You are here

P T. 2011;36(5): 263-268, 277-279

Roles of EGFR and KRAS Mutations in the Treatment Of Patients With Non–Small-Cell Lung Cancer

Corey J. Langer MD

After decades of empirical treatment, molecular subtypes of non–small-cell lung cancer (NSCLC) are now emerging that may enable us to target treatment for patients and increase the likelihood of response. Of the biomarkers under evaluation, gene mutations are gaining recognition as predictive markers for anti–epidermal-growth factor receptor (EGFR) therapy. To date, unlike the situation in colorectal cancer, mutation of the v-Ki-Ras-2 Kirsten rat sarcoma viral oncogene homolog (KRAS) has an inconclusive role in NSCLC and should not be used to exclude patients from anti-EGFR therapy. For first-line NSCLC therapy, EGFR mutation status constitutes a prudent test to identify patients who are most likely to benefit from EGFR–tyrosine kinase inhibitor therapy rather than from chemotherapy. In first-line maintenance and relapsed (second-line or third-line) settings, clinical data support the use of erlotinib (Tarceva), as currently indicated, without regard to evaluation of EGFR mutation status. All patient subsets have been shown to benefit with prolonged progression-free and overall survival.


For decades, therapy for advanced non–small-cell lung cancer (NSCLC) was largely empirical; no biological characteristics were known to enable physicians to differentiate among the numerous active agents for this disease. In the past five to 10 years, however, safety and efficacy data have emerged supporting the differential use of some agents according to histology. In a phase 2 trial of bevacizumab (Avastin, Genentech/Roche), a high rate of hemoptysis in patients with squamous cell carcinoma (SCC) resulted in restricting this agent’s further development and clinical use to nonsquamous histology.13 Subsequently, a randomized phase 3 trial comparing first-line pemetrexed (Alimta, Eli Lilly) plus cisplatin (Platinol AQ, Bristol-Myers Squibb) with gemcitabine (Gemzar, Eli Lilly) plus cisplatin showed no difference in efficacy overall between the two regimens. When histological features were analyzed, however, this study revealed greater efficacy for pemetrexed in patients with adenocarcinoma and greater efficacy for gemcitabine in patients with SCC.4,5

An analysis of a second-line trial comparing pemetrexed with docetaxel (Taxotere, sanofi-aventis) corroborated these results, showing a benefit with pemetrexed over docetaxel in nonsquamous histology.5 In the maintenance setting, similar data have emerged, showing benefits in progression-free survival and overall survival with pemetrexed, compared with placebo, when used only in nonsquamous histology.6,7

Based on these data, many oncologists are increasingly reserving pemetrexed for adenocarcinoma patients; further, they also prefer to prescribe gemcitabine in patients with SCC. However, the predictive value of histology, although statistically significant, is modest. Median overall survival times with first-line pemetrexed/cisplatin versus gemcitabine/cisplatin in patients with nonsquamous tumors were 11 months and 10.1 months, respectively, corresponding to a hazard ratio (HR) of 0.84 (P = 0.011).5 Clearly, identifying additional biological markers that can better predict the efficacy of agents for NSCLC would be beneficial. In colorectal cancer, KRAS mutation is now used to identify patients who will not benefit from anti-EGFR therapy, thereby sparing patients from needless toxicity, permitting the selection of more appropriate therapy, and avoiding unnecessary expenditures.810

Molecular subtypes of NSCLC are now being elucidated (Figure 1). Markers that may confer sensitivity or resistance to anti-EGFR therapy, as well as other agents, are being investigated. These include EGFR mutations, EGFR gene copy number, the presence of the echinoderm microtubule-associated protein-like 4/anaplastic lymphoma kinase (EML4/ALK) fusion gene, KRAS gene mutations, B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) gene mutations, and phosphatase and tensin homolog (PTEN) gene expression.

The search for a biomarker with the same predictive value as KRAS in colorectal cancer is ongoing in NSCLC, but such a biomarker remains elusive. The most promising candidate is the presence of EGFR mutation that confers sensitivity to EGFR–tyrosine kinase inhibitors (TKIs).11 However, EGFR mutations are not 100% predictive of anti-EGFR–TKI efficacy in NSCLC. Therefore, EGFR mutation status cannot be used to definitively guide anti-EGFR therapy for NSCLC in the same way that KRAS mutation status is used in colorectal cancer. Indeed, a substantial body of data supports the use of erlotinib in NSCLC regardless of EGFR or KRAS mutation status.

The managed care community is challenged to critically analyze the clinical evidence for the expanding role for prognostic and predictive biomarkers in NSCLC and to apply this information when making coverage decisions about anti-EGFR therapy in this difficult-to-treat disease. Payers are responding in their decision-making. For instance, in 2009, United-Healthcare decided to base coverage for cetuximab (Erbitux, Bristol-Myers Squibb/ImClone) and panitumumab (Vectibix, Amgen) on KRAS test results for patients with colorectal cancer.12 Other payers have followed suit. This follows a study in 2009 that showed potential cost savings of $753 million for cetuximab and panitumumab if KRAS genetic testing had been implemented earlier.10

This article examines the current clinical application of EGFR and KRAS mutations in patients with NSCLC.


Because a subset of patients clearly responded to the anti-EGFR–TKIs erlotinib (Tarceva, OSI/Genentech) and gefitinib (Iressa, AstraZeneca), investigators were prompted to search for traits that would prospectively identify patients more likely to benefit. Clinical characteristics became apparent: Asian ethnicity, female sex, never-smokers, and patients with histological features of adenocarcinoma.13,14 Yet the governing biology was still undetermined. Several key studies demonstrated that patients with certain EGFR mutations were significantly more likely to respond to anti-EGFR–TKIs.1517 Furthermore, these mutations were more common in patients with the clinical characteristics of responders.16,17

Types of Mutations

Two general types of EGFR mutations have been identified (Table 1): (1) activating mutations, which confer sensitivity to anti-EGFR therapies, and (2) resistance mutations.

Two specific activating mutations predominate and comprise 75% to 85% of all EGFR mutations: deletion in exon 19 (del exon 19) and the single-point mutation leucine-to-arginine substitution at position 858 (L858R) in exon 21.1517 The proportion of NSCLC patients with activating mutations ranges from 10% to 40%.18 The wide range reflects the diverse populations studied and the variability of favorable phenotypes (women, those of Asian ethnicity, never-smokers, and patients with adenocarcinoma); each of these phenotypes suggests the presence of an EGFR mutation. The relationship between these clinical characteristics and the rate of EGFR mutations is illustrated in a sample of recent trials that tested patients for EGFR mutations (Table 2).

In other populations, the incidence of EGFR mutations is lower; analyses of three phase 3 trials of anti-EGFR–TKIs conducted in broad NSCLC populations—SATURN (Sequential Tarceva in Unresectable NSCLC), INTEREST (Iressa Non–Small-Cell Lung Cancer Trial Evaluating Response and Survival Against Taxotere), and BR.21—yielded rates of 11% to 17%.1921

Resistance mutations become clinically relevant in patients already treated with anti-EGFR–TKIs who acquire resistance to these drugs.22 Approximately 50% of patients with acquired resistance to anti-EGFR–TKIs show a resistance mutation in EGFR.23,24 The most commonly acquired resistance mutation—the point mutation—involves a threonine-to-methionine amino acid change at position 790 (T790M). Resistance mutations are relatively rare in patients who are new to anti-EGFR–TKI therapy, and they tend not to exist in people lacking EGFR-activating mutations.18,22

Most KRAS mutations in NSCLC tumors are activating by nature and involve point mutations in codons 12 or 13. These mutations are more common in patients with adenocarcinoma and in smokers.2528 The incidence of mutation in patients with NSCLC ranges from 8% to 24% in clinical trials (Table 3), compared with observed rates of 35% to 43% in colorectal cancer.9,19,2937KRAS mutations predict a lack of response to EGFR biologic therapy for colorectal cancer, and KRAS status testing is now standard clinical practice in this disease.8,9,38,39 However, KRAS testing has not achieved that status in NSCLC.

The EML4-ALK fusion gene is formed by an inversion within chromosome 2p and occurs in 2% to 5% of NSCLC patients.4045 The fusion gene is more common in younger patients with adenocarcinoma who never smoked or who are light smokers. The abnormality, compared with the EGFR mutation, is found in relatively more males.41,4347 To date, EML4-ALK appears to be mutually exclusive with EGFR and KRAS mutations.44,45

Similar to KRAS mutations, BRAF mutations are more common in colorectal cancer (8% to 20%) than in NSCLC (less than 5%).4856 In patients with colorectal cancer, BRAF has proved to be a poor prognostic factor but not predictive of outcomes with anti-EGFR therapy.48,57 Clinical data in NSCLC are just beginning to emerge.

Clinical Role of Biomarkers

EGFR Mutations as a Predictor of Anti-EGFR–TKI Efficacy

After EGFR mutations were first identified as a predictor of efficacy with anti-EGFR–TKIs in NSCLC, several small studies evaluating its role in European and Asian patients confirmed this observation. Combining results from 21 small studies, Sequist et al. calculated that the response rate to anti-EGFR–TKIs (any line of therapy) in all studies was 78% in 268 patients who harbored mutations but only 10% in 659 patients without mutations.58 In a meta-analysis of 54 studies, Paz-Ares et al. reported an overall median progression-free survival of 13.2 months with erlotinib, 9.8 months with gefitinib, and 5.9 months with chemotherapy in patients with EGFR mutations.59 An analysis of pooled median progression-free survival in the first-line setting was similar to the overall results.

Three large prospective, randomized trials have evaluated anti-EGFR–TKIs in a selected treatment-naive population with EGFR mutations.6062

Maemondo et al. reported that patients treated with gefitinib had significantly longer progression-free survival, compared with patients receiving paclitaxel/carboplatin chemotherapy (10.8 vs. 5.4 months, respectively; P < 0.001) (Table 4).60 The difference in median overall survival was not statistically significant (30.5 vs. 23.6 months, respectively; P = 0.31). The absence of a survival benefit could have been a result of the crossover effect, the premature discontinuation of the trial, or inadequate power of the study.

Mitsudomi et al. reported a similar significant benefit of progression-free survival for gefitinib (9.2 months), compared with cisplatin/docetaxel (6.3 months) (P < 0.0001).61 Final median overall survival has yet to be reported. Significant crossover of patients (51 of 86) was noted in the chemotherapy arm.

In a randomized phase 3 study (OPTIMAL), Zhou et al. compared the efficacy of first-line erlotinib and gemcitabine/carboplatin in 154 Chinese patients with advanced NSCLC with EGFR-activating mutations.62 The primary endpoint (median progression-free survival) was significantly prolonged with erlotinib (13.1 months), compared with chemotherapy (4.6 months) (HR = 0.16; P < 0.0001). The one-year progression-free survival rate was also greater with erlotinib (56%) than with chemotherapy (1.7%).62 The overall response rate was significantly improved with erlotinib (83% vs. 36% for chemotherapy, respectively; P < 0.0001). Median overall survival data are not yet available.

A similar ongoing study, the European Randomized Trial of Tarceva Versus Chemotherapy (EURTAC), conducted by the Spanish Lung Cancer Group, has enrolled 146 patients with advanced, untreated, EGFR-mutated NSCLC to receive either erlotinib or four cycles of chemotherapy (platinum plus either gemcitabine or docetaxel).63

In the largest prospective study evaluating EGFR mutation to date, conducted by the Spanish Lung Cancer Group, 2,105 patients with untreated or relapsed advanced NSCLC were screened for EGFR mutations.11 A total of 350 patients (16.6%) carried EGFR mutations. In the 217 patients who received erlotinib as first-line, second-line, or third-line therapy, the response rate was 70.5% in 197 evaluable patients. Median progression-free survival was 14 months, and median overall survival was 27 months. Similar results were observed when overall survival was evaluated by line of treatment: 28 months with first-line erlotinib and 27 months with second-line erlotinib.

According to EGFR mutation status in three gefitinib trials, retrospective analyses of efficacy support the predictive role of EGFR mutations. The Iressa Pan-Asia Study (IPASS) included patients based on clinical characteristics associated with sensitivity to anti-EGFR–TKIs.64 Asian patients (n = 1,217) who were never-smokers or light smokers and who had adenocarcinoma were randomly assigned to receive first-line gefitinib or paclitaxel/carboplatin.

In the overall population, gefitinib led to significantly prolonged progression-free survival compared with chemotherapy (HR = 0.74; P < 0.001). An analysis of 437 available samples revealed EGFR mutations in 60% of this enriched population. When efficacy was analyzed by EGFR mutation status, progression-free survival was significantly prolonged with gefitinib compared with chemotherapy in patients with an EGFR mutation (HR = 0.48; P < 0.001).

Conversely, in patients with wild-type (normal) EGFR status, gefitinib led to significantly shorter progression-free survival (HR = 2.85; P < 0.001). IPASS,64 in combination with the prospective, randomized Japanese study by Maemondo et al.,60 led to the National Comprehensive Cancer Network (NCCN) recommendation to consider first-line erlotinib for patients with EGFR mutations.3

In the First-Line Single Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-smokers with Adenocarcinoma of the Lung (First-SIGNAL), first-line gefitinib was compared with gemcitabine/cisplatin in Korean NSCLC patients with adenocarcinoma who had never smoked.65 In the overall population, progression-free survival was superior with gefitinib (HR = 0.81; P = 0.04), but overall survival did not differ (HR = 1.00; P = 0.43). In 96 patients evaluated according to EGFR mutation status, HRs for gefitinib, compared with chemotherapy, were 0.61 for progression-free survival and 0.82 for overall survival in patients with the EGFR mutation. Corresponding HRs for patients with wild-type EGFR status were 1.52 for progression-free survival and 1.2 for overall survival. Overall survival results were likely affected by the high rate of post-study anti-EGFR–TKI use (81%) in the chemotherapy arm. Median overall survival times were 30.6 months in patients with EGFR mutation and 18.4 months in those with wild-type EGFR status.

In the second-line setting, a phase 3 randomized study (INTEREST) enrolled 1,466 patients with previously treated advanced NSCLC to receive gefitinib or docetaxel.21,66 The primary endpoint was overall survival. In the overall population, which was not enriched for characteristics associated with EGFR mutations, median survival was similar for gefitinib (7.6 months) and docetaxel (8 months) (HR = 1.02).

An analysis of outcomes, based on EGFR mutation status, indicated that progression-free survival and response were superior with gefitinib when compared with docetaxel. Progression-free survival was more prolonged with gefitinib than with docetaxel (HR = 0.16; P = 0.001), and response rates were better with gefitinib (42.1%) than with docetaxel (21.1%) (P = 0.04).21 However, EGFR mutation status had no little or no effect on median survival (gefitinib, 14.2 months; docetaxel, 16.6 months; P = 0.59).

Taken together, these cumulative data support a predictive role for EGFR mutations with respect to response rates and progression-free survival, especially in the first-line setting.

Wild-Type EGFR and Erlotinib Benefits

Analyses of two pivotal large randomized phase 3 trials—BR.21 and SATURN—clearly demonstrate a benefit with erlotinib therapy in patients regardless of their EGFR mutation status (Table 5).19,67 This conclusion is supported by NCCN guidelines, which recommend the use of erlotinib as second-line or third-line therapy in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3 or as maintenance therapy in the first-line setting, without the need for EGFR mutation testing.3

In the BR.21 study, erlotinib and placebo were compared in patients previously treated with NSCLC. For the entire erlotinib population, the median survival was 6.7 months, consistent with other second-line agents, pemetrexed and docetaxel, and with results from open-label studies of erlotinib in this setting.13,6871 When results from BR.21 were analyzed in the subpopulation for whom EGFR mutation status was known (n = 204 of 731; 28%), the HR for survival for erlotinib, compared with placebo, in the entire population with known EGFR mutation status was 0.64.19

In patients whose tumors were EGFR wild-type, the HR was 0.74 (P = 0.09); median overall survival time was 7.9 months with erlotinib and 3.3 months with placebo. In those with EGFR mutation, the HR was 0.55 (P = 0.12); median overall survival was 10.9 months with erlotinib and 8.3 months with placebo. The interaction between EGFR mutation status and overall survival was not statistically significant (P = 0.47). These data demonstrate that second-line erlotinib prolongs overall survival in advanced NSCLC patients regardless of their EGFR mutation status.

Patients also benefited from maintenance therapy with erlotinib in SATURN. In this phase 3 randomized trial, 1,949 untreated patients with advanced NSCLC were enrolled and received platinum doublet chemotherapy.67,72 Of these patients, 889 who did not have disease progression received maintenance erlotinib or placebo until disease progression or unacceptable toxicity. Baseline characteristics for the two arms were well balanced and were not enriched for clinical characteristics associated with an increased response to anti-EGFR–TKI therapy.

The primary endpoint, progression-free survival, was significantly prolonged with erlotinib, compared with placebo (HR = 0.71; P = 0.000003), as was overall survival (HR = 0.81; P = 0.0088).67 A prospective analysis showed that the EGFR mutation was present in 49 of 437 evaluable patients (11%).

An analysis of progression-free survival, based on EGFR status, showed a significant benefit in patients with either wild-type EGFR (HR = 0.78; P = 0.018) or EGFR mutations (HR = 0.10; P < 0.0001). The HR for overall survival was 0.77 (P = 0.02) and 0.83 (P = 0.68) for patients with EGFR mutation.72 The lower survival benefit observed in patients with EGFR mutation may reflect the small numbers involved in the analysis, the crossover to erlotinib in the control arm at the time of disease progression, and the relative immaturity of survival data at the time of the report.

An Inconclusive Role for KRAS

Several large studies have failed to show a significant predictive effect for KRAS mutation.21,22,32 In addition, smaller studies have yielded inconclusive data supporting a role for KRAS in predicting the response to treatment.19,30,73KRAS mutations in INTEREST were found in 18% of evaluable patients.21 No differences in overall survival, progression-free survival, or response rates were observed between docetaxel and gefitinib. In a comparison of gefitinib and docetaxel, the HR was 0.81 in patients with the KRAS mutation (median overall survival, gefitinib 7.8 months; docetaxel, 4.2 months) and 1.03 in patients with wild-type KRAS (median overall survival: gefitinib, 7.5 months vs. docetaxel, 6.2 months). The interaction between KRAS mutation status and treatment was not statistically significant (P = 0.51) (Table 6).

Data from prospective biomarker analyses in SATURN showed little effect of the KRAS mutation status on outcomes with erlotinib.20 HRs for progression-free survival (maintenance erlotinib versus placebo) were 0.77 in 90 patients with KRAS mutation (P = 0.22) and 0.70 in 403 patients with KRAS wild-type tumors (P = 0.0009). The test for interaction between erlotinib and KRAS mutation status was not significant (P = 0.95).

KRAS mutation was reported in 85 of 368 evaluated samples (23%) in the randomized phase 3 Bevacizumab/Tarceva (BeTa Lung) trial. This study compared second-line erlotinib plus bevacizumab with erlotinib/placebo. No significant difference in overall survival (P = 0.67) or in progression-free survival (P = 0.54) was observed in terms of KRAS mutation status.32

As previously stated, the role of KRAS in NSCLC is not well defined because studies conducted to date either have been retrospective or underpowered or have lacked a control group.19,30,73 Retrospective biomarker analysis from BR.21 identified KRAS mutations in 30 of 206 analyzed samples (15%) from 731 enrolled patients.19 HRs for survival with erlotinib versus placebo were 0.69 in patients whose tumors were KRAS wild-type (P = 0.03) and 1.67 in patients with KRAS mutation (P = 0.31) (Table 6). In patients with KRAS mutation, the overall survival time was 3.7 months with erlotinib and seven months with placebo.

These data suggest lower efficacy in patients with KRAS mutations; however, the analysis was retrospective and was extremely underpowered to show a real difference in survival between arms. Therefore, data for KRAS mutation status from this trial were inconclusive. Further, in a multivariate Cox regression model, KRAS mutation status was not a significant predictive marker for a differential survival benefit from erlotinib therapy (P = 0.13).

TRUST (Tarceva Lung Cancer Survival Treatment) a large, multinational observational cohort study, has been evaluating more than 7,000 patients with NSCLC who received erlotinib after disease progression on one to two previous chemotherapy regimens.30 In a patient subset, tissues were analyzed for biomarkers; however, the lack of a control group in this study has made it difficult to interpret the data for efficacy of anti-EGFR–TKIs.30,73

In a group of 393 German patients enrolled in TRUST and evaluated for biomarkers, KRAS mutation was present in 17 of 114 evaluable patients (15%).30 None of these patients responded to erlotinib. Progression-free survival and overall survival were shorter in duration in patients with KRAS mutation, compared with wild-type KRAS, but differences were not significant. The HR was 1.56 for progression-free survival (P = 0.094) and 1.64 for overall survival (P = 0.064). Because of the small number of patients, a definitive conclusion cannot be drawn.

In a second report from a separate subpopulation of 270 patients, 32 of 152 of patients (21%) had KRAS mutations.73 These patients also had shorter overall survival (HR = 1.59; P = 0.0313) and shorter progression-free survival (HR = 1.36; P = 0.1443) than patients whose tumors were wild-type KRAS; however, only the difference in overall survival reached statistical significance. The rate of response did not differ with KRAS mutation status (i.e., 14% in patients with KRAS mutation and 11% in patients with wild-type KRAS). In this same group, 12 of 135 patients (9%) had EGFR mutations, and the presence of KRAS and EGFR mutations were mutually exclusive.

This observation is consistent with another large series of 447 NSCLC specimens in which only four of them (0.9%) harbored both EGFR and KRAS mutations.74 In patients whose tumors were EGFR wild-type (i.e., most patients in the sample), the presence of KRAS mutation did not correlate with either overall or progression-free survival. This analysis is important because it corroborates evidence suggesting that KRAS mutation status is not consistently predictive in NSCLC patients treated with anti-EGFR–TKIs. If patients are tested for EGFR mutation, those who carry the mutation are considered candidates for anti-EGFR therapy and would not be expected to have a KRAS mutation because it is rare for both mutations to coexist.

For patients without EGFR mutation, KRAS mutation status provides no further predictive value. These results, although intriguing, must be corroborated in larger populations that include a control group.


Genetic mutations are emerging as potential biomarkers of response and treatment selection in patients with NSCLC. Since the approval of erlotinib and gefitinib, the presence of EGFR mutation has shown predictive value for response to anti-EGFR–TKIs. Even though this sequence of events is similar to the discovery that KRAS mutation predicted a lack of efficacy of anti-EGFR monoclonal antibodies in colorectal cancer, crucial clinical differences exist between KRAS status in colorectal cancer and the role of EGFR mutations in NSCLC. Although EGFR mutation is predictive for response to erlotinib, the larger NSCLC patient population whose tumors are wild-type for EGFR also derives a benefit from therapy in first-line maintenance and relapsed settings. This benefit applies to men, smokers, and those with squamous histological features, in whom the incidence of mutations is generally low.

Overall, the role of gene mutation status in the current treatment of NSCLC is far from definitive; however, we can draw several conclusions from the available data. KRAS mutation status plays different roles in NSCLC and colorectal cancer. The lack of conclusive data regarding anti-EGFR–TKI therapy in patients with KRAS mutation illustrates the biological difference between the two cancers and suggests that KRAS mutation cannot be used at this time to preclude NSCLC patients from receiving anti-EGFR–TKIs. Indeed, recent studies suggest that tobacco carcinogenesis-associated mutation of KRAS in NSCLC may contribute to molecular differences between these two cancers.27,74

Continued elucidation of the role of these biomarkers—as well as the fusion protein EML4/ALK; BRAF, PTEN, and genes that may confer sensitivity or resistance to chemotherapy, for example, excision repair cross-complementing-1 (ERCC1) and thymidylate synthase (TS)—may lead to the development of new therapies, the personalized selection of patients for treatment, and improved outcomes. Additional methods are being investigated to better predict patients who will respond to anti-EGFR therapy.

One example of a new test is VeriStrat (Biodesix), a proteomic-based biomarker analysis.75 From serum samples of 441 patients in BR.21, VeriStrat, retrospectively, identified patients with an increased likelihood of a response to erlotinib (a Veri-Strat Good result).76 Median overall survival in these patients was 10.5 months, compared with 4 months in patients with a VeriStrat Poor result.

Figure and Tables

Signaling pathway for epidermal growth factor receptor (EGFR). Akt = serine–threonine protein kinase B; Grb-2 = growth factor receptor–bound protein; K = EGFR kinase domain; MAPK = mitogen activated protein-kinase; MEK = mitogen-activated protein (MAP) kinase/Erk kinase; mTOR = mammalian target of rapamycin; P13K = phosphatidylinositol-3 kinase; PTEN = phosphatase and tensin homolog; RAF = protooncogene serine/threonine-protein kinase; RAS = rat sarcoma viral oncogene homolog; SOS = son of sevenless homolog; STAT = signal transduction and activation of transcription.

EGFR Mutations

Type Mutation Population Primarily Affected Clinical Implication For Anti-EGFR–TKI Therapy
Activating Exon 19 del Anti-EGFR–TKI-naive patients Confers sensitivity
Activating L858R Anti-EGFR–TKI-naive patients Confers sensitivity
Resistance T790M Anti-EGFR–TKI-treated patients Confers resistance
Resistance Exon 20 Anti-EGFR–TKI-naive patients Confers resistance

EGFR = epidermal growth factor receptor; Exon 19 del = deletion in exon 19; L858R = leucine-to-arginine substitution at position 858; T790M = threonine-to-methionine amino acid change at position 790; TKI = tyrosine kinase inhibitor.

Proportion of Patients With Activating EGFR Mutations and Key Characteristics in Selected Clinical Trials

Study Na Female (%) Never-Smoker (%) Adenocarcinoma (%) Asian (%) Presence of ActivatingEGFRMutation (%)
Clinically Selected Study Population
  IPASS (Mok, 200964) 437 77 93 96b 100 60
  First-SIGNAL (Lee, 200965) 96 85 100 100 100 44
  Sequist, 200877 98 70 38 91 5 35
  Rosell, 200911 2,105 39 29 78 0.5c 17
  Zhou, 201062 549 58 71 87 100 34
Non-clinically Selected Study Population
  INTEREST (Douillard, 201021) 297 31 17 57 16 15
  SATURN (Brugger, 200920) 437 25 17 46 9 11
  BR.21 (Zhu, 200819) 204 36 23 52 6 17
  Rotella, 200978 53 36 13 55 NR 17
  Chiari, 200979 128 44 34 64 NR 25
  ISEL (Hirsch, 200655) 215 36 14 50 7 12

First-SIGNAL = First-line Single Agent IressaVersus Gemcitabine and Cisplatin Trial in Never-smokers with Adenocarcinoma of the Lung; INTEREST = Iressa Non–Small-Cell Lung Cancer Trial Evaluating Response and Survival Against Taxotere; IPASS = Iressa Pan-Asia Study; ISEL = Iressa Survival Evaluation In Lung Cancer; NR = not recorded; SATURN = Sequential Tarceva in Unresectable NSCLC.

aNumber of patients evaluated for an EGFR mutation.

bFor the total study population (n = 1,217); not reported for the EGFR mutation-evaluable population.

cValue represents the proportion of Asian patients (1 of 217 patients) who received study treatment.

Activating KRAS Mutations in Large Clinical Trials Of Non–Small-Cell Lung Cancer

Study Patient No. Analyzed Rate ofKRASMutations (%)
  ECOG 4592 (Schiller, 200129) 197 24
  INTEREST (Douillard, 201021) 275 18
  BeTA Lung (Herbst, 200932) 368 18
  BMS-099 (Khambata-Ford, 201031) 202 17
  BR.21 (Zhu, 200819) 206 15
  TRUST (Schneider, 200830) 195 9
  ISEL (Hirsch, 200655) 152 8

BeTA Lung = Bevacizumab/Tarceva study; ECOG = Eastern Cooperative Oncology Group; INTEREST = Iressa Non–Small-Cell Lung Cancer Trial Evaluating Response and Survival Against Taxotere; ISEL = Iressa Survival Evaluation in Lung Cancer; KRAS = v-Ki-Ras-2 Kirsten rat sarcoma viral gene homolog; TRUST = Tarceva Lung Cancer Survival Treatment.

Outcomes in Large Clinical Trials of Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor Therapy in Patients With an EGFR Mutation

Study N* Setting Treatment Overall Response Rate,EGFRMutation Overall Response Rate,EGFRWild-Type Hazard Ratio for PFS (EGFR–TKIs vs. Chemotherapy)
EGFRMutation EGFRWild-Type
Rosell, 200911 2,105 First-line and relapsed Erlotinib 70.5% NAb NA (Median PFS = 14 mo) NA
IPASS (Mok, 200964) 437 First-line Gefitinib vs. carboplatin/paclitaxel 71.2% vs. 47.3% 1.1% vs. 23.5% 0.48 2.85
INTEREST (Douillard, 201021) 297 Relapsed Gefitinib vs. docetaxel 42.1% vs. 21.1% 6.6% vs. 9.8% 0.16 1.24
Maemondo, 201060 230 First-line Gefitinib vs. carboplatin/paclitaxel 73.7% vs. 30.7% NA 0.30 N/A
WJTOG3405 (Mitsudomi, 201061) 172 First-line Gefitinib vs. cisplatin/docetaxel 62.1% vs. 32.2% NA 0.489 N/A
OPTIMAL (Zhou, 201062) 154 First-line Erlotinib vs. carboplatin/gemcitabine 83% vs. 36% NA 0.16 N/A
First-SIGNAL (Lee, 200965) 96 First-line Gefitinib vs. gemcitabine/cisplatin 84.6% vs. 37.5% 25.9% vs. 51.9% 0.61 1.52

*Patient number was analyzed for an EGFR mutation.

Only EGFR-mutated tumors were treated.

EGFR = epidermal growth factor receptor; First-SIGNAL = First-Line Single Agent IressaVersus Gemcitabine and Cisplatin Trial in Never-smokers with Adenocarcinoma of the Lung; NA = not available; OPTIMAL = Open Label, Multicenter Phase III Study of TarcevaVersus Cisplatin plus Gemcitabine as First-Lline Treatment In Stage IIIB/IV Advanced/Metastatic Non–Small-cell Lung Cancer Patients with EGFR Activating Mutations in Exon 19 or 21; PFS = progression-free survival.

Benefits of Erlotinib in the EGFR Wild-Type Cohort: Phase 3 Randomized, Placebo-Controlled Trials Of Non–Small-Cell Lung Cancer

Study N* Setting Treatment Results forEGFRWild-Type (Erlotinib vs. Control Drug)
Hazard Ratio for Progression-Free Survival Hazard Ratio for Overall Survival
SATURN (Cappuzzo, 200967) 388 First-line maintenance Erlotinib vs. placebo 0.78 (P = 0.018) 0.77 (P = 0.02)
BR.21 (Zhu, 200819) 176 Relapsed (second-line and third-line) Erlotinib vs. placebo NR 0.74 (P = 0.09)

*Number of patients with EGFR wild-type tumors.

EGFR = epidermal growth factor receptor; NR = not reported; SATURN = Sequential Tarceva in Unresectable Non–Small-Cell Lung Cancer.

Clinical Studies Evaluating the Role of KRAS Mutation in the Treatment of Non–Small Cell Lung Cancer (NSCLC) With an Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor

Study N* Setting Treatment KRASMutation KRASWild-Type Interaction Between Status and Treatment
SATURN (Cappuzzo, 200967); Brugger, 200920) 493 First-line maintenance Erlotinib PFS HR = 0.77 (P = 0.22) PFS HR = 0.70 (P = 0.0009) P = 0.95
BeTa Lung (Herbst, 200932) 368 Relapsed Erlotinib/placebo vs. erlotinib/bevacizumab 1.23 1.08 P = 0.6699
BR.21 (Zhu, 200819) 206 Relapsed (second-line and third-line) Erlotinib vs. placebo OS HR = 1.67 (P = 0.31) OS HR = 0.69 (P = 0.03) P = 0.13
TRUST (Schneider, 200830) 114 Relapsed (second-line and third-line) Erlotinib KRAS mutation vs.
KRAS wild-type:
  • PFS HR = 1.56 (P = 0.094)
  • OS HR = 1.64 (P = 0.064)
TRUST (Pirker, 200873) 152 Relapsed (second-line and third-line) Erlotinib KRAS mutation vs.
KRAS wild-type:
  • PFS HR = 1.36 (P = 0.14)
  • OS HR = 1.59 (P = 0.03)

*Number of patients analyzed for KRAS mutation.

BeTa Lung = Bevacizumab/Tarceva study; HR = hazard ratio; KRAS = v-Ki-Ras-2 Kirsten rat sarcoma viral gene homolog; NA = not available; OS = overall survival; PFS = progression-free survival; SATURN = Sequential Tarceva in Unresectable NSCLC; TRUST = Tarceva Lung Cancer Survival Treatment.


  1. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 2004;22;(11):2184–2191.
  2. Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 2006;355;(24):2542–2550.
  3. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: Non-small cell lung cancer. Version 3. 2011;Updated January 7, 2011. Available at: Accessed April 21, 2011.
  4. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol 2008;26;(21):3543–3551.
  5. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: A review of two phase III studies. Oncologist 2009;14;(3):253–263.
  6. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non–small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 2009;374;(9699):1432–1440.
  7. Belani CP, Brodowicz T, Ciuleanu T, et al. Maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non–small cell lung cancer (NSCLC). Abstract CRA8000. J Clin Oncol 2009;27;(Suppl):18s
  8. Lievre A, Bachet J-B, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66;(8):3992–3995.
  9. Van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360;(14):1408–1417.
  10. Shankaran V, Bentrem DJ, Mulcahy MF, et al. Economic implications of Kras testing in metastatic colorectal cancer (mCRC). Abstract 298. Presented at the 2009 American Society of Clinical Oncology, Gastrointestinal Cancers SymposiumJanuary 15–17, 2009San Francisco
  11. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361;(10):958–967.
  12. UnitedHealthcare. KRAS testing. 2009;Available at: Accessed August 9, 2010.
  13. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non–small-cell lung cancer. N Eng J Med 2005;353;(2):123–132.
  14. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non–small cell lung cancer: A randomized trial. JAMA 2003;290;(16):2149–2158.
  15. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 2004;350;(21):2129–2139.
  16. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101;(36):13306–13311.
  17. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304;(5676):1497–1500.
  18. Herbst RS, Heymach JV, Lippman SM, et al. Molecular origins of cancer: Lung cancer. N Engl J Med 2008;359;(13):1367–1380.
  19. Zhu C-Q, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008;26;(26):4268–4275.
  20. Brugger W, Kim J-H, Hansen O, et al. Biomarker analyses from SATURN, a phase III placebo-controlled study of erlotinib as first-line maintenance therapy for advanced NSCLC. Abstract P-9176. Eur J Cancer 2009;7;(559, Suppl):
  21. Douillard J-Y, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non–small cell lung cancer: Data from the randomized phase III INTEREST trial. J Clin Oncol 2010;28;(5):744–752.
  22. Gazdar AF. Activating and resistance mutations of EGFR in non–small-cell lung cancer: Role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009;28;(Suppl 1):S24–31.
  23. Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12;(21):6494–6501.
  24. Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non–small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 2006;12;(19):5764–5769.
  25. Riely GJ, Marks J, Pao W. KRAS mutations in non–small cell lung cancer. Proc Am Thorac Soc 2009;6;(2):201–205.
  26. Rodenhuis S, van de Wetering ML, Mooi WJ, et al. Mutational activation of the K-ras oncogene: A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med 1987;317;(15):929–935.
  27. Mack PC, Redman MW, Chansky K, et al. KRAS and EGFR mutations in the molecular epidemiology of NSCLC: Interim analysis of S0424. Abstract 7013. J Clin Oncol 2010;28;(Suppl):
  28. Lea IA, Jackson MA, Li X, et al. Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns. Carcinogenesis 2007;28;(9):1851–1858.
  29. Schiller JH, Adak S, Feins RH, et al. Lack of prognostic significance of p53 and K-ras mutations in primary resected non–small-cell lung cancer on E4592: A laboratory ancillary study on an Eastern Cooperative Oncology Group prospective randomized trial of postoperative adjuvant therapy. J Clin Oncol 2001;19;(2):448–457.
  30. Schneider CP, Heigener D, Schott-von-Romer K, et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non–small cell lung cancer: An analysis of patients from German centers in the TRUST study. J Thorac Oncol 2008;3;(12):1446–1453.
  31. Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non–small-cell lung cancer. J Clin Oncol 2010;28;(6):918–927.
  32. Herbst RS, Stern H, Amler L, et al. Biomarker evaluation in the phase III, placebo-controlled, randomized BeTa trial of bevacizumab and erlotinib for patients with advanced non–small cell lung cancer (NSCLC) after failure of standard 1st-line chemotherapy: Correlation with treatment outcomes. Abstract LB-131. Presented at the 100th annual meeting of the American Association for Cancer ResearchApril 18–22, 2009Denver, Colo
  33. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: Results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 2010;28;(3):466–474.
  34. Ogino S, Meyerhardt JA, Irahara N, et al. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res 2009;15;(23):7322–7329.
  35. Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: Results from the MRC FOCUS trial. J Clin Oncol 2009;27;(35):5931–5937.
  36. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360;(6):563–572.
  37. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27;(5):663–671.
  38. Lievre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26;(3):374–379.
  39. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: Colon cancer. Version 3. 2011;updated February 25, 2011. Available at: Accessed April 21, 2011.
  40. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non–small-cell lung cancer. Nature 2007;448;(7153):561–566.
  41. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 2008;3;(1):13–17.
  42. Shinmura K, Kageyama S, Tao H, et al. EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non–small cell lung carcinomas. Lung Cancer 2008;61;(2):163–169.
  43. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008;14;(13):4275–4283.
  44. Wong DW, Leung EL, So KK, et al. The EML4–ALK fusion gene is involved in various histologic types of lung cancers from non-smokers with wild-type EGFR and KRAS. Cancer 2009;115;(8):1723–1733.
  45. Takahashi T, Sonobe M, Kobayashi M, et al. Clinicopathologic features of non–small-cell lung cancer with EML4-ALK fusion gene. Ann Surg Oncol 2010;17;(3):889–897.
  46. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27;(26):4247–4253.
  47. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK rearranged lung adenocarcinoma in the Western population. Clin Cancer Res 2009;15;(16):5216–5223.
  48. Bokemeyer C, Kohne C, Rougier P, et al. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. Abstract 3506. J Clin Oncol 2010;28;(Suppl):
  49. Tol J, Dijkstra JR, Vink-Börger ME, et al. BRAF mutation is associated with a decreased outcome in patients (pts) with advanced colorectal cancer (ACC) treated with chemotherapy and bevacizumab with or without cetuximab. Abstract O-6002. Eur J Cancer 2009;7;(321, Suppl):
  50. Saridaki Z, Tzardi M, Papadatos-Patsos D, et al. Prognostic and predictive significance of BRAF mutation in patients with metastatic colorectal cancer treated with 5-fluorouracil-based 1st line chemotherapy Abstract PD-1016. Eur J Cancer 2009;7;(91, Suppl):
  51. Salvatore L, Loupakis F, Fontanini G, et al. KRAS and BRAF mutational analyses in a phase II trial of first-line FOLFOXIRI plus bevacizumab (BV) in metastatic colorectal cancer (mCRC) patients (pts). Abstract P-6060. Eur J Cancer 2009;7;(339, Suppl):
  52. Farina A, Moerland E, van Lijnschoten G, et al. K-ras and Braf mutation analysis has clinical value in stage III colon carcinoma. Abstract P-6114. Eur J Cancer 2009;7;(357, Suppl):
  53. Ueda M, Toji E, Nunobiki O, et al. Mutational analysis of the BRAF gene in human tumor cells. Hum Cell 2008;21;(2):13–17.
  54. Marks JL, McLellan MD, Zakowski MF, et al. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4. PLoS One 2007;2;(5):e426
  55. Hirsch FR, Varella-Garcia M, BunnPAJret al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non–small-cell lung cancer. J Clin Oncol 2006;24;(31):5034–5042.
  56. Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002;62;(23):6997–7000.
  57. Van Cutsem E, Lang I, Folprecht T, et al. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. Abstract 3570. J Clin Oncol 2010;28;(Suppl):
  58. Sequist LV, Bell DW, Lynch TJ, et al. Molecular predictors of response to epidermal growth factor receptor antagonists in non–small-cell lung cancer. J Clin Oncol 2007;25;(5):587–595.
  59. Paz-Ares L, Souliéres D, Melezínek I, et al. Clinical outcome in non–small-cell lung cancer patients with EGFR mutations: Pooled analysis. J Cell Mol Med 2010;14;(1–2):51–69.
  60. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362;(25):2380–2388.
  61. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non–small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11;(2):121–128.
  62. Zhou C, Wu Y-L, Chen GY, et al. Efficacy results from the randomised phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM), in Chinese advanced non–small-cell lung cancer (NSCLC) patients (pts) with EGFR activating mutations. Abstract LBA13. Presented at the European Society for Medical OncologyOctober 8–12, 2010Milan, Italy
  63. National Institutes of Health. Phase III study (Tarceva®) vs. chemotherapy to treat advanced non–small-cell lung cancer (NSCLC) in patients with mutations in the TK domain of EGFR. NCT00446225. Available at: Accessed July 21, 2010.
  64. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361;(10):947–957.
  65. Lee JS, Park K, Kim SW, et al. A randomized phase III study of gefitinib (IRESSA) versus standard chemotherapy (gemcitabine plus cisplatin) as first-line treatment for never-smokers with advanced or metastatic adenocarcinoma of the lung. Abstract PRS.4. Presented at the 13th World Conference on Lung CancerJuly 31–August 4, 2009San Francisco
  66. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non–small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008;372;(9652):1809–1818.
  67. Cappuzzo F, Coudert BP, Wierzbicki R, et al. Efficacy and safety of erlotinib as first-line maintenance in NSCLC following non-progression with chemotherapy: Results from the phase III SATURN study. Abstract 2.1. Presented at the 13th World Conference on Lung CancerJuly 31–August 4, 2009San Francisco
  68. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non–small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18;(10):2095–2103.
  69. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22;(9):1589–1597.
  70. Spigel DR, Lin M, O’Neill V, et al. Final survival and safety results from a multicenter, open-label, phase 3b trial of erlotinib in patients with advanced non–small cell lung cancer. Cancer 2008;112;(12):2749–2755.
  71. Groen H, Arrieta OG, Riska H, et al. The global TRUST study of erlotinib in advanced non–small-cell lung cancer (NSCLC). Abstract 19000, ASCO meeting, May 20, 2008. J Clin Oncol 2008;26;(Suppl):
  72. Cappuzzo F, Coudert B, Wierzbicki R, et al. Overall survival analyses from the SATURN phase III placebo-controlled study of erlotinib as first-line maintenance therapy in advanced non–small-cell lung cancer (NSCLC). Abstract 22LBA. Eur J Cancer 2009;7;(12, Suppl):
  73. Pirker R, Su W-C, Rooneem R, et al. Clinical outcomes with erlotinib in relation to biomarker status: Analyses from the open-label TRUST study in advanced non–small-cell lung cancer (NSCLC). Abstract 265P. Presented at the European Society for Medical OncologySeptember 12–16, 2008Stockholm
  74. Danenberg KD, Grimminger PP, Mack PC, et al. KRAS mutations (MTs) in non–small cell lung cancer (NSCLC) versus colorectal cancer (CRC): Implications for cetuximab therapy. Abstract 10529. J Clin Oncol 2010;28:
  75. VeriStrat. Available at: Accessed August 18, 2010.
  76. Carbone P, Seymour L, Ding K, et al. Serum proteomic prediction of outcomes in advanced NSCLC patients treated with erlotinib/placebo in the NCIC clinical trials group BR.21 trial. Abstract 2030. J Thorac Oncol 2010;5;(5, Suppl 1):
  77. Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non–small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26;(15):2442–2449.
  78. Rotella V, Mazzoni F, Pratesi N, et al. Erlotinib as a second-line therapy in advanced non–small cell lung cancer: correlation between clinical characteristics and biomarkers. Abstract P-9136. Eur J Cancer 2009;7;(Suppl 2):
  79. Chiari R, Ludovini V, Bianconi F, et al. EGFR, KRAS, PIK3CA mutations and response to tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients. Abstract P-9162. Eur J Cancer 2009;7;(Suppl 2):