Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials

Abstract

Purpose: The impact of epidermal growth factor receptor (EGFR) and KRAS genotypes on outcomes with erlotinib or gefitinib therapy continues to be debated. This study combines patient data from five trials in predominantly Western populations to assess the impact of EGFR and KRAS mutations on first-line therapy with an EGFR-tyrosine kinase inhibitor (TKI) and compare clinical versus molecular predictors of sensitivity.

Experimental design: Chemotherapy-naïve patients with advanced non-small cell lung cancer and known EGFR mutation status treated with erlotinib or gefitinib monotherapy as part of a clinical trial were eligible for inclusion. Patients received daily erlotinib (150 mg) or gefitinib (250 mg) until disease progression or unacceptable toxicity. Data were collected in a password-protected web database. Clinical outcomes were analyzed to look for differences based on EGFR and KRAS genotypes, as well as clinical characteristics.

Results: Patients (223) from five clinical trials were included. Sensitizing EGFR mutations were associated with a 67% response rate, time to progression (TTP) of 11.8 months, and overall survival of 23.9 months. Exon 19 deletions were associated with longer median TTP and overall survival compared with L858R mutations. Wild-type EGFR was associated with poorer outcomes (response rate, 3%; TTP, 3.2 months) irrespective of KRAS status. No difference in outcome was seen between patients harboring KRAS transition versus transversion mutations. EGFR genotype was more effective than clinical characteristics at selecting appropriate patients for consideration of first-line therapy with an EGFR-TKI.

Conclusion: EGFR mutation status is associated with sensitivity to treatment with an EGFR-TKI in patients with advanced non-small cell lung cancer. Patients harboring sensitizing EGFR mutations should be considered for first-line erlotinib or gefitinib.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

D.M. Jackman, consultant, Genentech; honoraria, Roche. V.A. Miller, consultant, Genentech. P.A. Janne, consultant, AVEO Pharmaceuticals, Boehringer Ingelheim, Roche; research funding, Pfizer, Genentech; patent holder, Genzyme. G.J. Riely, consultant, Astra Zeneca, Roche. M.I. Gallegos Ruiz, employment, Roche. B.E. Johnson, consultant, patent holder, Genzyme. The other authors report no conflicts of interest.

Figures

Fig. 1

A, OS in patients with exon 19 deletions versus L858R point mutations. B, OS based on EGFR and KRAS status.

Fig. 2

Comparison of outcomes by clinical enrichment and EGFR mutation analysis.

Fig. 3

Maximal reduction for indicator lesions (Response Evaluation Criteria in Solid Tumors classification) by EGFR and KRAS genotype.