Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer

// Silvia Park 1, * , Emma Langley 2, * , Jong-Mu Sun 1 , Steve Lockton 2 , Jin Seok Ahn 1 , Anjali Jain 2 , Keunchil Park 1 , Sharat Singh 2 , Phillip Kim 2 , Myung-Ju Ahn 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Prometheus Laboratories Inc, A Nestle Health Science Company, Department of Research and Development, San Diego, CA, USA * These authors have contributed equally to this work Correspondence to: Myung-Ju Ahn, e-mail: silkahn@skku.edu Phillip Kim, e-mail: pkim@prometheuslabs.com Keywords: NSCLC, EGFR TKI, PFS, EGFR/MET ratio, HER3 Received: April 07, 2015      Accepted: August 19, 2015      Published: September 03, 2015 ABSTRACT Purpose: Although activating mutations in the epidermal growth factor receptor ( EGFR ) gene are predictive markers for response to EGFR inhibitors, 30–40% of EGFR -mutant non-small cell lung cancer (NSCLC) patients are de novo non-responders. Hence, we sought to explore additional biomarkers of response. Methods: We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors. A total of 37 patients were enrolled and 34 underwent EGFR inhibitor treatment. Results: As expected, patients bearing activating EGFR mutations showed increased progression free survival (PFS) compared to patients with wild-type EGFR status (9.3 vs 1.4 months, p = 0.0629). Analysis of baseline tumor RTK profiles revealed that, regardless of EGFR mutation status, higher levels of EGFR relative to MET correlated with longer PFS. At multiple EGFR/MET ratio cut-offs, including 1, 2 and 3, median PFS according to below vs. above cut-offs were 0.4 vs. 6.1 ( p = 0.0001), 0.5 vs. 9.3 ( p = 0.0006) and 1.0 vs. 11.2 months ( p = 0.0008), respectively. Conclusion: The EGFR/MET ratio measured in tumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors.