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Roles of EGFR and KRAS Mutations in the Treatment Of Patients With Non–Small-Cell Lung Cancer
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.1–3 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.8–10
Molecular subtypes of NSCLC are now being elucidated (
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.15–17 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 (
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 21.15–17 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 (
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 (
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.25–28 The incidence of mutation in patients with NSCLC ranges from 8% to 24% in clinical trials (
The EML4-ALK fusion gene is formed by an inversion within chromosome 2p and occurs in 2% to 5% of NSCLC patients.40–45 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.41,43–47 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%).48–56 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.
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) (
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
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 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 (
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.13,68–71 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) (
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
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) (
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).
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
|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
| IPASS (Mok, 2009
| First-SIGNAL (Lee, 2009
| Sequist, 2008
| Rosell, 2009
| Zhou, 2010
| INTEREST (Douillard, 2010
| SATURN (Brugger, 2009
| BR.21 (Zhu, 2008
| Rotella, 2009
| Chiari, 2009
| ISEL (Hirsch, 2006
aNumber of patients evaluated for an
bFor the total study population (n = 1,217); not reported for the
cValue represents the proportion of Asian patients (1 of 217 patients) who received study treatment.
| ECOG 4592 (Schiller, 2001
| INTEREST (Douillard, 2010
| BeTA Lung (Herbst, 2009
| BMS-099 (Khambata-Ford, 2010
| BR.21 (Zhu, 2008
| TRUST (Schneider, 2008
| ISEL (Hirsch, 2006
BeTA Lung =
Outcomes in Large Clinical Trials of Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor Therapy in Patients With an
||2,105||First-line and relapsed||Erlotinib||70.5%||NAb||NA (Median PFS = 14 mo)||NA|
|IPASS (Mok, 2009
||437||First-line||Gefitinib vs. carboplatin/paclitaxel||71.2% vs. 47.3%||1.1% vs. 23.5%||0.48||2.85|
|INTEREST (Douillard, 2010
||297||Relapsed||Gefitinib vs. docetaxel||42.1% vs. 21.1%||6.6% vs. 9.8%||0.16||1.24|
||230||First-line||Gefitinib vs. carboplatin/paclitaxel||73.7% vs. 30.7%||NA||0.30||N/A|
|WJTOG3405 (Mitsudomi, 2010
||172||First-line||Gefitinib vs. cisplatin/docetaxel||62.1% vs. 32.2%||NA
|OPTIMAL (Zhou, 2010
||154||First-line||Erlotinib vs. carboplatin/gemcitabine||83% vs. 36%||NA
|First-SIGNAL (Lee, 2009
||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
Benefits of Erlotinib in the
|SATURN (Cappuzzo, 2009
||388||First-line maintenance||Erlotinib vs. placebo||0.78 (
|BR.21 (Zhu, 2008
||176||Relapsed (second-line and third-line)||Erlotinib vs. placebo||NR||0.74 (|
*Number of patients with
Clinical Studies Evaluating the Role of
|SATURN (Cappuzzo, 2009
||493||First-line maintenance||Erlotinib||PFS HR = 0.77 (
||PFS HR = 0.70 (
|BeTa Lung (Herbst, 2009
||368||Relapsed||Erlotinib/placebo vs. erlotinib/bevacizumab||1.23||1.08|
|BR.21 (Zhu, 2008
||206||Relapsed (second-line and third-line)||Erlotinib vs. placebo||OS HR = 1.67 (
||OS HR = 0.69 (
|TRUST (Schneider, 2008
||114||Relapsed (second-line and third-line)||Erlotinib||
|TRUST (Pirker, 2008
||152||Relapsed (second-line and third-line)||Erlotinib||
*Number of patients analyzed for
BeTa Lung =
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