. Roche, Eli Lilly, and other companies have also faced clinical troubles with their own IGF-IR compounds.

Produced by the liver during puberty, IGF-I ordinarily governs skeletal growth and height, and it's also elevated in cancer. Conversely, people with low circulating levels of the hepatic growth hormone appear to be protected from malignancies. These findings are in part what spurred the development of IGF-IR inhibitors more than 20 years ago.

Michael Pollak, MD, a professor of oncology at McGill University in Montreal, who detected the IGF receptor on cancer cells in the late 1980s, says it's possible that the trials failed because they were conducted with unselected patients.

“Tumor cells driven by epidermal growth factor, activating mutations in PI3 [phosphoinositide 3] kinase, or something else, don't care about IGF,” he says. “So they're not upset by IGF deprivation. Tumors that take the trouble to synthesize their own IGF might respond, but they will likely account for a small percentage of otherwise eligible patients.”

Stambolik adds that cancer cells can adapt to IGF-IR inhibition by up-regulating other survival programs, leading to treatment resistance. “So the path forward with IGF-IR blockers should involve combination treatment with other targeted therapies,” he says.

Pollak agrees. “The hypothesis that IGF-IR inhibitors would add benefit when added to chemotherapy in unselected patients has been rigorously tested and disproven,” he says. “But we still have unanswered questions about how the inhibitors might work in specific populations treated with rational combinations.”