522P - Broad detection of alterations predicted to confer lack of benefit from EGFR antibodies or sensitivity to targeted therapy in advanced colorectal c...

Date 08 October 2016
Event ESMO 2016 Congress
Session Poster Display
Topics Colon and Rectal Cancer
Presenter Samuel Klempner
Citation Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370
Authors S.J. Klempner1, A. Rankin2, R.L. Erlich2, J. Sun3, A. Grothey4, M. Fakih5, T.J. George, Jr.6, J. Lee7, J.S. Ross8, P.J. Stephens9, V.A. Miller10, S. Ali10, A.B. Schrock10
  • 1Medical Oncology, The Angeles Clinic and Research Institute, 90025 - Los Angeles/US
  • 2Biomedical Informatics, Foundation Medicine, Inc., Cambridge/US
  • 3Biomarker Development, Foundation Medicine, Inc., Cambridge/US
  • 4Medical Oncology, Mayo Clinic, 55905 - Rochester/US
  • 5Internal Medicine, City of Hope, 91010 - Duarte/US
  • 6Hematology And Oncology, University of Florida College of Medicine, Gainesville/US
  • 7Hematology And Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul/KR
  • 8Pathology, Foundation Medicine, Inc., Cambridge/US
  • 9Clinical Genomics, Foundation Medicine, Inc., Cambridge/US
  • 10Clinical Development, Foundation Medicine, Inc., Cambridge/US

Abstract

Background

KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti-EGFR antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance, as well as alterations predicting response to targeted therapies is limited and further study is needed.

Methods

We prospectively analyzed 4,422 clinical samples from patients with advanced CRC using hybrid-capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results when available was performed to assess concordance.

Results

We identified RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non-codon 12/13 alterations for which prior test results were available, 79/90 (88%) were missed by focused testing. Of 1,644 RAS/RAF wild-type cases analyzed by CGP, 28% harbored a genomic alteration (GA) associated with resistance to anti-EGFR therapy in advanced CRC including mutation of PIK3CA, EGFR, and ERBB2 genes. We also identified other targetable GA including novel kinase fusions, RTK amplification, activating point mutations, as well as microsatellite instability.

Conclusions

Comprehensive genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc.

Disclosure

S.J. Klempner: Has received honoraria from Foundation Medicine. A. Rankin, R.L. Erlich, J. Sun, J.S. Ross, P.J. Stephens, V.A. Miller, S. Ali, A.B. Schrock: Employee and stock ownership in Foundation Medicine. All other authors have declared no conflicts of interest.