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.

Effectiveness of erlotinib treatment in advanced KRAS mutation-negative lung adenocarcinoma patients: Results of a multicenter observational cohort study (MOTIVATE)

“…without the knowledge of patients' EGFR status) has a predictive role for the second or third-line erlotinib therapy of NSCLC. Importantly, although the role of KRAS mutational analysis in NSCLC treatment is still debated [30][31][32], our data suggest a predictive role of KRAS status for NSCLC patients treated with erlotinib and, furthermore, are in line with subsequently published NCCN NSCLC guidelines which has been incorporated the proposal that "KRAS mutations are associated with intrinsic TKI resistance, and KRAS gene sequencing could be useful for the selection of patients as candidates for TKI therapy" [18].…”

Molecular pathology of lung cancer: key to personalized medicine

“…The mutations were associated with a 67% response rate, with a time to progression of 11.8 months, and overall survival of 23.9 months. 85 Exon 19 deletions were associated with a relatively longer median time to progression and overall survival compared with L858R (exon 21) mutations. Wild-type EGFR was found in 139 patients (62%), and this finding was associated with poor outcomes (response rate, 3%; time to progression, 3.2 months), irrespective of KRAS status.…”

“…6,[80][81][82][83][84] The response-associated mutations are linked with response rates of 470% in patients treated with either erlotinib or gefitinib. 85,86 However, upto 25% of patients with TKI resistanceassociated mutations will also respond to the therapy. 67 Pao et al 7 analyzed EGFR mutation of exons 18-24 in tumors from 10 gefitinib-responsive and from 7 erlotinib-responsive patients.…”

“…85 EGFR mutations are generally associated with sensitivity to TKI therapy. 71,87 Both retrospective and prospective studies have demonstrated that lung adenocarcinoma patients carrying such an EGFR mutation and who were treated with TKIs had significantly higher response rates and longer progression-free survival than patients without an EGFR mutation, [5][6][7]25,29,71,83,85,87,88 with some patients experiencing rapid, complete, or partial responses that were persistant. 55 Jackman et al 85 studied 223 chemotherapy-naïve patients with advanced lung cancer of non-small cell type, among which 86% were adenocarcinomas.…”

“…Thus, primary drug insensitivity is likely linked to the absence of drug-sensitizing mutations in EGFR and is more likely to be a result of mutations in other genes. 15,85 Further complicating matters are the findings that even in tumors with EGFR mutations, certain mutations appear to confer greater sensitivity to treatment than others. 33 This emphasizes that predicting response to treatment is a complex process that is not completely understood at this time.…”