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Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007: pp. 2248-2255 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4300 Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization–Positive/Phospho-Akt–Positive or Never Smoker Patients With Advanced Non–Small-Cell Lung Cancer: The ONCOBELL Trial
From the Department of Hematology-Oncology, Istituto Clinico Humanitas IRCCS, Rozzano; Department of Medical Oncology, Bellaria-Maggiore Hospital; CINECA-Interuniversity Consortium, Bologna; Department of Medical Oncology, Seconda Universita' di Napoli, Napoli; Department of Medical Oncology, Policlinico Monteluce, Perugia, Italy; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and Department of Medicine/Medical Oncology, University of Colorado Cancer Center, Aurora, CO Address reprint requests to Federico Cappuzzo, MD, Istituto Clinico Humanitas IRCCS, via Manzoni 56, 20089-Rozzano, Italy; e-mail: federico.cappuzzo{at}humanitas.it
Purpose: In non–small-cell lung cancer (NSCLC), clinical and biologic predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitivity have been identified in retrospective studies, and there is urgent need to validate these results in prospective trials. The ONCOBELL trial is a prospective phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or have increased EGFR gene copy number or activation of the antiapoptotic protein Akt. Patients and Methods: EGFR gene copy number was evaluated using fluorescence in situ hybridization (FISH), and presence of phospho-Akt was evaluated using immunohistochemistry. Additional tests included immunohistochemistry analysis of EGFR, FISH analysis of HER2, and mutation analysis of EGFR, HER2, and K-ras. Results: From November 2004 to February 2006, 183 patients were screened, and 42 patients were enrolled onto the trial. We observed one complete and 19 partial responses, for an overall response rate (RR) of 47.6% (95% CI, 32.5% to 62.7%). Median duration of response was 6.1 months, median time to progression (TTP) was 6.4 months, 1-year survival rate was 64.3%, and median survival time was not reached. EGFR FISH–positive patients, compared with negative patients, had higher RR (68.0% v 9.1%, respectively; P < .001), longer TTP (7.6 v 2.7 months, respectively; P = .02), and a trend for longer survival (median survival not reached v 7.4 months, respectively; P = .3). Therapy was well tolerated, and there were no drug-related deaths. Median follow-up time was too short for significance tests of differences in survival outcomes. Conclusion: Gefitinib is active and well tolerated in patients with trial characteristics, and EGFR FISH analysis is an accurate predictor for such therapy.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib (Iressa; AstraZeneca, London, United Kingdom) and erlotinib (Tarceva; Genentech, South San Francisco, CA), have established new hope for non–small-cell lung cancer (NSCLC) patients as demonstrated by the relative lack of adverse effects, oral availability, and the ability to relieve symptoms and prolong survival.1-3 Since the first reports, it clearly emerged that responses to EGFR-TKIs were more frequent among certain NSCLC subgroups, and smoking history seemed to be the most relevant factor.2-5 Large phase III randomized studies showed a significant survival improvement for never smokers when treated with chemotherapy plus a TKI6-7 or with a TKI alone1,8 probably because of the spectrum of molecular abnormalities associated with cigarette smoking exposure.9-12 Several reports have shown that somatic mutations in exons 18 through 21 of the tyrosine kinase domain of EGFR were significantly associated with response to TKIs.13-17 These mutations were more frequently observed in never smokers,13-18 and the likelihood of EGFR mutations decreases as the number of cigarette pack-years increases.19 Increased EGFR gene copy number emerged as another important predictor for TKI sensitivity.15,17,20-22 In our previous study,15 patients with increased EGFR gene copy number assessed by fluorescence in situ hybridization (FISH; FISH-positive patients) had significantly higher response rate (RR), longer time to progression (TTP), and longer survival than patients with no EGFR genomic gain (FISH-negative patients). These findings were confirmed by our group in other studies21,22 and by an independent group.20 Of note, increased EGFR gene copy number was significantly associated with never-smoking history and EGFR mutations.15 Additional studies showed that other mechanisms are involved in TKI sensitivity, such as the activation of the antiapoptotic protein Akt.23,24 We have reported that patients positive for both EGFR FISH and phospho-Akt (P-Akt) had a statistically significant higher RR, longer TTP, and longer survival than individuals negative for EGFR and/or P-Akt.15,23 Although clinical and biologic predictors for TKI sensitivity have been identified, most available data originated from retrospective studies, and there is an urgent need to validate these results in prospective trials. Therefore, we conducted a prospective study evaluating gefitinib sensitivity in a cohort of NSCLC patients selected based on smoking history and EGFR FISH/P-Akt status. Additional biomarkers, such as EGFR expression, HER2 gene copy number, and presence of EGFR, HER2, or K-ras mutations, were also evaluated.
Patient Selection The ONCOBELL trial was a prospective phase II study evaluating gefitinib sensitivity in NSCLC patients who never smoked or, irrespective of the smoking history, in patients who were EGFR FISH and P-Akt positive. In smokers, histologically confirmed diagnosis of NSCLC and positive status for both EGFR FISH and P-Akt were mandatory for trial inclusion. In never smokers, patients were considered eligible if at least one biomarker was positive (EGFR FISH or P-Akt) or irrespective of biologic status if no tissue was available for biomarker analyses. Inclusion criteria included the following: presence of at least one measurable lesion; stage IIIB or IV disease not suitable for surgery or radiotherapy with curative intent; evidence of tumor relapse or progression; patient pretreated with standard chemotherapy or patient not suitable for chemotherapy because of age more than 75 years, concomitant illness contraindicating chemotherapy, or refusal; age  18 years; and Eastern Cooperative Oncology Group performance status of 0 to 2. No concomitant chemotherapy, immunotherapy, or radiotherapy was allowed; prior radiotherapy was acceptable if completed 4 weeks before study entry and measurable lesions were outside the field of radiation therapy. Patients with brain metastases were eligible. Patients were classified as never smokers (< 100 cigarettes per lifetime), former smokers (quit smoking 6 months before starting therapy), or current smokers (quit smoking < 6 months before starting therapy or active smokers), according to previously published definitions.15,25 Written informed consent was obtained from each patient before entering the study. The study was approved by the local ethics committee and was conducted in accordance with ethical principles stated in the most recent version of the Declaration of Helsinki or the applicable guidelines on good clinical practice, whichever represented the greater protection of the individuals. Eligible and consenting patients received gefitinib 250 mg/d until disease progression, unacceptable toxicity, or refusal. When feasible, primary tumor biopsy was performed immediately before starting gefitinib therapy and was repeated during the first month of treatment and at disease progression. Within 4 weeks of study entry, all eligible patients received a complete disease staging, including thoracic and abdominal computed tomography scan and blood sampling. Brain computed tomography scan and bone scan were performed if clinically indicated. Disease assessment was performed every 2 months, with a confirmatory evaluation in all patients with response or disease stabilization no less than 4 weeks after the response assessment, according to the Response Evaluation Criteria in Solid Tumors.26
Tissue Preparation, FISH, Immunohistochemistry, and Mutation Analyses
Immunohistochemistry analyses were carried out with antibodies against P-Akt (Cell Signaling Technology, Beverly, MA) and against the external domain of EGFR (Zymed Laboratories Inc, San Francisco, CA), according to the manufacturers' instructions. Specimens were P-Akt positive if they had a score of 2+ or 3+ in Mutation analyses were performed using a previously published method.29 DNA was prepared from 10 mmol/L of formalin-fixed paraffin-embedded specimens. No tumor microdissection was performed, and all mutations were independently confirmed. The following genes and exons were examined: EGFR, exons 18 to 21; K-ras, exon 2; and HER2, exon 20. The specific polymerase chain reaction primers and conditions are available on request.
Statistical Analyses
Patient Characteristics From November 2004 to February 2006, 183 patients (147 smokers and 36 never smokers) were seen, and 42 (23%) were enrolled onto the trial at three Italian institutions (Bellaria-Maggiore Hospital, Bologna; Ospedale Silvestrini, Perugia; and Seconda Universita' di Napoli, Napoli). Patients were eligible if positive for both EGFR FISH and P-Akt (12 patients). Never smokers were eligible if at least one biomarker was positive (20 patients) or, irrespective of biologic status, if tumor tissue was not available before trial inclusion (10 patients, including five with cytologic diagnosis and five for whom tumor tissue was available after trial inclusion). A total of 141 patients were not eligible for the study because of smoking history with unknown (n = 14) or negative EGFR FISH (n = 114) or negative P-Akt pattern (n = 13). Patient characteristics are listed in Table 1, and considering the criteria for patient selection, it is not surprising that the majority of patients were female (73.8%) and never smokers (85.7%). It is relevant to note that 39 patients (92.9%) had stage IV disease, with involvement of brain in 17 patients (40.5%). One third of individuals (33.4%) had four or more metastatic sites.
Biologic Characteristics Among the 42 participating patients, 37 (88%) had sufficient tumor tissue collected at the time of original diagnosis for biologic analyses (Table 2). The EGFR FISH–positive group (69.4%) included 18 patients with high polysomy and seven patients with gene amplification. In 12 patients (36.4%), both EGFR FISH and P-Akt were positive. EGFR mutations were detected in 24 patients (66.8%), including 17 in frame deletions within exon 19, seven exon 21 mutations (L858R), and four exon 20 insertions. Four patients presented double EGFR gene mutations (exons 19 and 21 in three patients and exons 19 and 20 in one patient). EGFR mutations in exon 19 or 21 were detected in 16 (51.6%) of 31 never smokers and in five (83.3%) of six smokers (two current and three former smokers). Two patients (5.4%) had HER2 gene mutation (ins 776), and one patient had K-ras mutation (G12V). HER2 FISH assessment was positive in 20 individuals (55.6%); 15 patients had high polysomy, and five had gene amplification.
EGFR FISH–positive status was significantly associated with mutations in EGFR exon 19 or 21 (P = .005) and with HER2 FISH–positive status (P = .006). Interestingly, the two patients carrying an HER2 gene mutation were both EGFR and HER2 FISH–positive, and one patient also carried an EGFR exon 19 deletion.
Biologic Markers and Tissue Timing Collection
Toxicity
Response to Treatment
As shown in Table 4, response to gefitinib therapy did not differ according to clinical characteristics or previous chemotherapy exposure. EGFR FISH–positive patients had an RR significantly higher than EGFR FISH–negative patients, with no difference in EGFR FISH–positive/P-Akt–positive patients versus negative patients for one or both biomarkers. Response was higher in patients with EGFR amplification compared with patients with high polysomy (85.7% v 61.1%, respectively), but the difference was not significant (P = .3). Among never smokers, RR was significantly higher in EGFR FISH–positive patients, with only one EGFR FISH–negative responder.
Patients carrying EGFR gene mutation in exons 19 and/or 21 had a significantly higher RR compared with EGFR wild-type patients. Response to gefitinib was similar in patients with exon 19 versus exon 21 mutation (70.6% v 71.4%, respectively; P = .99). Significantly higher RR was observed in HER2 FISH–positive patients compared with HER2 FISH–negative patients. Of note, no response was observed in the four patients with mutation in EGFR exon 20, in the two patients with mutation in HER2 exon 20, or in the one patient with K-ras mutation.
TTP and Survival
No difference in TTP was observed in patients with EGFR mutations versus EGFR wild type (3.8 v 3.1 months, respectively; P = .4). Patients with mutations in EGFR exon 19 or 21 had longer TTP than patients without these mutations (7.1 v 3.1 months, respectively), but the difference was not statistically significant (P = .3). A similar trend for longer TTP was observed in patients with EGFR exon 19 mutation versus no exon 19 mutation (7.1 v 3.1 months, respectively; P = .3) and in patients with exon 21 mutation versus no exon 21 mutation (6.4 v 3.4, respectively; P = .6). HER2 FISH–positive patients had a nonsignificant longer TTP than HER2 FISH–negative patients (6.4 v 3.1 months, respectively; P = .2). The median follow-up time was too short and the sample size provided insufficient power for significance tests of differences in survival outcomes. Nevertheless, median survival time was longer in EGFR FISH–positive patients versus EGFR FISH–negative patients (not reached v 7.4 months, respectively; P = .3), in patients with exon 19 and/or 21 EGFR mutation versus no exon 19 and/or 21 mutation (not reached v 11.1 months, respectively; P = .5), in HER2-positive patients versus HER2-negative patients (not reached v 10.4 months, respectively; P = .1), and in never smokers versus smokers (not reached v 5.1 months, respectively; P = .004).
This prospective study, which is the first, to our knowledge, to use EGFR FISH for selection of patients for TKI therapy, has shown that gefitinib is effective and well tolerated in patients with trial characteristics. Objective response was observed in half of the patients, including individuals with brain metastases and irrespective of previous chemotherapy. These findings confirm that gefitinib may cross the blood-brain barrier33,34 and suggest that the drug is equally effective in untreated and pretreated individuals. Occurrence of interstitial lung disease is a serious and potentially lethal adverse effect of gefitinib that is mainly observed in Asians.35,36 There are few data evaluating the incidence of this relevant adverse effect in a selected cohort.37 In our study, only one patient developed acute interstitial lung disease, suggesting that the drug could be safely administered to white patients with the study characteristics. Selection of patients was based on both clinical and biologic characteristics because of the relevance of smoking history in TKI sensitivity1,8,38 and the evidence that responses also occur among smokers.39,40 The method selected for EGFR assessment was FISH based on the positive results of our previous retrospective study showing improved survival for EGFR FISH–positive patients treated with gefitinib.15 The results of the present prospective trial showed that EGFR FISH–positive patients had better RR and longer TTP and survival than EGFR FISH–negative patients, confirming that EGFR FISH analysis is an accurate predictor for gefitinib sensitivity. It is relevant to observe that RR and TTP did not significantly differ according to smoking history or P-Akt status. Nevertheless, among never smokers, only EGFR FISH–positive patients responded to gefitinib therapy, and FISH-positive patients who never smoked had a significantly longer survival than smokers. These data indicate that an increased level of the molecular target EGFR is required for response to the target inhibitor agent gefitinib and that smokers have worse prognosis independent of response to the therapy. Preclinical data indicate that, although gefitinib selectively inhibits EGFR activity, tumors with HER2 overexpression are particularly sensitive to the drug.41 In a previous study, we observed that HER2 FISH–positive patients were more sensitive to gefitinib.25 The present study confirmed the relevant role of HER2 gene gain in gefitinib sensitivity, supporting HER2 FISH analysis as a complementary test to EGFR assay for selection of candidate patients for TKI therapy. Retrospective studies13-17 and a small prospective trial37 showed that presence of EGFR gene mutations is invariably associated with response to TKIs. In our study, RR and TTP favored patients with exon 19 or 21 EGFR gene mutations, confirming the relevance of these mutations in TKI sensitivity. Although retrospective studies suggested that patients with exon 19 deletion had better RR and longer survival than patients with L858R mutations,15,42-45 in this trial, no difference in RR was observed, and the median survival was not reached in patients harboring one of these mutations, precluding investigation of a possible survival difference. In our study, four patients harbored concurrent EGFR mutations. This phenomenon has been previously reported,39,46 and the relatively high frequency observed could be a result of the higher sensitivity of the adopted nonsequencing-based mutation detection method.29 Recent studies showed that, in patients with tumor-bearing TKI-sensitive EGFR mutations, resistant subclones containing an additional EGFR gene mutation (T790M) emerge in the presence of TKIs.47,48 Importantly, no tumor with this mutation also had the K-ras mutations typically occurring in smokers and significantly associated with TKI primary resistance.12 Mutation of the HER2 gene was reported in lung adenocarcinoma,46 and cancer cells presenting this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs.49,50 In our study, all patients with mutation in exon 20 of the EGFR gene or harboring HER2 or K-ras mutations did not respond to gefitinib, supporting that these are different mechanisms involved in primary TKI resistance. Because of the difficulty in performing serial biopsies in a not easily accessible disease, paired tumor samples were obtained in a fraction of patients. Nevertheless, there was a high concordance for EGFR FISH and mutation results between tissues collected at the original diagnosis and immediately before starting gefitinib therapy. These findings suggest that there is no need to rebiopsy patients with tumor tissue available, even if this tissue has been collected at the time of primary diagnosis and the patient has received subsequent therapies. In conclusion, the results of the ONCOBELL trial showed that gefitinib is highly active and well tolerated for patients with the trial characteristics. EGFR FISH analysis is an accurate predictor for gefitinib therapy, and DNA sequencing is of great relevance for the identification of sensitive and potentially resistant patients. The results of this study strongly support further studies in NSCLC comparing gefitinib with standard chemotherapy in EGFR FISH–positive patients, as well as new trials with anti-HER2 agents.
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: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: Pasi A. Jänne, Genzyme
Conception and design: Federico Cappuzzo Financial support: Federico Cappuzzo Administrative support: Federico Cappuzzo, Stefania Bartolini Provision of study materials or patients: Federico Cappuzzo, Rocco Trisolini, Daniela Paioli, Giovanna Finocchiaro, Alessandra Cancellieri, Fortunato Ciardiello, Marco Patelli, Lucio Crino Collection and assembly of data: Federico Cappuzzo, Pasi A. Jänne, Alison J. Holmes, Elisabetta Magrini, Giovanna Finocchiaro, Marileila Varella-Garcia Data analysis and interpretation: Federico Cappuzzo, Claudia Ligorio, Pasi A. Jänne, Luca Toschi, Elisa Rossi, Marileila Varella-Garcia Manuscript writing: Federico Cappuzzo, Marileila Varella-Garcia Final approval of manuscript: Federico Cappuzzo, Pasi A. Jänne, Luca Toschi, Elisa Rossi, Alessandra Cancellieri, Fortunato Ciardiello, Lucio Crino, Marileila Varella-Garcia
We thank AstraZeneca for providing the study drug and the Cytogenetics Core of the University of Colorado Cancer Center and the Dana-Farber Cancer Institute for technical assistance.
Supported by the Italian Association for Cancer Research (F.C. and L.T.) and National Institutes of Health Grants No. 1K12CA87723-01 (P.A.J.) and 1RO1CA114465-01 (P.A.J.). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10% of tumor nuclei, as previously reported.
statistic.
