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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3766-3773 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.2871 Phase II Trial of Sorafenib in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Nasopharyngeal Carcinoma
From the Princess Margaret Hospital, University Health Network; Bayer Inc, Toronto; London Health Sciences Centre, London, Ontario, Canada; and Bayer Health Care, Bayer Research Center, West Haven, CT Address reprint requests to Eric X. Chen, MD, PhD, Princess Margaret Hospital, University Health Network, Department of Medical Oncology and Hematology, 610 University Ave, Ste 5-719, Toronto, Ontario, Canada, M5G 2M9; e-mail: eric.chen{at}uhn.on.ca
Purpose To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC).
Patients and Methods In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had Results Twenty-seven and 26 patients were eligible for toxicity and efficacy evaluations, respectively. One patient (3.7%; 95% CI, 0.1% to 19.0%) achieved a partial response. Disease stabilization was maintained in 10 patients (37.0%; 95% CI, 22.4% to 61.2%). The median time to progression was 1.8 months (95% CI, 1.6 to 3.4 months), and median overall survival time was 4.2 months (95% CI, 3.6 to 8.7 months). Sorafenib was well tolerated with few grade 3 and no grade 4 toxicities. Biomarker analysis of paired tumor samples before and after treatment with sorafenib revealed a decrease of pERK in all five patients, with a decrease in Ki67 in four patients, consistent with a disruption of ERK signaling. The antiapoptotic protein Mcl-1 was downregulated in four patients, and there was also evidence of antiangiogenic activity. Conclusion Sorafenib was well tolerated and had modest anticancer activity comparable to monotherapy with other targeted agents in this group of patients. Further development in combination with radiation or other agents may be warranted.
Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have a median survival time of 6 to 9 months. No chemotherapy has been convincingly shown to improve survival.1 Single agents or platinum-based doublets have yielded similar survival outcomes, despite higher response rates being derived from combination regimens at the cost of increased toxicity.1-5 Although nasopharyngeal carcinoma (NPC) is a disease with distinctive epidemiology and clinical behavior, initial treatment is similar to that for SCCHN. For patients with locally recurrent or metastatic disease, platinum-based combination chemotherapy results in a response rate of 50% to 70% and a median survival time of approximately 11 months.6 Taken together, patients with recurrent and/or metastatic SCCHN and NPC have few, usually toxic, therapeutic options. There is no effective treatment for patients who experience treatment failure with first-line chemotherapy, and as such, their prognosis is dismal.7 Molecular targeting is a promising strategy to identify new therapies and to improve the therapeutic index in this population. Sorafenib (Nexavar; Onyx Pharmaceuticals, Emeryville, CA), a bisaryl urea, is an oral inhibitor of the serine/threonine kinases C-Raf and B-Raf and the receptor tyrosine kinases of vascular endothelial growth factor (VEGF) receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor, FLT3, and c-kit, among others. Therefore, it targets the following two major mechanisms of carcinogenesis: the epidermal growth factor receptor (EGFR) -Ras-Raf-MEK-ERK signaling pathway, which is a key regulator of cell growth, differentiation, apoptosis, and cellular transformation,8,9 and the VEGF-VEGFR pathway, which is essential for angiogenesis, consequently promoting tumor growth and metastasis.10-12 Sorafenib demonstrated broad-spectrum antitumor activity in xenograft models and a favorable toxicity profile in early clinical trials.13-21 It has received approval in several countries for treatment of advanced renal cell cancer22 and is currently undergoing clinical testing as single agent and in combination with chemotherapy, radiation, or other targeted agents in various tumor sites. Multiple lines of evidence support targeting the EGFR-Ras-Raf-MEK-ERK signaling pathway in head and neck cancers.23 First, although mutations in ras or BRAF genes are rare, members of the ras family are overexpressed in SCCHN and NPC,13-18,24 and in vitro evidence suggests that the level of K-ras expression is a determinant of proliferation of SCCHN cell lines.19 Second, EGFR is also overexpressed in a majority of SCCHN and NPC patients,20,21,25-27 representing an independent prognostic factor and a predictor of response to radiotherapy.23,28,29 Only a small proportion of SCCHN has mutations of EGFR.16,18,30-32 Agents targeting EGFR have been studied in recurrent and metastatic SCCHN with modest activity as single agents.33-37 However, combinations of EGFR inhibitors with chemotherapy or other targeted agents have shown promising preliminary results, and cetuximab has been shown to prolong survival in locally advanced SCCHN when administered with radiation.38-42 Cetuximab also demonstrated antitumor activity in NPC.43 The ability of sorafenib to inhibit VEGFR-2 and VEGFR-3 further supports its evaluation in head and neck cancer. SCCHN tumors overexpress VEGF, VEGFR-2, and VEGFR-3, and these markers have been associated with development of lymph node metastases and poor survival in some studies.28,44,45 In NPC, increased microvessel density and VEGF expression were associated with an aggressive clinical behavior in some series.46-48 We conducted a phase II study of single-agent sorafenib in patients with recurrent or metastatic SCCHN or NPC. The primary objective was efficacy of sorafenib in this patient population, using response rate as the primary end point. Secondary objectives included assessment of stable disease rate, time to progression (TTP) of disease, overall survival (OS), toxicity profile, and evaluation of pharmacodynamic markers.
Eligibility Patients enrolled onto this study had histologically confirmed, recurrent and/or metastatic HNSCC or NPC and had received no more than one prior systemic therapy for recurrent and/or metastatic disease. Prior chemotherapy as part of the initial curative treatment was permitted. Patients were required to be at least 18 years old, have an Eastern Cooperative Oncology Group performance status of 0 to 2, and have measurable disease. Adequate organ function was required as defined by ALT and AST  2.5x the upper limit of normal (ULN; patients with metastatic liver involvement 5x ULN); bilirubin, amylase, lipase, creatinine 1.5x ULN; and prothrombin time or international normalized ratio and partial thromboplastin time less than 1.5x ULN. Prior use of farnesyltransferase, Raf kinase, or MEK inhibitors was not allowed. Significant surgery, myelosuppressive radiotherapy, or drugs that target VEGF were not allowed within 4 weeks before the start of study. All patients gave written informed consent. Approval from the institutional ethics review boards of both participating centers was obtained before activation of the study.
Treatment Plan
Patient Assessment
Pharmacodynamic Sampling and Assessment The following biomarkers were assessed by quantitative immunohistochemistry: signal transduction (pERK), proliferation (Ki67), apoptosis (Mcl-1), and angiogenesis (CD31 and SMA). Slides were stained with the antibodies listed in Appendix Table A1 (online only). The detection systems used were the DakoCytomation Envision + System-HRP (Dako, Carpinteria, CA). All slides were counterstained using DakoCytomation automation hematoxylin (code No. S3301; Dako). Manufacturer's recommendations were followed. Staining conditions were optimized using human tumor xenografts as positive controls and control immunoglobulin G as negative controls. Stained slides were analyzed using Ariol SL-50 high-throughput image analysis system (Applied Imaging, San Jose, CA). Optimum instrument parameters were set for each study separately, using representative samples. Areas consisting primarily of tumor cells were selected with assistance of a pathologist blinded to the clinical data, whereas stromal and necrotic regions were excluded. Selected areas were analyzed automatically using the optimized classifiers associated with the specific study. The classifier parameters for pERK analysis were based on saturation, intensity, and hue (DAB chromophore). Results were analyzed by Multistain Assay protocol (Applied Imaging) and reported as area of color stained divided by total area analyzed to yield percent positive staining. For Ki67 antigen analysis, the KiSight Assay protocol (Applied Imaging) was used. The classifier selects cell nuclei and subsequently discriminates positively staining nuclei from negative nuclei based on color to yield the percentage of tumor nuclei positively stained.
Statistical Analysis The primary end point of this study is the objective response rate (complete response and partial response [PR]) according to the Response Evaluation Criteria in Solid Tumors. All patients receiving at least one dose of sorafenib were assessable for toxicity. Patient characteristics and safety parameters are presented in descriptive summary tables. The Kaplan-Meier method was used to estimate TTP and OS. All statistical tests were performed using SAS v9.1 for Windows (SAS Institute, Cary, NC) or S-Plus 2000 (Statistical Sciences, Seattle, WA) for Windows (MathSoft Inc, Seattle, WA).
Patient Characteristics A total of 28 patients were enrolled onto the study. One patient withdrew consent before treatment and was not assessable. Table 1 lists the demographics and disease characteristics of assessable patients. At enrollment, 11 patients (41%) had locally recurrent disease, five patients (19%) had metastatic disease only, and 11 patients (41%) had both. Nineteen patients (70%) received prior systemic therapy; six of these patients received chemoradiotherapy with curative intent only, eight received palliative systemic chemotherapy only, and five received both. Specifically, 14 patients (52%) received sorafenib as first-line systemic therapy for recurrent or metastatic disease, and 13 patients (48%) received sorafenib as second-line therapy.
Treatment Administration A total of 72 cycles were administered, with a median of two cycles per patient (range, one to seven cycles). Twenty dose reductions were required in 16 patients, and dosing had to be delayed in 14 patients. Reasons for discontinuing study treatment were objective disease progression in 15 patients (56%), symptomatic progressive disease in nine patients (33%), and death on study in two patients (7%). One patient withdrew consent after cycle 1.
Toxicity
Efficacy Efficacy data are listed in Table 3. Of 27 patients, one was not assessable for response because of withdrawal of consent after cycle 1. One patient had a PR observed in cycle 2 and confirmed in cycle 4 but developed symptomatic disease progression after cycle 4. Ten patients had stable disease after cycle 2, and two of these patients received six cycles of treatment. Ten patients had objective progressive disease at the end of cycle 2, and five patients had symptomatic progressive disease before the end of cycle 2. The objective response rate and stable disease rate by intent-to-treat analysis were 3.7% (95% CI, 0.1% to 19.0%) and 37.0% (95% CI, 19.4% to 57.6%), respectively.
Median TTP was 1.8 months (95% CI, 1.6 to 3.4 months), and the 6-month progression-free survival rate was 3.9% (95% CI, 0.6% to 26.4%) as illustrated in Figure 1A. To date, all but two patients have died. The median OS time was 4.2 months (95% CI, 3.6 to 8.7 months), with 6- and 12-month OS rates of 34.7% (95% CI, 20.5% to 58.8%) and 11.6% (95% CI, 4.0% to 33.5%; Fig 1B), respectively. TTP and OS were 1.8 months and 4.2 months for SCCHN, respectively, and 3.2 months and 7.7 months for NPC, respectively. Although a trend of longer TTP was seen for NPC, this was not statistically significant.
Pharmacodynamic Analysis The amount of pERK, Ki67, Mcl-1, SMA, and CD31 measured by immunohistochemistry in tumor islands of tumor biopsies before and after treatment was quantified by bright-field image capture. Results of these analyses are shown in Figure 2, together with each patient's clinical information.
The proportion of tumor area staining positive for pERK in pretreatment biopsies ranged from 19% to 48%. After 4 weeks of treatment with sorafenib, a reduction of tumor area that stained positive for pERK was seen in all five patients, with decreases ranging from 5% to 63%, consistent with an inhibition of the EGFR-Ras-Raf-MEK-ERK signaling pathway. In pretreatment biopsies, 43% to 54% of nuclei stained positive for Ki67, and four of five samples showed a reduction after sorafenib therapy, with decreases ranging from 22% to 57%. In pretreatment biopsies, 14% to 53% of tumor area stained positive for Mcl-1. After treatment with sorafenib, the staining was reduced by 26% to 84% in four of five patients. In pretreatment biopsies, the area staining positive for CD31 ranged from 1.7% to 7.3%, and the area staining positive for SMA ranged from 0.8% to 5.2%. After 4 weeks of treatment with sorafenib, staining with anti-CD31 was reduced in three of five samples by 47% to 74%, and staining with anti-SMA was reduced in four of five samples by 46% to 63%. Statistical analysis was not performed for changes in these markers because of the small numbers of patients with paired biopsies (Fig 2).
This study was conducted to evaluate the role of sorafenib in recurrent and/or metastatic SSCHN and NPC. There was a strong rationale for this approach because sorafenib targets the EGFR-Ras-Raf-MEK-ERK signaling pathway as well as tumor angiogenesis. Both mechanisms are thought to play important roles in the pathogenesis of SCCHN and NPC. Because the prognosis for recurrent and/or metastatic SSCHN and NPC is similarly poor and there is no standard treatment available for either disease after failure of first-line chemotherapy, both disease sites were included in this study. During the first stage of accrual, there was one PR observed in 21 assessable patients. This was below the a priori criteria; therefore, accrual was not continued to stage 2. However, the response rate of 3.7% and disease control rate of 40.7% observed in our study was not significantly different from results from other phase II trials of single agents targeting the EGFR-Ras-Raf-MEK-ERK signaling pathway in SCCHN.33-37,51,52 These studies reported response rates ranging from 0% to 11% and disease control rates ranging from 20% to 53%. However, the median TTP and OS of 1.8 and 4.2 months observed in our study were shorter than most results published in the literature, with TTP/progression-free survival ranging from 1.8 to 3.4 months and OS ranging from 4.3 to 8.1 months. Outcomes of single-arm phase II studies should be compared with caution because selection bias can arise from unmeasured factors influencing outcome, even when known adverse prognostic factors are similar between series.53 Many patients in our study were unfit to receive chemotherapy because of comorbidities, and five patients experienced early progression before the first scheduled assessment at the end of the second cycle, suggesting rapidly deteriorating disease. To further put our results into context, a retrospective analysis of platinum-refractory recurrent and/or metastatic SCCHN observed no response to second-line chemotherapy and a median survival time of 3.4 months. The frequency of specific toxicities was comparable with other trials of single-agent sorafenib,56,57 with the exception of diarrhea and rash, which occurred less often in our trial. In other trials, these adverse effects did not adversely impact health-related quality of life.58,59 Overall, the toxicity profile of sorafenib observed in this trial was also favorable when compared with combination chemotherapy trials in recurrent and metastatic SCCHN.38,60-62 To our knowledge, this is the first report of biologic effect of sorafenib on patient tumor samples, and our findings provide important insight into the action of sorafenib. A reduction of pERK in all five patients, with an inhibition of its downstream effector Ki67 in four patients, was consistent with a successful disruption of the EGFR-Ras-Raf-MEK-ERK signaling pathway.63 In addition, the antiapoptotic protein Mcl-1, which is expressed by more than 90% of SCCHN tumors,64 was downregulated by sorafenib in most paired biopsies, confirming a recent finding that drug-induced Mcl-1 downregulation contributes to proapoptotic effects of sorafenib in various tumor cell lines.65 There was also evidence that the angiogenic markers CD31 and SMA are decreased on treatment with sorafenib in some patients, but data were less convincing. Taken together, in head and neck cancers, sorafenib seems to act mainly by inhibiting EGFR-Ras-Raf-MEK-ERK signaling, tumor proliferation, and apoptosis. The lack of meaningful clinical activity, despite these findings, suggests that advanced head and neck cancers may not entirely depend on these pathways. Alternatively, the magnitude of biomarker inhibition may not be sufficient to lead to clinical benefit. Because there are only five patients with paired biopsies, these results should be considered preliminary. Further biomarker studies on a larger number of patients are warranted to confirm our findings and correlate them with clinical outcome. Given its modest efficacy in patients with recurrent and/or metastatic head and neck cancers, further study of sorafenib as a single agent in this population is not warranted. However, sorafenib is well tolerated and easy to deliver. The combination of sorafenib with other agents or radiation might be an attractive option. A phase I and II trial of sorafenib in combination with concurrent chemoradiotherapy in locally advanced SCCHN is currently being conducted at our institution.
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: James Elting, Bayer Health Care; Angela McNabola, Bayer Health Care; Dean Wilkie, Bayer Health Care; Oana Petreniuc, Bayer Health Care Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Lillian L. Siu, Oana Petreniuc, Eric X. Chen Administrative support: Robin Cheiken Provision of study materials or patients: Christine Elser, Lillian L. Siu, Eric Winquist, Mark Agulnik, James Elting, Angela McNabola, Oana Petreniuc, Eric X. Chen Collection and assembly of data: Soo F. Chin, Peggy Francis, Robin Cheiken Data analysis and interpretation: Christine Elser, Lillian L. Siu, Gregory R. Pond, James Elting, Eric X. Chen, Angela McNabola, Dean Wilkie Manuscript writing: Christine Elser, Lillian L. Siu, Eric X. Chen Final approval of manuscript: Lillian L. Siu, Oana Petreniuc, Eric X. Chen
Supported in part by Bayer Inc, Toronto, Ontario, Canada. Presented in part at the 13th Annual European Cancer Conference, October 30-November 3, 2005, Paris, France; at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; and at the 18th European Organisation for the Research and Treatment of Cancer, National Cancer Institute, American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics, November 7-10, 2006, Prague, Czech Republic. 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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TOP
ABSTRACT
INTRODUCTION
= .05, and ß = .10. The study did not proceed to stage 2 because there was only one objective response observed during stage 1. However, the protocol was amended to enroll five additional patients for pharmacodynamic evaluations. 
