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Originally published as JCO Early Release 10.1200/JCO.2005.08.326 on June 6 2005 © 2005 American Society of Clinical Oncology. Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer
From the Vall d'Hebron University Hospital; Hospital Clinic, Barcelona; Instituto Valenciano de Oncologia; Universitat de Valencia, Hospital Clínico Universitario de Valencia and CESAT Valencia, Spain; and AstraZeneca, Wilmington, DE Address reprint requests to José Baselga, MD, Chairman and Professor of Medicine, Medical Oncology Service, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129 08035 Barcelona, Spain; e-mail: jbaselga{at}vhebron.net.
PURPOSE: To evaluate the antitumor activity and pharmacodynamic/biologic effect of gefitinib 500 mg/day monotherapy in patients with previously treated, advanced breast cancer. METHODS: In this phase II multicenter trial, the primary objective was assessment of the tumor response rate with gefitinib; secondary objectives included analysis of the pharmacodynamic and biologic profiles in healthy and tumor tissue.
RESULTS: Of 31 assessable patients, 12 (38.7%) had stable disease, including 3 (9.7%) with recurrent breast cancer that stabilized for CONCLUSION: This study demonstrates a good correlation between the degree of inhibition of EGFR in skin and in breast tumors. The lack of significant clinical activity of gefitinib in our study population is not due to lack of receptor inhibition in these tumors but rather to lack of EGFR dependence in the tested population.
Breast cancer is the most common cancer in women in the world1,2 and despite improvements in treatment, the survival rate for patients with metastatic breast cancer remains poor, with a 5-year survival of only 23%.2 Although there is evidence that recent additions to the armamentarium of cytotoxic and hormonal agents may be producing an improvement in survival,3 there is increasing interest in the development of agents that act against the molecular targets that dictate malignant growth.4 In breast cancer, this approach is exemplified by the successful targeting of the ErbB family of growth factor receptors by trastuzumab (Herceptin; Genentech Inc, San Francisco, CA). Trastuzumab is a humanized monoclonal antibody directed at the ErbB2 receptor that is active and results in improved survival in patients with advanced breast cancer that has ErbB2 amplification.5-7 The epidermal growth factor receptor (EGFR), like ErbB2, is a member of the ErbB family of receptors (also known as type I receptor tyrosine kinases). This family of receptors plays a major role in promoting proliferation and the malignant growth of breast cancer cells. The expression of EGFR in breast cancer has been studied extensively and has been associated with poor prognosis.8-14 As a consequence, inhibiting EGFR function may be a fruitful approach in breast cancer therapy. Gefitinib (Iressa; AstraZeneca, Macclesfield, United Kingdom) is an oral nonpeptide anilinoquinazoline compound that inhibits the tyrosine kinase activity of EGFR with an inhibitory concentration (IC50) of 0.03 µM.15 Preclinical studies demonstrated that gefitinib inhibited proliferation of breast cancer cells both in vitro and in vivo.16-20 Interestingly, the antitumor activity in breast cancer cells has been seen in cells expressing varying degrees of EGFR and also in cells expressing high levels of ErbB2. In the clinical setting, phase I trials of gefitinib monotherapy showed that this agent was generally well tolerated, with the majority of adverse events (AEs) being grade 1 to 2 gastrointestinal or skin events.21-24 Furthermore, antitumor activity was demonstrated in a range of tumor types, including the observation of prolonged stable disease in patients with breast cancer. Phase II trials of gefitinib monotherapy in previously treated patients with advanced non–small-cell lung cancer resulted in a response rate ranging from 9% to 19% and disease control in more than 40% of patients.25,26 In addition to non–small-cell lung cancer, responses have been reported in patients with advanced head and neck carcinomas.27 The primary aim of this study was to determine the response rate of gefitinib 500 mg/day in pretreated patients with locally advanced or metastatic breast cancer. Another important goal was to analyze the pharmacodynamic effects of gefitinib in the tumor, in order to further clarify the mechanism of action of this agent. We had initially proposed and reported that skin is a good surrogate tissue to study EGFR inhibition with anti-EGFR agents.21,22,28 Subsequent studies have confirmed a significant inhibition of EGFR phosphorylation and downstream signaling in the skin with other anti-EGFR inhibitors, including the tyrosine kinase inhibitor erlotinib (OSI-774, Tarceva; OSI Pharmaceuticals, Genentech, and Roche, Melville, NY)29 and preliminary confirmatory results with CI-103330 and the monoclonal antibody EMD72000.31 However, an important question that was not addressed in our initial studies was whether there was a correlation between inhibition of EGFR in the skin and in the tumor, as well as the downstream effects of EGFR inhibition in the tumors. Therefore, this study included evaluation of sequential tumor biopsies in order to answer this question.
Study Design This was a multicenter, phase II, pharmacodynamic trial. Patients received gefitinib 500 mg/day, apart from day 1, when, in order to ensure that steady-state levels were rapidly reached, the patient received gefitinib 500 mg followed by a second 500 mg dose 12 hours later. Each treatment cycle was 28 days and patients received gefitinib until disease progression, unacceptable toxicity, or withdrawal of consent. The maximum period of treatment was 6 months after entry of the last patient (total maximum duration of 15 months). Administration of gefitinib could be prolonged at the discretion of the investigator, based on patient benefit and tolerability. The primary objective was to evaluate the objective tumor response rate to gefitinib 500 mg/day in patients with locally advanced or metastatic breast cancer previously treated with chemotherapy. Determination of the pharmacodynamic profile of gefitinib in skin versus tumor tissues and evaluation of the safety of gefitinib were secondary objectives.
Patients
The minimum anticipated number of patients was 21, based on a two-stage design for phase II studies, where the drug would be considered inactive in terms of response index if more than 5% of patients responded, giving a maximum response index of 20%. If a response of
To be eligible for inclusion, patients were required to be 18 years of age or older with a life expectancy of The trial was conducted in accordance with the Declaration of Helsinki32 and the principles of Good Clinical Practice, and with the approval of appropriate ethics committees.
Assessments Response and survival Response was assessed using Response Evaluation Criteria In Solid Tumors (RECIST).33 Disease control included those patients with objective response (complete or partial response) or stable disease, confirmed and maintained for at least a further 4 weeks. Tumor status was assessed at baseline, every 4 weeks after starting treatment, then every 8 weeks after the fourth treatment period. Progression-free survival was assessed from the date of random assignment until the date at which disease progression was observed. If death occurred before the disease had progressed, this was considered to be progression. Patients who did not have documented objective progression on the date of the last analysis were excluded. Overall survival was evaluated from the date of random assignment until the date of death, or until the last available date for the living patient. Tolerability All AEs were reported (including evaluation of causality) and graded according to the CTC scale (version 2.0). Dose reduction from 500 to 250 mg/day was allowed in the case of toxicity (CTC grade 3 or 4 toxicity reversible within 14 days). Administration of gefitinib could be interrupted for a maximum of 14 days in the event of CTC grade 3 or above or unacceptable toxicity. The patient could resume taking the assigned dose, or a reduced dose, once the severity of the AE decreased to CTC grade 1 to 2. Pharmacodynamic assessments In those patients who gave their consent, skin and tumor biopsies were taken before treatment (at the time of giving consent [baseline]), after 28 days of treatment, and at the time of disease progression, if possible. Samples of skin and tumor tissue were analyzed at Vall d'Hebron University Hospital, Barcelona, Spain.
The following pharmacodynamic markers were assessed with appropriate antibodies: EGFR (mouse monoclonal antibody [MAb] clone 2-18C9, DAKO, Carpinteria, CA), activated/phosphorylated (p) EGFR (mouse MAb clone 74, Chemicon, Temecula, CA), the ligand transforming growth factor alpha (TGF
Patients The first patient was recruited in April 2001 and the last in November 2002. In total, 31 patients were assessable, and their demographic characteristics are shown in Table 1. Nineteen patients had previously received first-line chemotherapy and 10 patients had received second-line chemotherapy. The majority of patients had previously received hormone therapy or trastuzumab in addition to chemotherapy.
Clinical Activity The median length of treatment period was 56 days (range, 27 to 350 days). Of the 31 patients, 12 (38.7%) had stable disease, of whom 10 (32.3%) were stable for  3 months, 6 (19.4%) were stable for 4 months, and 3 (9.7%) were stable for 6 months. Duration of stable disease was 84 to 349 days. No complete or partial responses were observed. Progressive disease occurred in 19 patients (61.3%), with a median time to progression of 55 days (95% CI, 42 to 88). Median overall survival was 503 days (95% CI, not assessable; range, 56 to 617 [censored] days). The proportion of patients alive at 6 months was 80.6% (95% CI, 66.7 to 94.6) and the proportion alive and progression free at 6 months was 9.7% (95% CI, 0.0 to 20.1).
Tolerability
Pharmacodynamic Analysis Paired baseline and day-28 skin biopsies were obtained from 31 patients, and 27 paired samples showed good antigen preservation in the tissue and were satisfactorily analyzed by immunohistochemistry.
A Spearman's correlation test showed a significant relationship between EGFR expression and expression of the signaling markers TGF
Basal expression levels of EGFR, p-EGFR, p-MAPK, TGF  , Ki67, and p27 were analyzed in skin biopsies and compared with expression levels on day 28 following gefitinib treatment (Fig 2). Gefitinib inhibited the phosphorylation of EGFR and MAPK, decreased the expression of Ki67, and resulted in an increase in expression of inhibitor p27 in the keratinocytes of the epidermis. Expression levels of EGFR and TGF were not affected by gefitinib treatment. In addition, gefitinib treatment resulted in morphologic changes in the epidermis, including thinning of the stratum corneum with eosinophilia and loss of its characteristic normal basket-weave configuration, associated with weak perivascular inflammatory lymphocytic infiltrates around the superficial blood vessels of the dermis.
Similar analyses were carried out in tumor samples. Mandatory baseline samples were available for 31 patients (archival tissue from 11, fresh tissue from 20), 16 of whom also had optional on-study tumor samples (taken on day 28) available (Table 3). Treatment with gefitinib did not appear to have an effect on tumor expression of EGFR or TGF . In a similar manner as in the skin, gefitinib inhibited phosphorylation of EGFR and MAPK in tumor biopsies (Figs 3, 4a, 4b). Inhibition of MAPK phosphorylation also occurred in EGFR-negative tumor biopsies (Fig 4b); this could be an indication that immunohistochemistry fails to detect low EGFR levels in some tumors, or that gefitinib may be inhibiting other members of the ErbB receptor family.17 However, gefitinib did not result in inhibition of pAkt, and did not decrease proliferation (Ki67) or increase p27 levels (Fig 3). Taken together, the comparison of the data in the skin and the tumor revealed that the effects of gefitinib were identical at the level of receptor phosphorylation but not in receptor downstream markers, where there was discordance between changes in Ki67 and p27 levels.
In EGFR-positive tumors, treatment with gefitinib induced a significant increment of apoptotic index (P = .042), as determined by TUNEL assay. There was no significant difference in EGFR expression between patients with progressive disease and those with stable disease (P = .612). Similarly, there was no association of longer stability with the expression of p-EGFR (P = .33) or of ErbB2 (P = 1).
Although there was a strong scientific and clinical rationale behind this study of single-agent gefitinib in patients with breast cancer, the clinical benefit observed was modest in our study population: more than one third of patients experienced stable disease, which lasted for 6 months in three patients but no objective tumor responses as per RECIST were observed and the study was terminated, as per protocol design.
Two other phase II studies of gefitinib 500 mg/day in patients with advanced breast cancer have demonstrated similar results. The first, by Robertson et al,34 evaluated gefitinib in 33 patients with tamoxifen-resistant estrogen receptor (ER) -positive and ER-negative breast cancer. Preliminary results showed that, of 19 assessable patients, two had a partial response by RECIST and three had stable disease for A potential explanation for the limited activity of gefitinib monotherapy in advanced breast cancer could be that the dose used was suboptimal to block the receptor in the tumor. This study, like the studies by Robertson et al and Albain et al, used 500 mg/day gefitinib, a relatively high dose. Although we had previously reported that gefitinib at the dose used in this study resulted in complete inhibition of EGFR phosphorylation and EGFR-dependent processes in the skin,28 the effects of gefitinib on receptor phosphorylation in the tumor were unknown. In this study we have demonstrated that, at this dose, gefitinib results in complete inhibition of receptor phosphorylation both in the skin and the analyzed tumors. This good correlation between receptor inhibition in the skin and the tumor provides additional support to the use of skin as a surrogate tissue to predict inhibition of EGFR activation in the tumor. The lack of meaningful clinical activity, despite inhibition of EGFR phosphorylation and some EGFR-dependent processes, could be due to the fact that the treated tumors are not EGFR dependent and, in this setting, blocking the receptor may not be enough to induce an antitumor effect. This could also explain the lack of concordance in downstream markers in the skin, where a marked inhibition of Ki67 and an increase in p27 is seen, in contrast with the absence of change in Ki67 and p27 in the tumor samples. In a phase I study of the anti-EGFR monoclonal antibody EMD72000in patients with advanced tumors, there was complete inhibition of tumor p-EGFR and p-MAPK in all patients, whereas pAkt and Ki67 was inhibited only in responding patients.31,37 This suggests that some, but not all, downstream markers correlate with clinical response. In light of the successful blockade of EGFR activation in breast cancer and the lack of activity in a broad-based breast cancer patient population, it will be important to study the activity of gefitinib in selected patient populations with EGFR-dependent tumors and to explore rational combination with other targeted agents. Among a series of potential combinations, there is a growing impetus to combine gefitinib with hormonal treatments. This stems from cross talk between the ErbB family of receptors and ER signaling in breast cancer.38 In vitro data show that endocrine-resistant or -insensitive cells are highly sensitive to gefitinib.11 Furthermore, when antihormone-responsive MCF-7 breast cancer cells were treated with gefitinib in combination with tamoxifen or fulvestrant (Faslodex; AstraZeneca), there was added growth-inhibitory activity and the development of antihormone resistance was blocked or delayed.11,39,40 The molecular basis underlying the cross talk between ErbB and ER is currently being established. For example, studies in tumors from breast cancer patients have shown that high-level co-expression of the ER coactivator amplified in breast cancer-1 (AIB1) and of ErbB2 has a role in tamoxifen resistance.41 EGFR and ErbB2 signaling phosphorylates and activates both ER and AIB1 and, in this setting, tamoxifen behaves as an ER agonist. In experimental model systems, gefitinib blocks receptor cross talk and fully reverses tamoxifen resistance.42 These results indicate that the combination of gefitinib with hormonal therapy should be tested in the clinical setting and phase II trials are ongoing, including evaluation of gefitinib in combination with tamoxifen and with anastrozole (Arimidex; AstraZeneca). Other treatment combinations include the combination of gefitinib with trastuzumab20,43,44 and this is also currently being studied in clinical trials with patients with metastatic breast cancer. It is unclear at this time how to select a patient population most likely to be sensitive to gefitinib. In addition to the possibility of selecting patients by ER status, acquired or primary tamoxifen resistance, and/or by the expression of AIB1, another factor for consideration is the potential role of ErbB2 in gefitinib sensitivity. Preliminary results from a phase II trial of a dual EGFR/ErbB2 inhibitor have shown modest antitumor activity in patients with ErbB2-overexpressing metastatic breast cancer.45 In preclinical models, gefitinib has shown activity in breast carcinoma cell lines that express high levels of ErbB2.17 Therefore, one possibility would be to study gefitinib in patients with high expression of ErbB2. The possible role of mutations in predicting response is also of interest. Recently, EGFR mutations have been associated with dramatic responses to gefitinib in patients with lung cancer.46,47 However, the rate of mutations in patients with breast cancer remains unclear. Lynch et al46 did not find any mutations of EGFR exons 19 and 21 in any of 15 primary breast cancer samples analyzed. A further point for consideration is that gefitinib may have more activity against earlier stage breast cancer, compared with the advanced disease of the patient population in the current study. Gefitinib 500 mg/day was generally well tolerated in this study, with the majority of drug-related AEs being grade 1 to 2 gastrointestinal or skin disorders, in agreement with reports from other clinical trials.21-25,48 Skin rash and diarrhea were the main grade 3 to 4 drug-related AEs to be observed, which resolved in all patients. In summary, despite the observed low activity with gefitinib in patients with advanced breast cancer in this study, complete inhibition of EGFR phosphorylation was observed in all the studied tumors that had pretherapy EGFR phosphorylation. Thus, inhibition of EGFR phosphorylation may be an indicator of target inhibition but not of sensitivity to anti-EGFR agents. Although target inhibition may be necessary to achieve antitumor activity, it is likely that sensitivity to this class of agents will be based on the level of receptor dependence of a given tumor. From our study, we conclude that gefitinib 500 mg/day results in an optimal target effect. Ongoing and future studies of gefitinib in combination with other agents and studies in selected subgroups of patients will hopefully identify the subsets of breast cancer patients susceptible to EGFR inhibition.
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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23. Nakagawa K, Tamura T, Negoro S, et al: Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid malignant tumours. Ann Oncol 14:922-930, 2003
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25. 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. J Clin Oncol 21:2237-2246, 2003 26. Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD 1839 (‘Iressa’) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 21:292a, 2002 (abstr 1166)
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29. Malik SN, Siu LL, Rowinsky EK, et al: Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. Clin Cancer Res 9:2478-2486, 2003 30. Zinner RG, Donato NJ, Nemunaitis JJ, et al: Biomarker modulation in tumor and skin biopsy samples from patients with solid tumors following treatment with the pan-erbB tyrosine kinase inhibitor, CI-1033. Proc Am Soc Clin Oncol 21:15a, 2002 (abstr 58) 31. Tabernero J, Rojo F, Jimenez E, et al: A phase I PK and serial tumor and skin pharmacodynamic (PD) study of weekly (q1w), every 2-week (q2w) or every 3-week (q3w) 1-hour (h) infusion EMD72000, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients (pt) with advanced tumors. Proc Am Soc Clin Oncol 22:192, 2003 (abstr 770)
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33. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 34. Robertson JFR, Gutteridge E, Cheung KL, et al: Gefitinib (ZD 1839) is active in acquired tamoxifen (TAM)-resistant oestrogen receptor (ER)-positive and ER-negative breast cancer: Results from a phase II study. Proc Am Soc Clin Oncol 22:7, 2003 (abstr 23) 35. Albain K, Elledge R, Gradishar WJ, et al: Open-label, phase II, multicenter trial of ZD 1839 (‘Iressa’) in patients with advanced breast cancer. Breast Cancer Res Treat 76:S33, 2002 (suppl 1; abstr 20)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1 was observed from the 21 patients, more patients would not be included. If the response was more than 1 of 21 patients, recruitment would continue until 41 patients had been included to permit a better estimate of the response index. The probability of accepting a drug as active with a response index less than 5% is 5% (
