Journal of Clinical Oncology, Vol 21, Issue 14
(July), 2003: 2658-2663
© 2003 American Society for Clinical Oncology
Gefitinib in Pretreated Non–Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC
Federico Cappuzzo,
Vanesa Gregorc,
Elisa Rossi,
Alessandra Cancellieri,
Elisabetta Magrini,
Carlo Terenzio Paties,
Giovanni Ceresoli,
Laura Lombardo,
Stefania Bartolini,
Cesare Calandri,
Marisa De Rosa,
Eugenio Villa,
Lucio Crinò
From the Division of Medical Oncology, Bellaria Hospital, and CINECA-Interuniversity Consortium, Bologna; and Division of Radiochemotherapy, Scientific Institute University Hospital San Raffaele, Milano, Italy.
Address reprint requests to Federico Cappuzzo, MD, Bellaria Hospital, Division of Medical Oncology, Via Altura 3, 40139 Bologna, Italy; email: federico.cappuzzo{at}ausl.bo.it.
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ABSTRACT
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Purpose: To evaluate the correlation between HER2 expression and gefitinib (ZD 1839, Iressa; AstraZeneca, London, United Kingdom) efficacy in terms of response rate, time to progression (TTP), and overall survival (OS) time.
Patients and Methods: Patients with pretreated advanced non–small-cell lung cancer (NSCLC) received gefitinib at a daily dose of 250 mg until disease progression. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine HER2/epidermal growth factor receptor (EGFR) status by immunohistochemistry.
Results: From February 2001 to June 2002, 63 consecutive patients were enrolled onto the study. The overall disease control rate was 58.7% (partial response [PR], 15.9%; stable disease [SD], 42.8%), median TTP was 3.3 months, and median OS was 4.1 months. Among the 43 patients in whom EGFR/HER2 status was determined, we observed six PRs (14%) and 18 SDs (42%). Disease control, including PR and SD, was 40% in the 15 patients overexpressing HER2 and 64.3% in the 28 patients not overexpressing HER2 (P = .126). No difference was found between the two groups in terms of TTP (3.5 v 3.7 months, respectively) and OS (5.7 v 6.8 months, respectively). In addition, we did not find any difference in TTP, OS, toxicity, and symptom outcome in the group of patients overexpressing both HER2 and EGFR compared with patients who had no overexpression of HER2
Conclusion: According to these data, efficacy, toxicity, and symptom outcome in patients with NSCLC treated with gefitinib do not seem to be related to HER2 expression.
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INTRODUCTION
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ALTHOUGH IN the last decade several new chemotherapeutic agents, such as taxanes, gemcitabine, and vinorelbine, have been introduced into clinical practice, the prognosis of advanced non–small-cell lung cancer (NSCLC) remains poor. Recent large phase III trials showed that, compared with older regimens, the impact on survival of new combinations is minimal, and no one regimen is clearly superior, with overall response rates (RRs) of approximately 30%, median survival benefit of 8 to 9 months, and 1-year survival rates of approximately 30%.1–5 Since its identification, the epidermal growth factor receptor (EGFR) has emerged as a significant factor in the development and growth of many types of cancers. It is now accepted that the EGFR signal transduction network plays an important role in multiple tumorigenic processes, contributing to cancer-cell proliferation, angiogenesis, and metastasis, as well as protection from apoptosis.6 The EGFR family includes the following four distinct receptors: EGFR/ErbB-1, HER2/ErbB-2, HER3/ErbB-3, and HER4/ErbB-4. A number of different ligands, including epidermal growth factor, transforming growth factor alpha, and neuregulins, activate the receptor by binding to the extracellular domain and inducing the formation of receptor homodimers or heterodimers, followed by internalization of the receptor/ligand complex and autophosphorylation. As a result, the tyrosine kinase (TK) signal transduction pathways are activated.7,8 In this signal network, HER2 is the major partner of EGFR9 because activated heterodimeric complexes containing HER2 are more stable at the cell surface than complexes containing other EGFR family members.10 In addition, HER2 can decrease the rate of ligand dissociation from the cognate receptor EGFR.11 EGFR signaling, via phosphorylation of the intracellular TK domain of the protein, can be blocked by small-molecule EGFR TK inhibitors (TKIs).
Gefitinib (ZD 1839, Iressa; AstraZeneca, London, United Kingdom) is an orally active, selective EGFR-TKI that demonstrated antitumor activity against a variety of human cancer cell lines expressing EGFR, including ovarian, breast, and colon, and it is active in a range of xenograft models, including colon, prostate, and NSCLC.12,13 Phase I studies evaluating the safety and tolerability of gefitinib identified rash and diarrhea as unique and dose-related toxicities. Notably, an 11% RR has been observed among the 100 NSCLC patients enrolled onto these trials.14 To confirm the objective response data and symptomatic benefit seen in phase I trials, investigators conducted two large phase II studies in pretreated NSCLC patients. In the first trial (IDEAL 1),15 210 pretreated NSCLC patients were randomly assigned to either a 250-mg or 500-mg daily dose of gefitinib. This trial demonstrated an 18% RR and symptomatic improvement in 40% of patients, without any significant difference between the two dose levels. In the United States trial (IDEAL 2), 216 NSCLC patients, whose disease had failed to respond to two or more prior chemotherapy regimens containing platinum and docetaxel, were randomly assigned to gefitinib 250 mg or 500 mg daily. This trial confirmed that gefitinib is active in heavily pretreated NSCLC patients, with an RR of 11.8% and symptom improvement in 43% of patients in the 250-mg arm.16 The degree of EGFR expression seems not to affect response, but clinical responses to EGFR-blocking agents indicate that, in some of the patients with NSCLC, EGFR may be the critical pathway signaling tumor growth. It is possible that differences in expression of members of the HER family may be responsible for differences in response to EGFR-blocking drugs.17 Preclinical studies indicate that HER2-overexpressing tumors are particularly sensitive to gefitinib; therefore, combining EGFR blockade with HER2 blockade could improve antitumor effects.18 Based on these data, we analyzed the correlation between the efficacy and tolerability of gefitinib and EGFR and HER2 expression in pretreated NSCLC patients. The primary end point of the study was to evaluate the correlation between HER2 expression and gefitinib efficacy in terms of RR, time to progression (TTP), and overall survival (OS). We also evaluated whether coexpression of both HER2 and EGFR correlates with TTP, OS, symptom outcome, and toxicity.
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PATIENTS AND METHODS
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Patient Selection
Patients included in this study all had histologically confirmed, measurable, locally advanced or metastatic NSCLC, pretreated with at least one line of platinum-based chemotherapy. Patients with locally advanced disease were considered eligible if they were pretreated with front-line platinum-based chemotherapy and radiation. Patients were older than 18 years of age and had an Eastern Cooperative Oncology Group performance status of 2 or less, a life expectancy of at least 12 weeks, a white blood cell count  3.5 x 109/L, platelets 100 x 109/L, hemoglobin 9 g/dL, an absolute granulocyte count greater than 2.0 x 109/L, bilirubin less than 1.5-fold of the upper limit of normal (ULN), prothrombin time or activated partial thromboplastin time less than 1.5 times the control, ALT or AST less than three-fold of the upper limit of normal (elevated to five-fold of the ULN in patients with known hepatic metastases), and a calculated creatinine clearance rate of more than 45 mL/min. Patients were ineligible if they had evidence of prior/concurrent malignancy other than in situ carcinoma of the cervix, adequately treated basal cell carcinoma of the skin, or other malignancy treated 5 or more years previously without evidence of recurrence. Written informed consent was obtained from each patient before he or she entered onto the study. The study was conducted after the approval of the appropriate ethical review boards, and the guidelines for good clinical practice were followed. Recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed.
HER2 and EGFR Determination
HER2 and EGFR expression were evaluated on tissue specimens collected at the time of initial diagnosis. The level of HER2 expression was determined by immunohistochemistry (IHC) using the Dako Herceptest (DAKO, Copenhagen, Denmark). Staining was performed according to the protocol described in the manufacturer’s guide. Membrane staining intensity and patterns were evaluated using the 0 to 3+ scale as illustrated by the HercepTest kit scoring guidelines. Scores of 0 or 1+ were considered negative for HER2 overexpression, scores of 2+ were considered weakly positive, and scores of 3+ were considered strongly positive. To qualify for 2+ and 3+ scoring, complete membrane staining of more than 10% of tumor cells had to be observed. EGFR expression was evaluated by IHC using a monoclonal antibody against the external domain of the EGFR (Zymed Laboratories, San Francisco, CA). The result was reported as negative (score 0 to 1+) or positive (score 2+ to 3+) based on the percentage of stained cells and staining intensity.
Study Design and Treatment
In this study, consecutive patients with pretreated NSCLC received gefitinib at a daily dose of 250 mg administered until disease progression. Gefitinib was taken once daily in the morning, at approximately the same time each day. The drug was provided by AstraZeneca on a compassionate-use basis. Before inclusion in the trial, tumor specimens were collected to perform HER2 and EGFR determination. Baseline evaluation included a complete history and physical examination, complete blood cell count and serum chemistry analysis, urinalysis, ECG, chest x-ray, and total-body computed tomography scan. Other imaging modalities, such as magnetic resonance imaging and bone scintigraphy, were performed according to specific clinical indications. All baseline imaging procedures were performed within 4 weeks before study entry. Biochemical screening was performed every 4 weeks, assessing serum creatinine, electrolyte, alkaline phosphatase, bilirubin, AST, ALT, calcium, magnesium, and protein levels. Toxic effects were assessed every 28 days according to the National Cancer Institute common toxicity criteria.19 A clinical symptom assessment was performed every 28 days, using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. Patients were evaluated for response according to the Response Evaluation Criteria in Solid Tumors.20 Tumor response was assessed by computed tomography scan every 2 months, with a confirmatory evaluation to be repeated in responding patients at least 4 weeks after the initial determination of response.
Statistical Considerations
Statistical analysis was performed to evaluate the correlation between HER2 expression and gefitinib efficacy. A sample size of 56 patients was chosen to have an 80% power and a significance level of 0.05 to detect a difference in terms of RR of 40%. Impact on toxicity, symptom outcome, and response to therapy were examined in the two groups, with descriptive analysis comparing the differences using the  2 test (for categorical variables) and Student’s t test (for quantitative variables). A P value less than .05 was considered significant. Survival time was measured from the date of registration to the date of death or last follow-up examination, and OS time was estimated using the Kaplan-Meier method.21 Differences in survival between the two groups (ie, with and without HER2 overexpression) were tested using the log-rank test. Statistical analysis has been computed using SAS software (SAS Institute, Cary, NC).
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RESULTS
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Patient Characteristics
From February 2001 to June 2002, 63 consecutive patients were treated with a 250-mg daily dose of gefitinib in two Italian institutions. Characteristics of the eligible patients are listed in Table 1 . The majority of the patients were male (63.5%), with a mean age of 58.5 years (range, 31 to 79 years) and with a good Eastern Cooperative Oncology Group performance status (0 to 1, 89%). Histology was adenocarcinoma in 57.1% of patients, bronchiolar-alveolar in 15.9%, and squamous cell carcinoma in 14.3%. Lung represented the main metastatic site (26 patients), and nine patients had brain metastases. Twenty-three patients (37%) had two or more metastatic sites. All patients included onto the trial had received platinum-based chemotherapy, and 79% had received at least two lines of chemotherapy, including platinum, gemcitabine, and taxanes. All stage IIIB patients were pretreated with mediastinal radiotherapy as part of a chemoradiation integrated approach. In 20 patients, EGFR and HER2 determination was not performed because tumor tissue specimens were not suitable to perform IHC. In the 43 patients evaluated for EGFR/HER2 status, EGFR resulted positive in 24 patients (55.8%) and negative in 19 patients (44.2%); HER2 resulted negative (0 to 1+) in 28 patients (65.1%), weakly positive (2+) in seven patients (16.3%), and strongly positive (3+) in eight patients (18.6%; Table 2). Fluorescence in situ hybridization (FISH) was performed in the 15 patients labeled as HER2 positive (2+/3+) after IHC. Only three patients (3+ by IHC) were FISH positive.
Response to Therapy
Response to treatment was evaluated in all 63 patients. Gefitinib was administered orally, with a median treatment duration of 3.3 months (range, 0.3 to 19.2 months). We observed 10 partial responses (PRs; 15.9%) and 27 stable diseases (SDs; 42.8%), for an overall disease control rate of 58.7% (95% confidence interval, 52.5% to 64.9%). For the entire population, median TTP was 3.3 months, and median OS time was 4.1 months. In the 43 patients in whom EGFR/HER2 status was determined, we observed six PRs (13.9%) and 18 SDs (41.9%). The disease control rate, including PR and SD, was 40% in the 15 patients overexpressing HER2 and 64.3% in the 28 patients not overexpressing HER2. This difference was not statistically significant (P = .126; Table 3). There was also no difference found between patients overexpressing HER2 and patients not overexpressing HER2 in terms of TTP (3.5 v 3.7 months, respectively) and OS duration (5.7 v 6.8 months, respectively; Figs 1 and 2). We also evaluated TTP and median OS in patients overexpressing both HER2 and EGFR versus patients not overexpressing HER2. Again, we did not observe any difference in terms of TTP (3.5 v 3.7 months, respectively) and median OS time (5.7 v 6.7 months, respectively; Figs 3 and 4)
Toxicity and Symptom Outcome
All 63 patients were evaluated for toxicity and symptom outcome. Side effects were generally mild and consisted of grade 2 skin toxicity, reported in 31.7% of patients, and grade 2 diarrhea, reported in 14.3% of patients. Symptom outcome was evaluated in all 63 patients, and symptomatic improvement and symptom stabilization were observed in 28.6% and 58.7% of patients, respectively. Toxicity and symptom outcome in the nine patients overexpressing both HER2 and EGFR were not statistically different from those reported in the 34 patients without co-overexpression of both receptors (grade 2 toxicity, 33.3% v 29.4%, respectively; symptom improvement, 44.4% v 32.3%, respectively; Tables 4 and 5).
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DISCUSSION
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We have studied the correlation between HER2 status and sensitivity to gefitinib therapy in patients with advanced NSCLC, and we have shown that response to gefitinib is not related to HER2 overexpression. Although there is an increasing amount of information concerning the genetic heterogeneity of human cancers, the factors that specifically influence their responsiveness to targeted therapies are not understood. Several studies indicate that ErbB family members form homo- and heterodimers with each other, that they respond to a number of receptor-selective soluble ligands, and that they interact with a large number of intracellular signaling proteins.9,22 After these studies, an effort to develop bifunctional inhibitors capable of inhibiting the TK activity of both the EGFR and HER2 receptors has been initiated. The rationale for choosing these two targets is based on the following considerations: EGFR and HER2 are commonly overexpressed in human cancers6,23,24; HER2 is the preferred dimerization partner for other members of the ErbB family and, therefore, most likely to be included in functional dimers when it is expressed at high levels9; and EGFR/HER2 heterodimers are a functionally potent signaling combination.22
The TKI gefitinib is a synthetic anilinoquinazoline TKI selective for EGFR. Because gefitinib has good oral bioavailability and has demonstrated antitumor activity in a broad range of mouse xenograft models, it was selected for clinical development. Phase I trials of gefitinib in patients with solid tumors refractory to standard chemotherapeutic agents have shown good tolerability and evidence of antitumor activity.25,26 These successes have led to additional clinical studies to better determine its potential in the treatment of cancer patients. More recently, the results of two large phase II trials (IDEAL 1 and 2) demonstrated that gefitinib is active in pretreated NSCLC patients, with an RR of approximately 10%.15–16 These data indicate that, in patients responding to TKI therapy, the EGFR pathway is crucial in the development and maintenance of the neoplastic process. Unfortunately, most patients do not respond to gefitinib therapy, and the disappointing results of two recent large phase III trials comparing standard chemotherapy with standard chemotherapy plus gefitinib (INTACT 1 and 2) justify the necessity of identifing patients that are most likely to respond to TKI therapy.27,28 The degree of EGFR expression does not seem to affect response to TKIs,29 but recent preclinical data indicated that HER2-overexpressing tumors are particularly sensitive to gefitinib.18
Based on these premises, we evaluated the correlation between gefitinib activity and HER2 expression in terms of RR, TTP, and OS time. Gefitinib toxicity, particularly skin rash, is related to EGFR expression on skin cells, and there is a correlation between tumor response to TKIs and skin toxicity.30 Therefore, as a secondary end point, we evaluated whether coexpression of both receptors, HER2 and EGFR, was related to an increased toxicity. In our study, the RR was 40% and 64.3% for HER2-overexpressing and HER2-nonoverexpressing patients, respectively. In contrast to our hypothesis, there was a trend favoring HER2-nonoverexpressing patients, although the difference was not statistically significant. Moreover, no differences were found in terms of TTP and OS. In addition, HER2 and EGFR co-overexpression was not related to an increased toxicity, and compared with HER2-nonoverexpressing patients, no difference in terms of symptom outcome was found.
A recent meta-analysis indicated that EGFR is a weak prognostic indicator in NSCLC.31 Interestingly, the expression of both HER2 and EGFR seems to identify patients with a poorer prognosis.32 Although in our study the number of patients was too small to allow any conclusion, no difference in terms of TTP and OS time was found in HER2/EGFR-overexpressing versus HER2-nonoverexpressing patients. Preclinical data indicate that it is more difficult to inhibit EGFR phosphorylation in vivo in cells that express high levels of HER2.33 In our trial, we did not evaluate the level of EGFR phosphorylation, and therefore, we have no information on the degree of EGFR activation in HER2 overexpressing patients. IHC has been chosen as a preferred method for HER2 and EGFR determination because it is the most commonly used and easy to perform technique. In breast cancer, comparisons of IHC and FISH techniques have shown that FISH is more specific than IHC, and gene amplification by FISH is the best predictor of response.34 In NSCLC, the best way to determine HER2 status has not been established because HER2 overexpression is more likely caused by chromosomal duplication rather than gene amplification.35 For these reasons, we also decided to perform FISH analysis in the 15 patients with HER2 overexpression (2+/3+). Unfortunately, the very low number of FISH-positive patients (only three patients) precluded the evaluation of any correlation with gefitinib efficacy.
Analysis of the entire population showed that gefitinib at a daily dose of 250 mg is active in pretreated NSCLC patients, with an RR of 15.9%, overall disease control rate (PR + SD) of 58.7%, TTP of 3.1 months, and median OS time of 4.1 months. Our data are similar to those obtained in the IDEAL 1 and 2 trials, confirming that gefitinib is an active treatment in this unfavorable population.15,16 Compared with the IDEAL 2 study,16 the higher RR reported in our study can be explained with the higher number of female patients and the higher number of patients with adenocarcinoma and bronchiolar-alveolar carcinoma enrolled. Analysis of toxicity indicates that gefitinib is well tolerated, with skin toxicity and diarrhea as main side effects occurring in 31.7% and 14.3% of patients, respectively. Symptom improvement occurred in 28.6% of patients, less than that reported in the IDEAL 1 and 2 trials, probably because of the less accurate method of symptom assessment used in our study. In fact, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 does not include an accurate evaluation of skin symptoms.
In conclusion, the results of this study confirm that gefitinib is an active drug, but efficacy, toxicity, and symptom outcome do not seem related to HER2 expression, when the receptor is assessed by IHC, in pretreated NSCLC patients. Further large and prospective trials need to identify predictive factors of targeted therapy effectiveness.
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NOTES
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Presented previously at the American Society for Clinical Oncology Molecular Therapeutics Symposium, San Diego, CA, November 8–10, 2002.
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Submitted January 6, 2003;
accepted April 24, 2003.
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TOP
ABSTRACT
INTRODUCTION
