|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 587-595 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.3585
Molecular Predictors of Response to Epidermal Growth Factor Receptor Antagonists in Non–Small-Cell Lung Cancer
From the Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA Address reprint requests to Daniel Haber, MD, PhD, MGH Cancer Center, CNY-7, Building 149, 13th St, Charlestown, MA 02129; e-mail: Haber{at}helix.mgh.harvard.edu
In the last 5 years the epidermal growth factor receptor (EGFR) has emerged as one of the most important targets for drug development in oncology. Monoclonal antibodies targeting the external domain of EGFR have been shown to have clinical benefit in colorectal and head and neck cancer when combined with chemotherapy and/or radiation. Small molecules that inhibit the tyrosine kinase (TK) domain of EGFR have become critical new weapons in the treatment of non–small-cell lung cancer (NSCLC). The discovery that mutations in the TK domain are associated with dramatic and sustained responses to EGFR TK inhibitors (TKIs) has allowed the design of trials to test these agents as potential first-line therapies and has provided a fascinating window into the future of genotype-directed targeted therapy. Recent advances in understanding the biologic basis of acquired resistance to these agents have great potential to improve the clinical effectiveness of this class of drugs. This review summarizes the biology of EGFR in NSCLC, the clinical and molecular predictors of benefit from treatment with EGFR TKIs, the use of patient-specific molecular profiling, and future directions of clinical and basic scientific research.
The success of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of chronic myelogenous leukemia has paved the way for similar approaches in common epithelial cancers.1 However, targeting the epithelial growth factor receptor (EGFR) kinase domain using the closely related inhibitors gefitinib and erlotinib has generally been ineffective against solid tumors, many of which overexpress the receptor. A subset of non–small-cell lung cancer (NSCLC) patients do achieve impressive responses, which are both dramatic and durable.2-4 Molecular studies of highly responsive cases revealed that the vast majority of these harbor activating mutations within the EGFR kinase domain that are associated with altered signaling properties of the receptor.5-7 Although the high frequency of EGFR mutations in TKI-responsive NSCLC cases is now well-established, retrospective analyses of clinical trials aimed at defining the predictive value of EGFR mutations have yielded controversial results. Some studies have shown that EGFR mutations are highly predictive of drug response and survival, whereas others have reported that EGFR gene amplification, while not as predictive of response, may be equally or more predictive of improved survival. Differences in technical approaches, clinical design, and interpretation of these studies have led to some confusion in the field, culminating in uncertainty as to the appropriate role of molecular diagnostics in guiding the clinical use of EGFR-targeted therapies. Here, we review the molecular abnormalities identified, their clinical relevance in NSCLC, and implications for current treatment strategies.
Targeting EGFR as a means of cancer therapy was proposed on the basis of its ubiquitous expression in multiple epithelial cancers.8 Clinical development of anti-EGFR antibodies was initially undertaken in colorectal cancer patients,9 whereas early studies of EGFR TKIs showed efficacy primarily in NSCLC.10,11 Subsequent clinical studies identified a population of NSCLC patients with remarkable response to TKIs,2,3 highlighting the potential value of using molecular markers to direct therapy. We will summarize the key clinical studies of TKIs in NSCLC before addressing data relevant to molecular predictors of response. For reference, newly diagnosed advanced NSCLC patients have a median survival (MS) of 8 to 10 months and a 1-year overall survival (OS) rate of 30% to 35% when treated with standard chemotherapy.12,13 Patients with refractory NSCLC face an MS of only 4 to 5 months and 1-year OS of 11% without further treatment.14 For those able to tolerate additional treatment, second-line chemotherapy yields a MS of 7 months and 1-year OS of 30%.14,15
Gefitinib Gefitinib was examined as monotherapy for refractory NSCLC in two large phase II studies called the IDEAL trials.2,3 Patients were randomly assigned to 250 mg or 500 mg of daily gefitinib. The objective response rate (RR) was 18% in IDEAL-1 and 10% in IDEAL-2, and did not differ by dose level. MS was 7 months, and 1-year OS was 27% to 35%, similar to that expected with chemotherapy. A key observation from the IDEAL trials was that although responses occurred in a minority of patients, they were often dramatic, accompanied by rapid symptom improvement. The IDEAL trials led to US Food and Drug Administration (FDA) approval of gefitinib as salvage third-line therapy for NSCLC via the accelerated approval mechanism in May 2003. Because efficacy did not differ between dose levels, but toxicity was greater at 500 mg, the 250-mg dose level was used in the new drug application. Notably, responses were more likely among patients with specific characteristics. Univariate analyses found that RR in Japanese patients was more than 2.5 times higher than that in non-Japanese patients (27% v 10%; P = .002), whereas multivariable analyses showed higher RR in females compared with males (odds ratio, 2.65; 95% CI, 1.19 to 5.91) and in patients with adenocarcinoma compared with other histologic types (odds ratio, 3.45; 95% CI, 1.29 to 11.02). Although unexplained at the time, these early clinical correlations proved to be the first evidence that TKI-responsive NSCLC constitutes a distinct subset of the disease. Given its unique mechanism of action, promising activity as a single agent, and lack of overlapping toxicity with chemotherapy, gefitinib was examined as first-line treatment with chemotherapy in two large randomized phase III trials, known as the INTACT trials.21,22 More than 2,000 patients were randomly assigned to chemotherapy plus 250 mg of gefitinib, 500 mg of gefitinib, or placebo. Although the triplet regimens were well tolerated, both INTACT studies failed to show a survival benefit with the addition of targeted therapy to chemotherapy. Most recently, the ISEL trial evaluated the role of second-line gefitinib therapy in NSCLC, with 1,692 chemotherapy-refractory patients randomly assigned in a 2:1 fashion to gefitinib (250 mg/d) or placebo.23 MS was 5.6 months in the gefitinib group and 5.1 months in the placebo group (P = .11), and 1-year OS was 27% and 22%, respectively. In June 2005, on the basis of the lack of survival benefit in the ISEL study, the FDA restricted use of gefitinib to patients participating in a clinical trial or continuing to benefit from treatment already initiated. This has effectively removed gefitinib from the US market, although the drug continues to be an important agent in several countries outside of the United States.
Erlotinib The BR.21 study evaluated the effectiveness of second-line erlotinib with 731 patients randomly assigned in a 2:1 fashion to salvage erlotinib or placebo.30 In contrast to the analogous ISEL trial of gefitinib, BR.21 demonstrated a survival advantage with an MS of 6.7 months in the erlotinib group versus 4.7 months in the placebo group (P < .001). This was the first study in which a novel targeted agent improved survival for patients with advanced NSCLC. On the basis of the BR.21 results, the FDA approved erlotinib for second- and third-line treatment of NSCLC in November 2004, and it is currently used for this indication in the United States. It is unclear why BR.21 demonstrated a survival benefit with erlotinib while ISEL failed to show such benefit with gefitinib, given that the drugs were nearly identical in preclinical models, single-arm clinical trials, and randomized trials with chemotherapy. As noted, erlotinib was administered at its MTD, whereas gefitinib was adminsitered at only one third of its MTD, a distinction that could be significant because the majority of cases treated likely carried wild-type EGFR, and hence would not be hypersensitive to either TKI. Alternatively, the different outcomes might reflect divergent populations enrolled in the two trials, with respect to clinical or molecular characteristics associated with responsive disease.
Clinical Predictors of Response As noted in initial clinical trials of both gefitinib and erlotinib, predictors of response include female sex, Asian origin, absence of smoking history, and adenocarcinoma histology, often with bronchioloalveolar (BAC) differentiation. Both the ISEL and BR.21 randomized trials further validated these clinical characteristics as predictive of TKI response. In ISEL, never-smoking predicted improved survival with gefitinib treatment compared with placebo (hazard ratio [HR], 0.67; 95% CI, 0.49 to 0.91), whereas there was no difference between treatment arms for patients with a positive smoking history.23 Asian origin also predicted increased survival with gefitinib (HR, 0.66; 95% CI, 0.48 to 0.91). In BR.21, multivariable analyses found that independent predictors of survival included never-smoking (HR, 0.8; 95% CI, 0.6 to 1.0), Asian origin (HR, 0.7; 95% CI, 0.5 to 0.9), and adenocarcinoma histology (HR, 0.8; 95% CI, 0.6 to 0.9).30 To prospectively assess the efficacy of TKIs in patients with the BAC subtype of adenocarcinoma, the Southwest Oncology Group (SWOG) initiated a phase II study of gefitinib (500 mg/d) in this clinically defined subset of patients.31 Survival was prolonged in women (19 months) compared with men (8 months; P = .025); in those who developed rash (16 months) compared with those who did not (5 months; P = .003); and in never-smokers (26 months) compared with former or current smokers (10 months; P = .049). Taken together, the preponderance of data indicate that clinical benefit, in terms of drug response and survival after treatment of NSCLC with EGFR TKIs, is considerably increased in patients with specific clinical characteristics.
EGFR Mutations As Molecular Predictors of Response
Approximately 90% of mutations affect a few specific amino acids. In-frame deletions in exon 19 centered around codons 746 to 750 make up 45% to 50% of mutations, and another 35% to 45% consist of the missense mutation leucine to arginine at codon 858 (L858R) in exon 21 (Fig 1B).33-36 The recurrent nature of these somatic mutations implies specific gain of function properties mediated by these alterations. Although this class of EGFR mutation is rare outside NSCLC, they have been described in cases of gefitinib-responsive ovarian cancer and small-cell lung cancer, as well as in untreated cases of colon cancer, squamous cell head and neck cancer, and cholangiocarcinoma.37-41 A large number of retrospective series have confirmed the link between clinical characteristics associated with TKI response and EGFR mutations.33-36,42-61 The increased prevalence of mutations in Asian (25% to 50%) compared with North American and Western European patients (10%) is currently unexplained. The retrospective RR to TKI treatment in mutation-positive cases is 77%, (range, 30% to 100%, with most series reporting RR > 60%), compared with 10% in mutation-negative cases (range, 0% to 33%; Table 1). Emerging data suggest that cases with exon 19 deletions may have increased response and survival with TKIs compared with L858R cases.35,61,62 This is in contrast to the reported natural history of such patients, where those with exon 19 deletions appear to have a shorter survival than those with L858R.33 Although the biologic basis for these differences is unknown, it is interesting to note that the receptors encoded by each class of mutation appear to have different biochemical signaling properties.63 Several studies have also demonstrated that patients with EGFR mutation-positive tumors gain improved survival with TKIs compared with wild-type cases, with an MS of up to 30 months in mutation-positive cases (Table 2). 35,46-52
A number of conceptual and technical issues may confound the correlative analysis of EGFR mutations and response. First, most retrospective studies include tumor specimens collected at initial diagnosis, whereas TKI therapy may have been administered after multiple courses of chemotherapy. As such, additional mutations leading to TKI resistance may have arisen in the interim, and may account for some mutation-positive unresponsive cases. Conversely, the limited sensitivity of nucleotide sequencing may in part explain mutation-negative responsive cases. Second, the combination of infrequent EGFR mutations in unselected NSCLC cohorts and the common use of fine-needle aspirates for diagnosis, which are often insufficient for molecular analysis, has resulted in relatively small numbers of mutation-positive cases in most series. Hence, the statistical power of most US and European studies has been limited, whereas studies from Asia, where EGFR mutations are more prevalent, have been more conclusive. Finally, technical difficulties in assessing EGFR mutations by polymerase chain reaction (PCR) amplification from archival formalin-fixed, paraffin-embedded tissue may explain differences in reported mutation frequencies across studies.
EGFR Amplification and Expression Levels As Molecular Predictors of Response
In a cohort of patients from Italy, 33% of cases had increased EGFR gene copy number, defined in this study as a composite end point that included gene amplification (tight EGFR gene clusters and a ratio of EGFR gene to chromosome of  2 or 15 copies of EGFR per cell in 10% of cells) and high-level polysomy (at least 4 copies in 40% of cells), and collectively termed FISH+.47 The FISH+ patients achieved higher RR to gefitinib therapy (36%) compared with FISH–patients (3%; P < .001) and had increased MS (18.7 v 7.0 months; P = .03). FISH+ status was associated with female sex and never-smoking. Within the same cohort, 17% of cases were EGFR mutation positive, which was associated with never-smoking, and had an RR of 53% compared with 5% in wild-type cases (P < .001), with a trend towards improved survival. EGFR protein overexpression (IHC+) was demonstrated in 59% of tumors, and was associated with increased response (21% v 5%; P = .03) and survival (11.5 v 5.0 months; P = .01), but not with specific clinical characteristics. The majority of mutation-positive cases that responded to treatment (seven of eight responders) were also FISH+; however, both IHC+ and EGFR mutations were associated with FISH+ status. Thus, in this cohort, FISH+ and IHC+ were more prevalent, albeit less predictive of response than EGFR mutations, but both FISH and IHC achieved statistical significance as predictors for survival, whereas the more infrequent mutation status did not (Table 4). One factor that may account for the lack of association between mutations and survival in this study was the rare occurrence (only one of 21) of mutations in cases with treatment-induced disease stabilization, which likely contributes substantially to the survival benefit.30 A separate analysis of gefitinib-treated patients with BAC also reported that FISH+ status (as previously defined) was associated with improved survival (MS not reached at 18 months v 8 months; P = .042), although it was not a significant predictor of either response or disease control.57 These tumors were not genotyped; hence, no comparison of mutations and copy number can be made. A comparison of EGFR amplification and mutations was undertaken in a Japanese NSCLC cohort treated with gefitinib.52 EGFR mutations predicted improved response (82% v 11%; P < .0001) and survival (MS 20.4 v 6.9 months; P = .0001). Increased EGFR copy number, measured by quantitative real-time PCR (qPCR) and defined as at least three copies per cell, was predictive of response (72% v 38%; P = .005) but not survival. However, in this series, increased copy number was observed more frequently in tumors with EGFR mutations (56%) than in wild-type cases (26%; P = .014), and all tumors with high level gain (at least six copies per cell) had amplification of a mutant allele. As with EGFR mutational analyses, technical considerations are important in assessing gene copy number and protein expression. FISH can be readily performed on tissue sections, and the quantity and distribution of hybridization signal is indicative of gene copy number. Although high-level amplification is readily quantified, scoring systems for increased ploidy are more subjective, reflecting variable degrees of genomic instability rather than specific EGFR gene amplification. In contrast, qPCR provides accurate quantification of copy number and is not subject to interoperator variability, but is affected by tumor purity within analyzed specimens. EGFR protein quantification by IHC is also readily available using tissue sections, but suffers from inherent subjectivity. IHC staining is typically graded using standards that reflect both the fraction of positive cells within a tumor and an estimate of signal intensity, which may depend on experimental conditions.
A number of groups have reported molecular analyses of available specimens from the landmark EGFR TKI clinical trials described herein. In an analysis of the IDEAL and INTACT trials with gefitinib, mutations were found in 18% of samples from IDEAL and 10% of samples from INTACT.65 EGFR gene copy number was quantified by qPCR, with amplification observed in 8% of IDEAL samples and 7% of INTACT samples. As expected, EGFR mutations were more common in patients with adenocarcinoma and nonsmoking history, females, and Asians, but remarkably EGFR amplification measured by qPCR defined a distinct patient subgroup and was not correlated with smoking, race/ethnicity, or histology. In IDEAL, patients with an EGFR mutation had an improved RR to gefitinib (46%) compared with wild-type patients (10%; P = .005), but no survival advantage. EGFR amplification was associated with a nonsignificant trend toward higher RR. It should be noted that the number of patients in each of these subgroup analyses was small. Available samples from the TRIBUTE study of chemotherapy with or without erlotinib were analyzed for EGFR mutations but not gene amplification.64 Mutations were identified in 13% of cases and were associated with an increased RR to erlotinib plus chemotherapy (53%) compared with wild-type cases (18%; P < .01). Here, mutation-positive patients also had increased response to either treatment (38%) compared with wild-type cases (23%; P = .01), and a prolonged survival independent of treatment arm (8 v 5 months for mutation-positive and -negative groups, respectively; P < .001). The overall effect of combining chemotherapeutic agents with TKIs in EGFR mutation-positive patients is uncertain, complicating interpretation of TKI-response in this cohort.66 Available samples from the BR.21 study were analyzed for EGFR mutations and FISH+ status (gene amplification and/or high polysomy).54 In this study, FISH+ (found in as many as 45% of tumors) was predictive for improved survival with erlotinib (HR, 0.44; 95% CI, 0.23 to 0.82); however, no molecular markers were predictive for survival in a multivariable analysis. The EGFR mutational analysis in this trial has come under significant criticism on technical grounds.67 Mutations were initially reported in 23% of tumors and did not correlate with drug response. However, although most studies have confirmed that 80% to 90% of EGFR mutations arise within a small number of hotspots, as many as half of the mutations initially reported in the BR.21 cohort were novel variants of unknown significance, suggestive of PCR artifacts. Subsequent data reanalysis, including only the few tumors with the classical exon 19 deletions and L858R mutations, failed to show a survival benefit over wild-type cases.68 Finally, the molecular subgroup analysis of the ISEL trial was recently reported, including analyses of EGFR mutations and FISH+ status.69 Twelve percent of patients were found to have EGFR mutations; these patients had a higher response rate (37.5%) with gefitinib treatment than mutation-negative patients (2.6%, P value not reported). Survival analysis by EGFR mutation status was not possible because there had been too few deaths in the mutation-positive cohort at the time of publication. FISH+ status was observed in 30.8% of patients and was associated with a nonsignificant trend toward improved survival with gefitinib treatment (HR 0.61; 95% CI, 0.36 to 1.04). However, a significant association was observed when the investigators added an interaction term between FISH+ status and gefitinib treatment to the model (P = .045), suggesting that gene copy number was in fact a predictor of survival benefit with gefitinib compared with placebo. Although it was somewhat unusual that the interaction test was positive when the basic test of treatment benefit in FISH+ patients was negative, this is consistent with the BR.21 analysis results.
Recent trials in Asia have extended TKI treatment for NSCLC to first-line therapy. A phase II study of gefitinib as primary treatment in a Korean population of never-smokers with adenocarcinoma demonstrated an RR of 69% and an estimated 1-year OS of 73%.70 Molecular analysis has not yet been reported. A similar study in a less stringently defined Japanese cohort, with 75% adenocarcinoma but only 20% never-smokers, yielded an RR of 30% and a 1-year OS of 55%.71 Tissue was available for only 13 cases, of which four (31%) were found to harbor an EGFR mutation; all four responded to therapy. Of note, an unacceptably high rate of interstitial lung disease (ILD) occurred in the Japanese trial, with 10% of patients experiencing fatal ILD. Rates of this rare, but potentially fatal, complication have consistently been higher in Asian populations (2%), compared with US or European populations (0.3%), although ILD was not reported in the Korean phase II trial.72 If confirmed, the elevated risk of ILD in Japan may prove a further incentive to developing reliable approaches to predict drug response and spare those with low chance of response from potentially significant toxicity. Thus far, three phase II studies have been reported using EGFR mutation screening to define a population of patients with newly diagnosed advanced NSCLC for first-line EGFR TKI therapy. Inoue et al73 in Japan screened 75 patients for EGFR mutations by direct sequencing of exons 18 to 23. They identified 25 (33%) patients with exon 19 deletions or L858R point mutations and treated 16 (64%) of these with up-front gefitinib. A response rate of 75% and a median progression-free survival of 9.7 months were observed, without any serious adverse events. Similarly, Asahina et al74 in Japan screened 82 patients and identified 20 (24%) with exon 19 deletions or L858R point mutations. Of these, 16 (80%) proceeded with first-line gefitinib treatment and achieved a response rate of 75% and a median PFS of 8.9 months. One patient was removed from study treatment for suspected ILD. Finally, Paz-Ares et al75 from Spain have presented preliminary findings from 428 patients screened specifically for exon 19 deletions or L858R point mutations. They identified 67 (19%) patients harboring mutations and reported the results of first-line erlotinib treatment for 40 (60%) of these. A response rate of 82% and a PFS of 13.3 months were observed, and exon 19 deletions and never-smoking status were significant predictors of response compared with L858R mutations and ever smokers, respectively. No cases of ILD were observed. A similar study performed in North American patients by our group will be reported this year. These three studies confirm that teatment of EGFR mutation-positive patients with first-line EGFR TKI agents is safe and can produce durable response in a high proportion of patients, in stark constrast to results typically observed with standard chemothearpy. Randomized trials comparing chemotherapy with first-line EGFR TKIs in a genotype-defined population are being planned to definitively study this approach.
As is apparent in this review, all current analyses of molecular markers to guide EGFR TKI therapy have been handicapped by small numbers of cases and subgroup bias in analysis. Investigators should be encouraged to require prospective tissue procurement for all patients participating in future clinical studies. This may in fact require a shift in diagnostic practice, from the current emphasis on fine-needle aspiration, which often provides insufficient material for molecular analysis, to obtaining more substantial biopsies. Serial sampling of tumor material during the course of therapy may also eventually become important in monitoring the emergence of drug-resistance mutations. The acquisition of drug resistance in previously sensitive, EGFR-mutated NSCLC is often due to a specific second somatic mutation in EGFR (T790M).76,77 Second-generation EGFR TKIs, which bind irreversibly through covalent bonds to the receptor, are now entering clinical trials, and preclinical data suggest that these new inhibitors may have preserved effectiveness against gefitinib-/erlotinib-resistant cases with a T790M mutation.78 Depending on the outcome of these clinical trials, these drugs may prolong the clinical benefit to TKI treatment in EGFR-mutated tumors, and lead to more significant differences in outcome. For current clinical practice, the optimal combination of clinical and molecular predictors of response to EGFR TKIs remains to be defined. Given the current knowledge in the field, we recommend different strategies for patients presenting with a new diagnosis of NSCLC and those with disease progression after initial chemotherapy. On the basis of results from the BR.21 study, erlotinib has the potential to provide a modest survival benefit to unselected chemotherapy-refractory NSCLC patients. In this trial, the improvement in OS was driven less by the dramatic responses evident in a small subset of cases than by disease stabilization in a larger fraction of cases. Therefore, erlotinib should be considered as a salvage treatment for any eligible chemotherapy-refractory patient. In contrast, patients apt to have a dramatic response to EGFR TKIs by virtue of tumor-associated EGFR abnormalities may be more likely to benefit from such treatments early in their course, with chemotherapy reserved for salvage treatment. This hypothesis requires validation in clinical trials of genotype-directed, first-line treatment of advanced disease. If successful, this strategy also raises the possibility of adjuvant therapy for patients with resected, early-stage disease at high risk of recurrence, which will also require genotype-guided clinical trials. The preponderance of clinical and laboratory data support the notion that EGFR activating mutations identify a subset of NSCLC (ie, a nonsmoker's lung cancer) with an inherently different biology and a marked dependence on the EGFR pathway. Although molecular markers of this NSCLC subtype are imperfect and are likely to be modified by additional currently unknown genetic abnormalities, they do provide a powerful predictive test that may guide increasingly sophisticated use of targeted agents. The clinical utility of EGFR mutational analysis and/or EGFR amplification analysis needs to be formally tested in adequately powered prospective studies with optimal tissue sampling, and which are designed to distinguish between first-line therapy in selected patients and salvage treatment in chemotherapy-refractory NSCLC. In summary, molecular characterization of EGFR gene abnormalities in NSCLC have provided a fascinating window into the future of genotype-directed targeted therapy for a common epithelial cancer. The lessons learned from the laboratory analysis and clinical application of molecular diagnostics guiding the use of EGFR inhibitors in NSCLC are likely to be important in the development of inhibitors targeting other signaling pathways that may prove effective in other subsets of epithelial cancers.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Lecia V. Sequist, Genentech; Thomas J. Lynch, Genentech, AstraZeneca Stock: N/A Honoraria: Thomas J. Lynch, Genentech Research Funds: Daphne W. Bell, AstraZeneca; Daniel A. Haber, AstraZeneca Testimony: N/A Other: Daphne Bell, Genzyme (named on patent licensed to Genzyme); Thomas J. Lynch, Genzyme (named on patent licensed to Genzyme); Daniel A. Haber, Genzyme (named on patent licensed to Genzyme)
Conception and design: Lecia V. Sequist, Daphne W. Bell, Thomas J. Lynch, Daniel A. Haber Collection and assembly of data: Lecia V. Sequist, Daphne W. Bell, Thomas J. Lynch, Daniel A. Haber Data analysis and interpretation: Lecia V. Sequist, Daphne W. Bell, Thomas J. Lynch, Daniel A. Haber Manuscript writing: Lecia V. Sequist, Daphne W. Bell, Thomas J. Lynch, Daniel A. Haber Final approval of manuscript: Lecia V. Sequist, Daphne W. Bell, Thomas J. Lynch, Daniel A. Haber
L.V.S. and D.W.B. contributed equally to this article. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Druker BJ, Sawyers CL, Kantarjian H, et al: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038-1042, 2001 2. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21:2237-2246, 2003 3. 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 290:2149-2158, 2003 4. Perez-Soler R, Chachoua A, Hammond LA, et al: Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol 22:3238-3247, 2004 5. 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 350:2129-2139, 2004 6. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 7. 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 U S A 101:13306-13311, 2004 8. Mendelsohn J: Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20:1S-13S, 2002[Medline] 9. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 10. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240-2250, 2002 11. Herbst RS, Maddox AM, Rothenberg ML, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial. J Clin Oncol 20:3815-3825, 2002 12. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 13. Sandler A, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial—E4599. Presented at the 41st Annual Meeting of the Amercian Society of Clinical Oncology, May 13-17, 2006, Orlando, FL 14. 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 18:2095-2103, 2000 15. 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 22:1589-1597, 2004 16. Barker AJ, Gibson KH, Grundy W, et al: Studies leading to the identification of ZD1839 (IRESSA): An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 11:1911-1914, 2001[CrossRef][Medline] 17. Wakeling AE, Guy SP, Woodburn JR, et al: ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62:5749-5754, 2002 18. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000 19. Ciardiello F, Caputo R, Bianco R, et al: Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459-1465, 2001 20. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292-4302, 2002 21. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004 22. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004 23. Thatcher N, Chang A, Parikh P, et al: Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527-1537, 2005[CrossRef][Medline] 24. Grunwald V, Hidalgo M: Development of the epidermal growth factor receptor inhibitor OSI-774. Semin Oncol 30:23-31, 2003[Medline] 25. Moyer JD, Barbacci EG, Iwata KK, et al: Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838-4848, 1997 26. Pollack VA, Savage DM, Baker DA, et al: Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: Dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther 291:739-748, 1999 27. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001 28. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005 29. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA 30. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 31. West HL, Franklin WA, McCoy J, et al: Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126. J Clin Oncol 24:1807-1813, 2006 32. Bailey LR, Kris M, Wolf M, et al: Tumor epidermal growth factor receptor (EGFR) expression levels does not predict for response in patients (pts) receiving gefitinib ("Iressa," ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer (NSCLC): IDEAL 1 and 2. Proc Am Assoc Cancer Res 44:1362, 2003 (abstr LB-70) 33. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339-346, 2005 34. Marchetti A, Martella C, Felicioni L, et al: EGFR mutations in non-small-cell lung cancer: Analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 23:857-865, 2005 35. Mitsudomi T, Kosaka T, Endoh H, et al: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23:2513-2520, 2005 36. Kosaka T, Yatabe Y, Endoh H, et al: Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res 64:8919-8923, 2004 37. Schilder RJ, Sill MW, Chen X, et al: Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: A Gynecologic Oncology Group study. Clin Cancer Res 11:5539-5548, 2005 38. Okamoto I, Araki J, Suto R, et al: EGFR mutation in gefitinib-responsive small-cell lung cancer. Ann Oncol 17:1028-1029, 2005[CrossRef][Medline] 39. Barber TD, Vogelstein B, Kinzler KW, et al: Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351:2883, 2004 40. Lee JW, Soung YH, Kim SY, et al: Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res 11:2879-2882, 2005 41. Gwak GY, Yoon JH, Shin CM, et al: Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas. J Cancer Res Clin Oncol 131:649-652, 2005[CrossRef][Medline] 42. Kim KS, Jeong JY, Kim YC, et al: Predictors of the response to gefitinib in refractory non-small cell lung cancer. Clin Cancer Res 11:2244-2251, 2005 43. Huang SF, Liu HP, Li LH, et al: High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 10:8195-8203, 2004 44. Tokumo M, Toyooka S, Kiura K, et al: The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 11:1167-1173, 2005 45. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17, 2005[CrossRef][Medline] 46. Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23:2493-2501, 2005 47. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005 48. Chou TY, Chiu CH, Li LH, et al: Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 11:3750-3757, 2005 49. Cortes-Funes H, Gomez C, Rosell R, et al: Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 16:1081-1086, 2005 50. Taron M, Ichinose Y, Rosell R, et al: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 11:5878-5885, 2005 51. Zhang XT, Li LY, Mu XL, et al: The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer. Ann Oncol 16:1334-1342, 2005 52. Takano T, Ohe Y, Sakamoto H, et al: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:6829-6837, 2005 53. Mu XL, Li LY, Zhang XT, et al: Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in Chinese patients with non-small cell lung cancer. Clin Cancer Res 11:4289-4294, 2005 54. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer—Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 55. Tomizawa Y, Iijima H, Sunaga N, et al: Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer. Clin Cancer Res 11:6816-6822, 2005 56. Rosell R, Ichinose Y, Taron M, et al: Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer. Lung Cancer 50:25-33, 2005[CrossRef][Medline] 57. Hirsch FR, Varella-Garcia M, McCoy J, et al: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol 23:6838-6845, 2005 58. Kondo M, Yokoyama T, Fukui T, et al: Mutations of epidermal growth factor receptor of non-small cell lung cancer were associated with sensitivity to gefitinib in recurrence after surgery. Lung Cancer 50:385-391, 2005[CrossRef][Medline] 59. Yang SH, Mechanic LE, Yang P, et al: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 11:2106-2110, 2005 60. Yatabe Y, Kosaka T, Takahashi T, et al: EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol 29:633-639, 2005[CrossRef][Medline] 61. Riely GJ, Pao W, Pham D, et al: Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 12:839-844, 2006 62. Jackman DM, Yeap BY, Sequist LV, et al: Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 12:3908-3914, 2006 63. Sordella R, Bell DW, Haber DA, et al: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163-1167, 2004 64. Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900-5909, 2005 65. Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081-8092, 2005 66. Gandara DR, Gumerlock PH: Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: Case closed or is the jury still out? J Clin Oncol 23:5856-5858, 2005 67. Marchetti A, Felicioni L, Buttitta F: Assessing EGFR mutations. N Engl J Med 354:526-528, 2006 68. Shepherd FA, Tsao MS: Unraveling the mystery of prognostic and predictive factors in epidermal growth factor receptor therapy. J Clin Oncol 24:1219-1221, 2006 69. Hirsch FR, Varella-Garcia M, Bunn FA Jr, et al: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006 70. Lee DH, Han JY, Lee HG, et al: Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clin Cancer Res 11:3032-3037, 2005 71. Niho S, Kubota K, Goto K, et al: First-line single agent treatment with gefitinib in patients with advanced non-small-cell lung cancer: A phase II study. J Clin Oncol 24:64-69, 2006 72. AstraZeneca: Iressa package drug insert, 2004 73. Inoue A, Suzuki T, Fukuhara T, et al: Prospective phase II study of gefitinib for chemotherapy-naïve patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24:3340-3345, 2006 74. Asahina H, Yamazaki K, Kinoshita I, et al: A phase II trial of gefitinib as first-line therapy for advanced non-small-cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer 95:99-1004, 2006 75. Paz-Ares L, Sanchez JM, Garcia-Velasco A, et al: A prospective phase II trial of erlotinib in advanced non-small-cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). J Clin Oncol, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition), 2006 (abstr 7020) 76. Kobayashi S, Boggon TJ, Dayaram T, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786-792, 2005 77. Pao W, Miller VA, Politi KA, et al: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73, 2005[CrossRef][Medline] 78. Kwak EL, Sordella R, Bell DW, et al: Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665-7670, 2005 79. Tracy S, Mukohara T, Hansen M, et al: Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 64:7241-7244, 2004 80. Jiang J, Greulich H, Janne PA, et al: Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression. Cancer Res 65:8968-8974, 2005 81. Greulich H, Chen TH, Feng W, et al: Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2:e313, 2005[CrossRef][Medline] |
TOP
ABSTRACT
INTRODUCTION