Clinical Development of Inhibitors of the Insulin-like Growth Factor Receptor in Oncology

The insulin-like growth factor I receptor (IGF-IR) pathway plays a major role in cancer growth, tumor cell survival and resistance to therapy. Ancillary evidence that targeting the IGF-IR may be useful in the treatment of cancer has been accumulating for almost two decades. Today, more than two dozen compounds have been developed and clinical trials are underway for at least 12 of those. The ability to pharmacologically control the IGF-IR pathway holds not only promising therapeutic implications but also the possibility to gather a better understanding of the role of the IGF axis in tumor initiation and progression. This review focuses on the preclinical rationale for targeting the IGF-IR and other components of the IGF-I system, early clinical results observed to date, biomarker approaches employed and the lessons from these early results for future study design. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence of receptor targeting. Instances of single-agent activity during phase I evaluations have been well documented and a recently reported randomized phase II study indicates that co-administration of an anti-IGF-IR antibody with chemotherapy improves objective response rate and progression-free survival in non-small cell lung cancer patients. These early results support ongoing research across a broad range of cancer indications.