Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva) and gefitinib (Iressa), have shown remarkable activity in a portion of patients with non–small-cell lung cancer (NSCLC).
Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva) and gefitinib (Iressa), have shown remarkable activity in a portion of patients with non–small-cell lung cancer (NSCLC). Based on a large randomized controlled trial showing a survival benefit compared with placebo, erlotinib gained US Food and Drug Administration approval for use in previously treated patients with NSCLC. However, its use in the firstline setting has been largely experimental. Recently, a large phase III randomized controlled trial demonstrated the superiority of first-line gefitinib therapy compared to combination chemotherapy in a clinically selected population consisting of Asian patients with adenocarcinoma and a light smoking history. This result was even more dramatic in the subset of patients whose tumors carried a mutation in the EGFR gene. Currently, randomized phase III trials of erlotinib as initial treatment of patients with EGFR mutant lung cancer are ongoing. In the setting of these recent developments, a review of the data regarding the use of erlotinib or gefitinib as initial therapy in the treatment of NSCLC is warranted. Currently active trials are referenced using their ClinicalTrials.gov identifier.
The development of tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) has revolutionized the care of patients with non–small-cell lung cancer (NSCLC). In 2004, erlotinib (Tarceva) received US Food and Drug Administration (FDA) approval for the treatment of previously treated NSCLC. Gefitinib (Iressa) was initially approved to treat NSCLC in May 2003, but in June 2005, the FDA approved new labeling that limited the approval, ie, only for patients who are currently benefiting (or have previously benefited) from this agent. Outside the United States, both drugs are used widely.
EGFR is a member of the HER/ErbB family of membrane-bound receptors, and it plays a role in signal transduction of extracellular ligands including transforming growth factor alpha (TGF-Î±), amphiregulin, and epidermal growth factor (EGF).1 EGFR is overexpressed in numerous epithelial and neuroectodermal malignancies, a finding that initially motivated the exploration of EGFR as a novel therapeutic target. Erlotinib (formerly named OSI-774) and gefitinib (formerly named ZD1839) are small molecules that were designed to selectively inhibit the phosphorylation of the EGFR intracellular kinase domain. Phase I studies identified diarrhea and rash as dose-limiting toxicities with once daily oral dosing, and occasional dramatic responses were observed in some patients.2,3
Initial phase II experience with gefitinib and erlotinib in previously treated patients with advanced NSCLC demonstrated promising antitumor activity with response rates of 12% to 19%.4-6 Gefitinib initially gained preliminary FDA approval in previously treated patients based on the phase II Iressa Dose Evaluation in Advanced Lung Cancer 2 (IDEAL-2) trial, demonstrating symptomatic improvement in 43% of patients receiving 250 mg daily, with a response rate of 12%.5 Erlotinib was then FDA approved in previously treated patients, based on the phase III randomized placebo-controlled BR.21 trial, demonstrating an overall survival advantage in the erlotinib arm (6.7 vs 4.7 months) with a response rate of 8%.7 However, the postapproval phase III placebo-controlled study of gefitinib, the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, was a negative study showing only a small difference in overall survival between the experimental arm and placebo (5.6 vs 5.1 months, P = .087).8 Interestingly, the BR.21 study showed a statistically significant association between response rate and four clinical factors: Asian race, adenocarcinoma histology, negative smoking history, and female gender. The association of these factors with antitumor activity was similarly found in several studies of gefitinib,5,8 which also noted particular activity against adenocarcinomas of the bronchioloalveolar carcinoma (BAC) subtype.9
An important feature of initial studies of erlotinib efficacy was that while the overall response rate was low, patients who did respond often had dramatic, rapid, and sustained improvement in their tumor burden.10 Several groups performed analyses of tumor samples from patients demonstrating sensitivity to erlotinib and gefitinib, with nucleotide sequencing of their target, EGFR. These tumors were found to commonly carry mutations in the tyrosine kinase domain of the EGFR gene, which were absent in tumors resistant to these agents11-13-a finding analogous to the presence of KIT mutations in imatinib (Gleevec)-sensitive gastrointestinal stromal tumors. Furthermore, these EGFR mutations were found to be more prevalent in patients with the clinical features associated with TKI sensitivity: Asian race, adenocarcinoma histology, negative smoking history, and female gender. The importance of mutations in the EGFR gene is further highlighted by the finding of highly prevalent acquired mutations in EGFR exon 20 in tumors that have developed resistance to EGFR TKIs.14,15
Given the efficacy of EGFR TKI therapy in previously treated patients, many groups have explored the use of erlotinib and gefitinib in the firstline setting. In the ensuing sections, we will discuss the first-line phase II experience with these agents in three different groups: patients unselected for TKI sensitivity, patients clinically selected for TKI sensitivity, and patients molecularly selected for TKI sensitivity. We will then discuss the recent randomized phase III experience. A summary of these studies can be found in Table 1.
Selected Studies Reporting Activity of First-Line Erlotinib and Gefitinib in NSCLC
Initial trials of first-line EGFR TKI therapy in unselected patients demonstrated modest efficacy at best. A phase II trial of erlotinib by Giaccone et al in 58 patients showed a response rate of 23%, though with a median progression-free survival of only 2.8 months.16 This study found that response was significantly associated with histology and smoking status, and noted that 4 of 7 patients with EGFR mutations responded. But another early phase II trial showed a much lower response rate of 5% in unselected patients treated with gefitinib,17 and a more recent trial has shown a borderline response rate of 15%, with responses noted in 3 of 4 patients with EGFR mutations.18
The relatively mild toxicity profile of EGFR TKI therapy has led to interest in using these agents as first-line therapy in patients who are elderly or have a poor performance status (PS). Two single-arm phase II studies of erlotinib, one in patients aged 70 and older and one in patients with a PS of 2, demonstrated response rates of 8% and 10%, respectively.19,20 The former study found a response rate of only 33% in 9 patients with EGFR mutations, though these patients did have a prolonged median progressionfree survival (> 15 months).
Two other phase II studies have evaluated first-line TKIs randomized against chemotherapy as a control. In the Iressa in NSCLC Versus Vinorelbine Investigation in the Elderly (INVITE) trial,21 untreated elderly patients (aged 70 years or older) were randomized to gefitinib vs vinorelbine, and the treatments were found to be statistically similar, with a response rate of only 3% for gefitinib. Lilenbaum et al compared erlotinib to combination carboplatin and paclitaxel in 52 patients with a PS of 2 and found a 4% response rate for erlotinib, with better survival in the chemotherapy arm (9.5 vs 6.6 months).22EGFR mutation status was available for 21 of these patients, with 5 testing positive, but all were in the chemotherapy arm. In summary, the available data indicate that conventional chemotherapy remains the preferred initial therapy for unselected patients, even those with a borderline PS.
A potential role for EGFR TKIs in unselected patients unfit for chemotherapy is currently being studied in a randomized phase II trial of first-line erlotinib vs placebo in this population (Tarceva or Placebo in Clinically Advanced Non Small Cell Lung Cancer, or TOPICAL; ClinicalTrials.gov identifier NCT00275132).
In the setting of the previously described data demonstrating that erlotinib sensitivity was correlated with specific clinical characteristics, much of the phase II experience with first-line EGFR TKIs comes from studies looking at various clinically selected subpopulations of patients. Two first-line phase II studies performed in Asia provide an opportunity to assess TKI activity in this inherently enriched population. A Japanese study of gefitinib in 40 patients led to a 30% response rate,23 whereas a more recent Taiwanese study of gefitinib in 106 patients showed an impressive response rate of 51%.24 It is worth noting that in this latter study, 43 of 90 patients tested were found to have gefitinib-sensitive EGFR mutations, with a response rate of 84% in this subgroup. An additional Japanese study by Ebi et al looked at gefitinib in elderly patients, 25 similar to the studies described in the prior section. In 49 Asian patients aged 75 or older, the investigators found a 25% response rate with a median survival of 10 months, which is more encouraging than the results found in unselected elderly populations.
The finding of TKI activity in adenocarcinomas with BAC features has led to several studies focusing on this historically difficult-to-treat subtype of lung cancer. Miller et al evaluated erlotinib in 101 patients, the majority of whom had adenocarcinoma with BAC features (n = 89) rather than pure BAC (n = 12).26 The response rate in 75 patients who were previously untreated was 21%, with a 17-month median overall survival. Two other studies have looked at first-line gefitinib in BAC type adenocarcinoma27,28 and have found slightly lower response rates of 13% and 17%, with median survival times of approximately 13 months. Interestingly, one of those studies showed that nonmucinous BAC histology had greater sensitivity to gefitinib than mucinous BAC histology, with a response rate of 30% in the former group and only 8% in the latter group.28 Notably, mucinous BAC is commonly characterized by the presence of a KRAS mutation-a negative predictive factor for response to EGFR TKIs.29,30
Several first-line studies have tried to select for a population with maximal sensitivity to TKI by requiring that eligible patients have three of the four clinical features associated with response, leading to modest improvements in response rate. A Korean study evaluated gefitinib in 55 Asian patients who were "never-smokers" with adenocarcinoma histology, resulting in a response rate of 33% and a median overall survival of 20 months.31 Jackman et al performed a similar study with erlotinib in the United States, enrolling female patients with adenocarcinoma who were never-smokers or former smokers; a similar response rate of 30% was demonstrated.32 However, in a subset of 33 patients harboring EGFR mutations, the response rate was much higher at 70%.
Considering the subgroup analyses of several early studies showing an association between TKI sensitivity and molecular markers of EGFR oncogene addiction, a number of phase II studies have specifically looked at molecularly selected populations. While one of the early phase II studies of erlotinib was restricted to patients staining for EGFR by immunohistochemistry (IHC),4 this specific subgroup has not been studied in a first-line phase II trial. Nevertheless, several first-line studies screening for EGFR fluorescence in situ hybridization (FISH) or EGFR mutations will be discussed below.
In the ONCOBELL trial of gefitinib in advanced NSCLC, 42 patients were accrued based on EGFR FISH and staining for phospho-Akt (P-Akt).33 Smokers were eligible only if both markers were positive, whereas neversmokers were eligible if either marker was positive or if no tissue was available for analysis. Response rate was 50% in the 16 patients who were previously untreated. In the whole study population, response rate was 57% in 23 patients positive for EGFR IHC, 68% in 25 patients positive for EGFR FISH, and 71% in 21 patients with TKI-sensitizing EGFR mutations.
A number of phase II studies have enrolled only patients with a documented EGFR mutation. Two Japanese studies each treated 16 patients with mutations in the EGFR gene with first-line gefitinib,34,35 and both reported a response rate of 75% with comparable progression-free survival results (8.9 and 9.7 months). Sequist et al performed a similar study in the United States, evaluating gefitinib in 31 patients with non–squamous cell carcinoma harboring EGFR mutations, and found a response rate of 55%.36 The lower response rate may have been due to the inclusion of five patients with exon 20 mutations, which have been associated with TKI resistance.14,15
The largest study to date treating only patients with EGFR mutations was recently published,37 nested within a large multicenter Spanish program screening for EGFR mutations in 2,105 lung cancer patients. EGFR mutations were found in 350 patients (16.6%), and 217 of these went on to enroll in a phase II trial of erlotinib. In the 113 patients with no prior systemic therapy, the response rate to erlotinib was 74%, with a median progression-free survival of 14 months and an impressive median overall survival of 28 months. Interestingly, this study found an equivalent progression-free survival (13 months, P = .62) and overall survival (27 months, P = .67) in patients who had received prior chemotherapy.
Lastly, a unique study in Japan evaluated first-line gefitinib in patients with EGFR mutations who were ineligible for chemotherapy due to poor PS.38 Eligible patients were required to meet molecular criteria (a sensitizing mutation in EGFR exon 19 or 21) as well as clinical criteria for poor PS (PS ≥ 3 if age < 75, PS ≥ 2 if age 75–79, or PS ≥ 1 if age ≥ 80). Of 549 patients evaluated for these criteria, 29 went on to receive gefitinib, and 22 of these were PS 3 or 4. The response rate was 66% and median overall survival was 17.8 months, compared to a median overall survival of 3.5 months in 31 patients who were clinically eligible but found to be EGFR wild-type during screening. Remarkably, 68% of patients had an improvement of PS from 3–4 to 0–1, a phenomenon described as a "Lazarus response,"39 with five patients going on to receive second-line therapy. Clearly, these results suggest that poor PS may not be a barrier to TKI therapy in patients with EGFR mutations, and the use of these targeted agents in this setting can have an important impact on quality of life and survival.
The above sections have described the activity of erlotinib and gefitinib in the first-line setting in three types of patient populations. As detailed in Table 1, response rate to these agents appears to be improved by selecting for clinical features of TKI sensitivity, and response rate is further improved to approximately 70% when treating patients with EGFR-activating mutations, with evidence of prolonged progression-free survival. Therefore the recently published Iressa Pan-Asia Study (IPASS) was designed to evaluate, in a randomized fashion, whether this improvement in response rate in a clinically selected population leads to a corresponding improvement in progression-free survival compared to conventional therapy.40
IPASS was a phase III randomized controlled trial evaluating first-line therapy with TKI vs combination chemotherapy, with a primary endpoint of progression-free survival. The study was performed in multiple Asian countries (99.8% of patients were Asian), enrolling 1,217 patients with adenocarcinoma of the lung who were either never-smokers (< 100 lifetime cigarettes) or former lightsmokers (≤ 10 pack-years and quit ≥15 years ago) and who had not received prior systemic therapy. Patients were randomized to daily gefitinib or combination carboplatin/paclitaxel (up to six cycles). The study met its primary objective, showing the superiority of gefitinib over chemotherapy for progression-free survival, with a logistic regression analysis demonstrating a hazard ratio (HR) of 0.74 (P < .001). Median progression-free survival was similar in the two arms (5.7 months for gefitinib, 5.8 months for chemotherapy); however, the curves crossed midway, and the 12-month rate of progression-free survival was clearly higher in the gefitinib arm (25% vs 7%). Overall response rate was 43% in the gefitinib arm and 32% in the chemotherapy arm, with preliminary overall survival similar in the two arms of the study at the time of analysis.
Kaplan-Meier Curves for PFS From IPASS Trial
A total of 1,038 patients from the study (85%) additionally consented to a preplanned biomarker analysis, which provides important context to the clinical outcomes. EGFR mutation analysis was available for 437 of these patients, with 60% of these tumors being positive for an EGFR mutation. EGFR mutation status was found to be highly predictive of response to gefitinib. The response rate was 71% in EGFR mutant cases with a median progression-free survival of approximately 10 months, vs a 1% response rate and a progression-free survival of less than 2 months in EGFR wildtype cases. Additionally, however, EGFR mutation status was predictive of response to chemotherapy, with a response rate of 47% in EGFR mutants and 24% in EGFR wild-types. Kaplan-Meier curves show a significant progression-free survival benefit for gefitinib in EGFR mutant patients, but a progression-free survival benefit for chemotherapy in EGFR wild-type patients (Figure 1).
Interpretation of survival results from this study is limited by our lack of information regarding treatment after progression of disease. Crossover was allowed, which means that EGFR mutant patients progressing on chemotherapy could be started on gefitinib or erlotinib, and thus could benefit significantly despite the shorter progression-free survival on chemotherapy. But considering the progression-free survival advantage, easy oral dosing, and mild toxicity profile, it would be appropriate based on these results to treat EGFR mutant lung cancer with first-line TKI, rather than with standard combination chemotherapy.
The ongoing European Randomized Trial of Tarceva vs Chemotherapy (EURTAC) will provide an opportunity to confirm the IPASS results in a molecularly selected Western population, randomizing patients with EGFR mutant lung cancer to first-line erlotinib vs first-line combination chemotherapy, with a primary endpoint of progression-free survival (NCT00446225).
EGFR Biomarker Analysis From IPASS Study
While recent studies have explored several tissue biomarkers associated with response to TKI, the results from the IPASS study have solidified the importance of EGFR mutations as the most important predictive biomarker for TKI sensitivity. A comparative biomarker analysis of the IPASS results was presented at the 2009 annual meeting of the American Society of Clinical Oncology,41 looking separately at EGFR mutation, EGFR FISH, and EGFR expression by IHC. The authors compared progressionfree survival on gefitinib to progression-free survival on chemotherapy in patients with and without each biomarker (Table 2). EGFR mutation strongly predicted a lower risk of progression on gefitinib rather than chemotherapy, with a hazard ratio of 0.48, while EGFR wild-type patients had a higher risk of progression on gefitinib (HR = 2.85).
EGFR FISH was also found to be predictive of disease progression, but with more modest HRs (0.66 and 1.24). However, a post hoc analysis of the FISH-positive population showed that the benefit was restricted to patients with EGFR mutations; those who were FISH-positive but EGFR wild-type had a median progressionfree survival of only 2 months and clearly did better with chemotherapy. EGFR expression by IHC did not demonstrate statistically significant predictive ability. Importantly, the IPASS data also show the challenge of trying to select EGFR mutant patients using only clinical features, because across multiple subgroups the prevalence of EGFR mutations peaked at 60% to 70%.
A separate analysis of 223 patients receiving first-line TKI therapy,42 compiled from five different phase II trials, compared the predictive ability of EGFR mutation status against the predictive ability of clinical factors. The authors found that the molecular biomarker was consistently more predictive of benefit from TKI therapy than clinical features.
Considering these data, implementation of EGFR testing in clinical practice becomes extremely important. A multi-institutional Spanish study discussed above has demonstrated the feasibility of screening for EGFR mutations in unselected patients,37 successfully screening 2,105 patients with lung cancer and finding EGFR mutations in 16.6%. It is not clear, however, how many additional patients were evaluated for EGFR mutation screening but could not have the testing done because inadequate tissue was obtained for analysis. While mutations were more common in tumors with adenocarcinoma histology, they were also found in 11% of patients with large cell carcinoma histology. No patients with squamous cell histology were screened, which is concordant with our practice of screening for EGFR mutations only in patients with non–squamous cell histology.
Understanding different EGFR mutation types is important when evaluating test results to determine whether a patient is suitable for first-line erlotinib therapy. The most common EGFR mutations are deletions in exon 19 (consisting of a loss of 9–24 base pairs), and point mutations in exon 21 (L858R, L861Q). Patients with exon 19 deletions have a median progression-free survival of 14.6 months on first-line TKI therapy, whereas patients with the L858R mutation have a median progression-free survival of 9.7 months.42 Mutations in exon 20, however, have been associated with resistance to TKI therapy,14,15 though it is not clear whether these mutations are necessarily predictive of resistance to TKI therapy when found in untreated patient specimens. Rare mutations in the EGFR gene include exon 18 point mutations and exon 19 insertions, which have been less well studied. Testing for EGFR mutations is done using many different methodologies, the details of which are outside the scope of this review but have been reviewed recently in Clinical Cancer Research.43
The significance of a negative test for an EGFR mutation is highly dependent upon the tissue studied as well as the type of test performed. Analysis of tissues of uncertain quality, including fluid cytology, decalcified bone biopsies, and frozen specimens, can lead to a higher false-negative rate. Additionally, different testing methods have different false-negative rates; some tests use mutation-specific primers and therefore can miss rare mutations (eg, L861Q or exon 18 mutations), while other tests can falsely call a tumor "wild-type" if the EGFR mutant DNA is present in small quantities due to a large amount of stromal tissue.43
When high-quality testing has been performed in clinical trials, the response rate to TKI therapy in patients with EGFR wild-type tumors has been very low (eg, only 1% in IPASS).40,42 Furthermore, in patients found to have mutations in the KRAS gene, response rates to EGFR TKIs have been consistently low,30,44 suggesting that these cancers (which are more common in smokers) represent a biologically distinct population of lung adenocarcinoma patients.
We would recommend against treatment with first-line erlotinib in patients without documented EGFR-activating mutations. In the secondline setting we might consider erlotinib in patients who are EGFR and KRAS wild-type, especially if a false-negative test is suspected, understanding that these patients are likely to have a low chance of response but might still garner clinical benefit.
Preliminary evidence has suggested that patients sensitive to EGFR TKIs can have an acceleration of their tumor growth if TKI therapy is discontinued, even after progression on TKI therapy or the development of "acquired resistance." This phenomenon was studied by Riely et al in an imaging analysis of patients with acquired resistance to TKI therapy.45 After progression on single-agent TKI, 10 patients underwent positron-emission tomography and computed tomography imaging- first before stopping the drug, then again 3 weeks after stopping the drug, then a third time 3 weeks after restarting the drug. Three weeks after stopping the drug, tumors demonstrated a median 18% increase in standardized uptake value (SUV) and 9% increase in tumor volume, while after restarting the drug, a median 4% decrease in SUV and 1% decrease in volume were found. In addition, preclinical studies of cell lines with acquired resistance have shown that discontinuation of TKI therapy leads to regrowth of a population of cells that are sensitive to TKIs.46
Considering these data and our biologic understanding of the oncogene addiction of EGFR mutant lung cancer, our practice is to continue erlotinib therapy in patients with EGFR mutant lung cancer after acquired resistance, in addition to any subsequent chemotherapy. This question is currently being studied in a randomized trial of pemetrexed (Alimta) with or without erlotinib in patients who previously responded to erlotinib therapy (NCT00660816).
The combination of chemotherapy and TKI therapy has been studied extensively in unselected patients with previously untreated advanced NSCLC. Four phase III, randomized, placebo-controlled trials evaluated the addition of erlotinib or gefitinib to combination chemotherapy,47-50 each failing to demonstrate a survival benefit. However, the Tarceva Responses in Conjunction with Carboplatin and Paclitaxel (TRIBUTE) study did show an improved survival in never-smokers with the addition of erlotinib (22.5 vs 10.1 months, P = .01),47 leading to the current Cancer and Leukemia Group B (CALGB) 30406 study randomizing never-smokers to erlotinib alone or with combination chemotherapy (NCT00126581). Planned subgroup analysis will evaluate whether the combination of chemotherapy and TKI leads to longer progression-free survival in EGFR mutant cancers.
Given the results of the IPASS trial, treatment with erlotinib or gefitinib (where available) is appropriate in untreated patients with NSCLC who test positive for a TKI-sensitizing EGFR mutation. While first-line TKI therapy leads to superior progressionfree survival compared to combination chemotherapy in patients who are Asian with adenocarcinoma and a light smoking history, only testing for EGFR mutations can accurately differentiate which of these patients will benefit from TKI therapy rather than chemotherapy. Routine screening for EGFR mutations in patients with adenocarcinoma of the lung, regardless of clinical characteristics, is feasible and appropriate.
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Financial Disclosure: Dr. Miller has received honoraria for consulting from Genentech and Roche.
Address all correspondence to:
Vincent A. Miller, MD
Department of Medicine
Thoracic Oncology Service
Memorial Sloan-Kettering Cancer Center
1275 York Ave
New York, NY 10021