Data on the role of KRAS mutations in non-small-cell lung cancer (NSCLC) and response to erlotinib are available from two Phase III trials, which conducted non-concurrent subgroup analyses of the efficacy of TKIs in patients with wild-type (non mutated) versus mutated KRAS lung tumors, three phase II trials and one retrospective single-arm study. The data from these studies suggest that KRAS mutations may be useful to predict non-response to TKIs in NSCLC.
Pao et al. were the first to suggest that patients with KRAS mutated lung tumors were non-responsive to treatment with EGFR TKIs. (1) Thirty-six patients with bronchioloalveolar carcinoma underwent KRAS mutation analysis; nine were found to harbor KRAS mutations. Response was measured by a single radiologist, who graded responses according to Response Evaluation Criteria in Solid Tumors (RECIST), blinded to patient outcome. Zero of the nine patients with KRAS-mutated tumors responded to erlotinib (p=0.5531).
Zhu et al. performed a non-concurrent subgroup analysis of KRAS mutations in a group of patients with advanced NSCLC who had failed standard chemotherapy treatment and had been previously randomized to receive erlotinib or placebo. (9) The original Phase III trial (National Cancer Institute of Canada Clinical Trials Group Study BR.21) was the first to demonstrate a significant survival advantage with the use of an EGFR TKI in previously treated NSCLC patients. (2) In the subsequent analysis, 206 of the original 731 tumors were tested for KRAS mutations, which were identified in 30 (15%) patients. Among the 206 patients tested for KRAS mutations, 118 were assessable for response to erlotinib. Of the 98 patients with wild-type KRAS, 10 (10.2%) responded to erlotinib, whereas of the 20 with mutated KRAS, only one (5.0%) patient responded [hazard ratio (erlotinib versus placebo) 1.67 (95% CI (confidence interval): 0.62–4.50; p=0.31) in patients with KRAS mutations and 0.69 (95% CI: 0.49–0.97; p=0.03) in wild-type patients]. In the Cox regression model, the interaction between KRAS mutation status and treatment was p=0.09.
Eberhard et al. performed a non-concurrent subgroup analysis of KRAS mutations in a group of previously untreated patients with advanced NSCLC who had been randomized to receive chemotherapy with or without erlotinib.(3) The original Phase III trial (TRIBUTE study) randomized patients to carboplatin and paclitaxel either with erlotinib or with placebo. (4) Of the original 1,079 patients, tumor DNA from 274 patients was sequenced for KRAS mutations. The baseline demographics between patients with available tumor DNA and those without were balanced. KRAS mutations were detected in 55 of the 274 (21%). The response rate for patients with wild-type KRAS tumors was 26%, regardless of which therapy they received. In patients with KRAS-mutated tumors, response rate was 8% for those receiving erlotinib with chemotherapy, versus 23% in the group receiving chemotherapy alone (p=0.16; 95% CI for difference -5% to 35%). Patients with mutated KRAS who received erlotinib had shortened overall survival of 4.4 months (95% CI: 3.4–12.9 months) versus 13.5 months (95% CI: 11.1–15.9 months) in those who received chemotherapy alone (p=0.019).
In a Phase II, multicenter, open-label study, Jackman et al. evaluated the treatment response to erlotinib in chemotherapy-naive patients 70 years of age or older and who had advanced NSCLC. (6) Of the 80 patients eligible for treatment, 41 had tumor analysis for KRAS mutations. Six of the 41 (15%) had KRAS mutations detected. None of the six patients with a KRAS mutation responded to erlotinib, whereas five of 35 (14%) patients with wild-type KRAS had a partial response.
In a Phase II trial, Miller et al. compared response to erlotinib in 101 patients with lung bronchioloalveolar carcinoma (n=12) or adenocarcinoma, bronchioloalveolar subtype (n=89) according to KRAS mutational status. (8) Of the patients with evaluable tumor, 18 patients (18%) had KRAS-mutated tumors, and none of them responded to erlotinib (zero of 18; 95% CI: 0% to 19%; p<0.01). Response rate was 32% in patients without a KRAS mutation. Median overall survival in patients with a KRAS-mutated tumor was 13 months versus 21 months in patients with KRAS wild-type tumors (p=0.30).
In a Phase II trial, Giaccone et al. studied response to erlotinib in 53 chemotherapy-naive patients with advanced NSCLC. (5) Histologic material was available to assess KRAS mutational status from 29 patients, 10 of whom had mutations. All 10 were non-responders to erlotinib (p=0.125).
2009 National Cancer Institute Clinical Trials Database (PDQ®) and Clinicaltrials.gov
Two Phase III trials are currently ongoing to assess erlotinib in NSCLC patients with concurrent analysis of KRAS mutations. One phase III trial will assess whether clinical and biological features are able to predict the efficacy of erlotinib in patients with NSCLC as second and subsequent line therapy (Tarceva Italian Lung Optimization Trial [TAILOR]; NCT00637910). Outcome measures are overall survival, progression free survival and tumor response. Only patients with available tumor tissue will be included, and patients must have an absence of EGFR mutations. KRAS mutation analysis will be performed to determine the value of identifying a KRAS mutation using this type of therapy. Estimated enrollment is 1,500, and study completion date is estimated to be May 2012.
Another Phase III trial will assess the efficacy of pemetrexed versus erlotinib as second-line therapy in patients with advanced NSCLC (Marker Validation of Erlotinib in Lung Cancer [MARVEL]; NCT00738881). Outcome measures are progression-free survival, overall survival and response rate, with analysis of EGFR and KRAS mutations. Estimated enrollment is 957, and study completion date is estimated to be May 2011.
National Comprehensive Cancer Network (NCCN) 2009 Guidelines
NCCN guidelines state that patients with NSCLC whose tumors harbor KRAS mutations should consider first line therapy other than erlotinib (Tarceva).
A search of peer reviewed literature through May 2013 was performed. The following is a summary of the key literature to date.
Boldrini and colleagues reported on the association between the status of KRAS and EGFR mutations and several clinical variables in 411 patients with lung adenocarcinoma, as well as a subset analysis of tumor response in patients treated with one of the TKIs (erlotinib or gefitinib). (15) Overall, KRAS mutations were observed in 17.9% of patients. The subset analysis consisted of 21 female patients with stage IV disease who received a TKI as second- or third-line therapy and were assessed for radiographic tumor response using the Response Evaluation Criteria for Solid Tumors (RECIST). Age of this subpopulation at the time of diagnosis ranged from 40–86 years (mean age 60.8 years). Nineteen of the 21 patients were KRAS wild-type, and of those, 8 showed partial response, 4 had stable disease, and 7 had progressive disease. The 2 patients with KRAS mutations had progressive disease.
Schneider and colleagues reported on the relationship between clinical benefits and putative tumor markers in a subset of patients participating in a global open-label single-arm study (the TRUST study) of erlotinib in advanced NSCLC, involving 7,043 patients in 52 countries. (16) The subset of patients in this publication were all from German centers and consisted of 311 patients with stage IIIB/IV disease treated with erlotinib because they had failed or were not medically suitable for standard first-line chemotherapy. Tumor response was assessed using RECIST. Seventeen patients (15%) had KRAS mutations, and none of them had a response to erlotinib, but 2 had stable disease. The impact of KRAS mutation status on progression-free survival (PFS) and OS was of borderline statistical significance.
Campos-Parra and colleagues evaluated the response and progression-free survival (PFS) in platinum-based chemotherapy (CT) versus EGFR-TKIs in the presence or absence of KRAS mutation. Three hundred fifty three patients with NSCLC were treated with first-line CT, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were used in the second or third line of treatment. Clinical characteristics, mutation profile, response and PFS to CT and EGFR-TKIs, and overall survival were analyzed. The authors note in their results presence of the wild-type (WT) KRAS was independently associated with increased response rate to first-line CT when compared with KRAS mutation (41.4% vs. 14.7%; P=0.001). Conclusions reported from the authors indicated that KRAS mutation status is a good biomarker for response to EGFR-TKIs in patients with NSCLC. (17)
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