90IN - Why were IGF-1R inhibitors disappointing? Can we improve activity by better patient selection or use of combinations?

Date 29 September 2012
Event ESMO Congress 2012
Session Subtyping soft tissue sarcomas for treatment approaches
Topics Anticancer agents
Soft Tissue Sarcomas
Pathology/Molecular Biology
Basic Scientific Principles
Therapy
Biological therapy
Presenter David Olmos Hidalgo
Authors D. Olmos Hidalgo
  • Ddu/prostate Unit, Royal Marsden Hospital NHS Foundation Trust, SM2 5PT - Surrey, Sutton/UK

Abstract

It is been known for many years that the insulin-like growth factor (IGF) signalling pathway is important in human cancer. The IGF-1 receptor (IGF-1R) is upregulated in colorectal, breast, prostate and lung cancers. It was also known to be a potential target in Ewing's sarcoma. The advent of specific monoclonal antibodies and small molecule tyrosine kinase inhibitors of IGF-1R led to many clinical trials. A combination of figitumumab with platinum doublet chemotherapy resulted in a higher response rate and improved progression-free survival (PFS) in phase II, but a phase III trial was negative. In Ewing's sarcoma activity was seen with R-1507, figitumumab and other agents. However, response rates in phase II studies were generally low, 14.2% with figitumumab, and duration generally short, e.g. with figitumumab median PFS 1.9 months, median survival 8.9 months. Occasionally, durable responses have been seen lasting for several years. Could better selection by the use of circulating biomarkers, e.g. IGF-1, or IGF binding proteins, be useful or does the answer lie with combinations? Laboratory studies suggest that combining IGF-1R inhibitors with inhibitors of AKT/mTOR, EGFR or MEK, could help to overcome resistance. Given the dearth of new agents for Ewing's sarcoma it is to be hoped that continued access to these agents will enable further work on mechanisms of resistance and appropriate combination phase I/II studies to be performed. The book is not yet closed on IGF-1R as a target.

Disclosure

The author has declared no conflicts of interest.