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Sarcoma Research Series

A Phase II Study of Gefitinib for Patients with Advanced HER-1 Expressing Synovial Sarcoma Refractory to Doxorubicin-Containing Regimens

¹Centre Léon Bérard and UJOMM H. E. Herriot, Lyon, France; ²I. Gustave Roussy, Villejuif, France; ³University College Hospital, London, United Kingdom; ⁴U.Z. Leuven, Leuven, Belgium; ⁵Institut Bergonie, Bordeaux, France; ⁶U.Z. and Erasmus, Rotterdam, The Netherlands; ⁷European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; ⁸University Leiden, The Netherlands

Key Words. Sarcoma • Synovial sarcoma • HER-1 • Expression microarrays • Gefitinib

Correspondence: J.-Y. Blay, M.D., Ph.D., Unité Cytokine et Cancer, Unité INSERM U590, Centre Léon Bérard, 28, rue Laennec, 69008 Lyon, France. Telephone: +33478782757; Fax: +3347878782716; e-mail: blay{at}lyon.fnclcc.fr

Received March 14, 2008; accepted for publication March 18, 2008.

Disclosure: This article references unlabeled use of gefitinib (AstraZeneca) for use in a phase II trial in HER-1 synovial sarcomas. J.-Y.B. has received consulting fees and has contracted research from Novartis, Pfizer, GlaxoSmithKline, and Roche; and has received unrestricted grant for research from Novartis. P.H. has received consulting fees from Novartis. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

	ABSTRACT

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Rationale. Advanced synovial sarcomas (SyS) refractory to doxorubicin and ifosfamide are highly resistant to the currently available cytotoxic agents. Based on a report showing a specific overexpression of HER-1 in SyS, we investigated an HER-1 inhibitor, gefitinib, in refractory SyS.

Subjects and Methods. To establish the efficacy and safety of gefitinib in HER-1 – positive SyS refractory to one or two lines of doxorubicin- and ifosfamide-based chemotherapy, a phase II study was conducted from December 2002 to October 2005 by 12 centers of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Gefitinib was given at a 500-mg/day oral dose until progression or intolerance.

Results. Forty-eight patients were included (46 eligible). All patients had previously received chemotherapy for metastatic disease, with a median number of two lines (range, 1–4). The most frequent metastatic sites were the lungs (n = 44, 92%), lymph nodes (n = 11, 23%), and soft tissues (n = 10, 21%). The median duration of treatment was 43 days (range, 13–315). Treatment was interrupted in five patients (10%). Treatment was halted for progression in 45 (94%) patients. The best response was stable disease in 10 patients (21%). Disease progression occurred in 32 patients (70%), with a median time to disease progression of 6 weeks. Progression-free survival at 4 and 6 months was 21% and 6%, respectively.

Conclusion. The results show that gefitinib monotherapy in advanced SyS refractory to conventional chemotherapy did not demonstrate sufficient activity to warrant further investigation in this setting. This may suggest that HER-1 is not a critical protein in tumor progression in this disease.

	INTRODUCTION

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Soft tissue sarcomas represent a heterogeneous group of rare malignant diseases from mesenchymal cells whose overall incidence is close to 6 per 100,000 per year [1]. There are multiple histological subtypes of soft tissue sarcoma, and histological classifications have actually evolved constantly in the past years as a consequence of the refinements of immunohistochemical and molecular investigations, which have enabled the identification of specific molecular alterations associated with discrete histological subtypes [2]. Synovial sarcoma represents 5%–10% of all sarcoma subtypes and is the fourth most common type of sarcoma. Synovial sarcoma occurs at all ages but predominantly in adolescent and young adults, between 15 and 40 years of age mostly, with a slight male predominance [3–5].

The local treatment for synovial sarcoma is similar to that of other soft tissue or visceral sarcomas and is based on surgical removal of the primary tumor and post- or preoperative radiotherapy [1]. Chemotherapy has not been demonstrated to produce longer survival in the adjuvant setting and is reserved for the treatment of advanced disease, most often with palliative intent [6–7]. Until recently, similar chemotherapy regimens were given to patients with all types of sarcomas in the advanced setting: doxorubicin and ifosfamide yield response rates in the range of 10%–25% in monotherapy and 20%–35% in combination therapy with few long-lasting responses and only a small proportion of patients achieving long-term survival [1, 8, 9].

In the last years, however, there has been a shift from the use of undifferentiated therapy for all sarcoma subtypes to specific chemotherapy regimens for distinct sarcoma subtypes. Patients with gastrointestinal stromal tumor (GIST) now receive imatinib and sunitinib, while leiomyosarcoma may exhibit a specific sensitivity to gemcitabine and docetaxel, angiosarcomas are now considered as taxane-sensitive diseases, and myxoid liposarcoma may be exquisitely sensitive to trabectedin [10–13].

The molecular characterization of these tumors guides the development of some of these novel treatments (GIST, dermatofibrosarcoma protuberans, tenosynovial giant cell tumor [14–17]. Specific t(X,18)(p11.2;q11.2) translocations have been reported to be associated with synovial sarcomas and represent a hallmark of the tumor [3–5]. These translocations fuse the SYT gene on chromosome 18p11 and three of the six members of the SSX gene family on chromosome Xq11, namely, the SSX1 or SSX2 genes, and less frequently the SSX4 gene. The t(X,18) translocation results in a gene encoding for a protein in which the addition of the C terminal domain of SSX to the SYT–SS18 protein affects its activation and repressive activities on gene expression.

Several groups have investigated gene-expression patterns in synovial sarcoma subtypes using cDNA microarrays [18–21]. Nielsen et al. [18] used a 42K gene array and identified a specific set of genes associated with the histological subtype of synovial sarcoma: 13 genes were found to be overexpressed in these specific subtypes, including the relevant SSX3 and SSX4 genes previously identified in translocation variants of synovial sarcomas and those encoding cytokines (transforming growth factor β2, bone morphogenic protein [BMP]2 and BMP7), and receptors (epidermal growth factor receptor [EGFR], also known as human epidermal growth factor receptor [HER]-1). The mechanisms through which these genes are overexpressed specifically in synovial sarcomas remain unclear. The HER-2/neu gene was also found to be overexpressed in a series of 37 synovial sarcoma tumor samples in another study reported by Allander et al. [19].

HER-1 is a well known proto-oncogene for a wide range of tumors; it promotes synovial sarcoma cell line proliferation in vitro and therefore may contribute to the progression of synovial sarcomas [22–24]. For this reason, with the assumption that HER-1 could be an important target gene of the fusion gene product that may contribute to tumor cell survival and mitosis, we initiated a phase II clinical trial to investigate gefitinib, an EGFR tyrosine kinase inhibitor [24], for the treatment of patients with synovial sarcomas expressing HER-1.

	PATIENTS AND METHODS

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Inclusion and Exclusion Criteria
Patients were required to be >15 years of age with histologically proven locally advanced and/or metastatic synovial sarcoma expressing HER-1 in the primary tumor or in metastases, with progressive disease, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2, and with a life expectancy of at least 3 weeks, measurable disease, and normal organ function as defined by a granulocyte count >1,500/µl, a platelet count >100,000/µl, bilirubin <20 µmol/l, and normal serum creatinine or creatinine clearance >60 ml/minute. Expression HER-1 antigen was evaluated on paraffin-embedded material using the DAKO monoclonal antibody (mAb) (DAKO Denmark A/S, Glostrup, Denmark). If not feasible, the Zymed clone 31G7 mAb (Zymed Laboratories, San Francisco, CA) could also be used for inclusion in the trial. All histological slides were externally reviewed according to the standard procedure of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC STBSG), and immunohistochemical assessment was done for CD99, Bcl-2, epithelial membrane antigen, and cytokeratin, (DAKO) [25].

No concurrent therapy was allowed and patients were required to give written informed consent prior to inclusion.

Treatment
Patients were given a dose of 500 mg/day of gefitinib. Dose adaptations were performed as follows: the dose of gefitinib was reduced in cases of severe skin toxicity not amenable to symptomatic treatments until resolution of the symptoms. In cases of gastrointestinal toxicity of grade >3, treatment was interrupted until recovery to grade <1. The gefitinib dose could be reduced to 250 mg/day if the side effects recurred despite appropriate measures.

Response Criteria
Response to therapy was evaluated every 6 weeks (two courses of therapy) using Response Evaluation Criteria in Solid Tumors. Complete response (CR) was defined as a complete disappearance of all known disease, determined by two observations not less than 4 weeks apart. Partial response (PR) was defined as a 30% decrease in total tumor size (relative to the initial tumor size), determined by two observations not less than 4 weeks apart, with no appearance of new lesions and no progression of any lesion. Progressive disease (PD) was defined as a 20% increase in the size of one or more measurable lesions (relative to the smallest size measured since the start of treatment) or the appearance of a new lesion or lesions. No change (NC) was recorded when neither a CR nor a PR nor PD was demonstrated at least 6 weeks after the start of treatment. In cases of CR of the target lesions, a PR or NC in a nontarget lesion resulted in a rating of PR. The evidence of progression of any lesion or appearance of a new lesion resulted in a rating of PD. All objective responses had to be reviewed and confirmed by external experts.

Statistical Considerations
The supposed mechanism of gefitinib is to interfere with the transformation and progression process of synovial sarcoma. Therefore, the principal endpoint of this phase II study was selected to be disease stabilization rather than objective response. The 12-week progression-free rate (taken as a binary variable) was chosen as the primary endpoint. Success was defined as the absence of progression after at least 12 weeks of therapy. The Simon optimal one-sample two-stage testing procedure (optimal design) was used with the following hypotheses: the absence of progression (at 12 weeks) in 45% of cases was considered as an acceptable result warranting further investigation of the drug in patients with synovial sarcoma, and therefore the value of P1 was taken as 45%; and the absence of progression (at 12 weeks) in 25% of cases was considered as unacceptable and would not warrant further investigation, and therefore the value of P0 was taken as 25%. These two reference values are based on a retrospective analysis of the EORTC STBSG database of patients treated with second-line therapy [26]. Under these hypotheses, in total, 44 eligible and treated patients needed to be recruited and followed for at least 3 months ( = β = .1). If 15 successes were observed in those 44 patients, the conclusion would be that gefitinib deserves further investigations in synovial sarcoma. The trial was to be conducted in two successive steps to avoid treating too many patients with an inactive drug. Fourteen eligible and treated patients were to be included in the first step of the study. If more than three successes were observed, the trial was to be stopped, with the conclusion that the drug should not be further investigated; otherwise, patients were to continue to be accrued until 44 eligible patients had been recruited and had started therapy.

	RESULTS

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Description of Patients
Forty-eight patients with histologically proven locally advanced and/or metastatic synovial sarcomas expressing HER-1 on immunohistochemical analysis of the primary or metastatic tumors and with progressive disease were entered into the study: two check patients were ineligible because of nonsynovial sarcoma histology. Forty-eight patients were evaluable for toxicity and 46 patients were evaluable for the primary endpoint. The clinical and biological characteristics of these patients and their tumors are depicted in Table 1.

HER-1 Expression
HER-1 expression was an inclusion criterion and was confirmed in 100% of the 30 cases reviewed centrally. It was apparent that the expression was not diffuse, staining a percentage of the tumor cells only. Most staining was cytoplasmic. There was no relation between immunoreactivity and the response pattern.

Response
A median duration of 43 days of gefitinib was given, with a range of 13–312 days. No objective CR or PR was seen. No minor responses were seen. Thirty-two (70%) patients experienced PD at their first evaluation. Ten (22%) patients experienced NC as their best response. The median time to progression was 6 weeks (Fig. 1). Only five of the 46 eligible patients had disease stabilization on day 84 (the primary endpoint), while 15 were needed to consider the drug active. Disease stabilization in these five patients lasted for 84–209 days. No prognostic factor for success could be identified (not shown).

View larger version (14K): [in this window] [in a new window]   Figure 1. Progression-free survival (PFS) and overall survival (OS). Abbreviations: N, total numbers; O, observed numbers.

Toxicity
The treatment was well tolerated (Table 2). A single patient experienced grade 4 neutropenia and thrombopenia (2%). A single patient (2%) experienced febrile neutropenia. One patient (2%) experienced grade 2 nausea, one patient (2%) experienced grade 3 lethargy, one patient (2%) experienced grade 3 headache, and one patient (2%) experienced grade 3 asthenia. One patient died on day 17 of treatment from pneumopathy considered not related to the treatment.

	DISCUSSION

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Advanced nonresectable soft tissue sarcomas are poorly susceptible to cytotoxic chemotherapy, and doxorubicin, ifosfamide, trabectedin, and the combinations of gemcitabine and docetaxel [8, 9, 11–13] are the only effective drugs and drug combinations demonstrated to be active in these diseases. The activity of other drugs has remained disappointingly low in first-line chemotherapy, even though two vascular endothelial growth factor receptor–targeting agents, pazopanib and sorafenib, were reported to exert antitumor activity in advanced soft tissue sarcomas during the 2007 American Society of Clinical Oncology annual meeting. Unfortunately, the results obtained indicate clearly that gefitinib is not an active agent in patients with advanced synovial sarcomas failing doxorubicin and/or ifosfamide. Only five of the 46 eligible patients had disease stabilization on day 84, while the drug would have been considered as worth further study in this disease if 15 such successes had been observed among 44 eligible patients.

The reason for this may be the marginal role played by HER-1 in synovial sarcoma growth and survival. For a targeted therapy inhibiting signal transduction pathways to be active, it is generally considered that the target protein should (a) be present, (b) be in an activated form, (c) contribute to the oncogenic process, and (d) be blocked efficiently by the administered agent. In the present case, HER-1 expression was one of the inclusion criteria of the trial, but HER-1 activation, as evaluated by phosphorylation status, was not investigated. While the first condition was fulfilled, conditions (b) and (c) were possibly not met. Another reason might be the nondiffuse expression of the protein in tumor cells. This explanation is, however, unlikely, because in that case at least some response would be expected.

The molecular hallmark of synovial sarcoma is the t(X,18) translocation, which fuses two genes encoding proteins with different functions: the SYT–SS18 protein is a transcriptional coactivator interacting with members of the epigenetic chromatin remodeling and modification machineries, while the SSX1, SSX2, and SSX4 proteins act as corepressors interacting with proteins of the polycomb complex. Although there is not yet a full understanding of the biological functions of the SS18–SSX1 and SS18–SSX2 fusion proteins, these have been reported to exert several biological functions that are likely important for neoplastic transformation: (a) restoration of E-cadherin expression blocking the Snail and Slug repressors, to interact with the cytoskeleton and Eph B2 causing altered morphology and migration capacities [27]; (b) promotion of cyclin D1 expression [28]; (c) promotion of p53 ubiquitinylation through stabilization of human homologue of murine double minute 2 [29]; (d) interaction with transcription factor LIM homeobox protein 4 [30]; (e) downregulation of candidate of metastasis 1, a regulator of cell proliferation [31]; (f) induction of cell adhesion molecule claudin7 expression, through an E74-like factor 3–dependent mechanism [32]; (g) induction of insulin-like growth factor (IGF)-2 and CD44 [33]; and (h) recruitment of β-catenin to the nucleus [34]. In addition, other growth factors are likely to contribute to synovial cell sarcoma survival and proliferation, including the c-Met receptor and its ligand [35] and IGF-1R [36].

Besides its overexpression in synovial sarcomas on expression arrays or immunohistochemistry [21, 37], no mechanistic link between the fusion protein and HER-1 has actually been reported, and the exact contribution of HER-1 to synovial sarcoma tumor growth is not clear.

Indeed, EGF induces proliferation of synovial sarcoma cell lines [21], and expression microarrays have detected overexpression of HER-1 or HER-2, but this has not been consistently observed in all studies [17–20]. Expression of HER-1 was reported previously in a large proportion of synovial sarcoma patients [37], but it is not consistently correlated with proliferation. Mutations of HER-1 exons 18–21 are rare (<15%) and of unknown significance [38]; no amplifications of EGFR/HER-1 were observed in fresh tumor tissues [38]. The membrane expression of HER-2, a major partner for heterodimerization for HER-1, was found to be correlated with Ki-67 expression in one study [39], but HER-2 expression was recently found to be associated with a lower risk for metastasis [40]. In fact, EGF has been found to induce cell proliferation in synovial sarcoma in vitro [22], but gefitinib was later found to be able to inhibit synovial sarcoma cell line proliferation only at high concentrations not achievable in vivo in patients [41].

The results reported in this paper show that HER-1, even though it contributes to synovial sarcoma proliferation, does not play a central role in this model, for example, like Kit in GIST. Even among patients who achieved stable disease, progression occurred rapidly afterward and no patient was progression free >320 days after the initiation of treatment. Whether gefitinib may be useful in combination with other agents, for example, IGF-1R or heat shock protein-90 inhibitors, cannot be ruled out. Similarly, the therapeutic role of EGFR antibody has not been assessed in this disease to our knowledge, and may deserve further investigations trying to exploit an antibody-dependent cell-mediated cytotoxicity effect.

In conclusion, these results show that the EGFR tyrosine kinase inhibitor gefitinib given as a single agent has no therapeutic role in advanced synovial sarcoma. The identification of a target, and a potential targeted therapy, using an expression microarray strategy was not successful in this case, pointing out the importance of identifying the critical steps in neoplastic transformation to select active cancer-targeted therapies in a given tumor type.

	AUTHOR CONTRIBUTIONS

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Conception/design: Jaap Verweij, Martine van Glabbeke, Jean-Yves Blay

Administrative support: Sandrine Marreaud, Martine van Glabbeke

Provision of study materials or patients: Isabelle Ray-Coquard, Axel Le Cesne, Jeremy S. Whelan, Patrick Schoffski, Binh N. Bui, Jaap Verweij, Jean-Yves Blay

Collection/assembly of data: Sandrine Marreaud, Martine van Glabbeke

Data analysis and interpretation: Isabelle Ray-Coquard, Axel Le Cesne, Jeremy S. Whelan, Patrick Schoffski, Binh N. Bui, Jaap Verweij, Sandrine Marreaud, Martine van Glabbeke, Pancras Hogendoorn, Jean-Yves Blay

Manuscript writing: Isabelle Ray-Coquard, Martine van Glabbeke, Jean-Yves Blay

Final approval of manuscript: Isabelle Ray-Coquard, Axel Le Cesne, Jeremy S. Whelan, Patrick Schoffski, Binh N. Bui, Jaap Verweij, Sandrine Marreaud, Martine van Glabbeke, Pancras Hogendoorn, Jean-Yves Blay

	ACKNOWLEDGMENT

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This study was performed with the support of Astra-Zeneca.

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Top Abstract Introduction Patients and Methods Results Discussion Author Contributions Acknowledgment References

 

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