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Sorafenib With Interferon Alfa-2b As First-Line Treatment of Advanced Renal Carcinoma: A Phase II Study of the Southwest Oncology Group

Christopher W. Ryan, Bryan H. Goldman, Primo N. Lara, Jr, Philip C. Mack, Tomasz M. Beer, Catherine M. Tangen, Dianne Lemmon, Chong-Xian Pan, Harry A. Drabkin, E. David Crawford

From the Oregon Health and Science University, Portland, OR; Southwest Oncology Group Statistical Center, Seattle, WA; University of California, Davis, Sacramento, CA; and the University of Colorado Health Sciences Center, Denver, CO

Address reprint requests to Southwest Oncology Group (S0412), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org

	ABSTRACT

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Purpose This phase II study evaluated the activity of combined treatment with interferon alfa-2b and sorafenib, a Raf and multiple receptor tyrosine kinase inhibitor, in patients with advanced renal carcinoma.

Patients and Methods Eligible patients had metastatic or unresectable renal carcinoma with a clear-cell component, no prior systemic therapy, performance status 0 to 1, and measurable disease. Treatment consisted of interferon alfa-2b 10 x 10⁶ U subcutaneously three times weekly and sorafenib 400 mg orally bid. The primary end point was confirmed Response Evaluation Criteria in Solid Tumors response rate.

Results Twelve (19%) of 62 assessable patients achieved an objective confirmed response. An additional 31 (50%) had an unconfirmed partial response or stable disease as best response. The median progression-free survival was 7 months (95% CI, 4 to 11 months). The most common adverse events were fatigue, anorexia, anemia, diarrhea, nausea, rigors/chills, leukopenia, fever, and transaminase elevation. Von Hippel-Lindau gene mutations were detected in four (22%) of 18 archival tumor specimens.

Conclusion The confirmed response rate for the combination of sorafenib and interferon in advanced renal carcinoma is greater than expected with either interferon or sorafenib alone. The toxicity of this combination is dominated by adverse events common to interferon that limit further development of this regimen.

	INTRODUCTION

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The advent of small-molecule tyrosine kinase inhibitors with activity in advanced renal carcinoma has greatly expanded the available treatment options for this disease.^1-4 Loss of von Hippel-Lindau (VHL) protein function caused by VHL gene mutation or promoter methylation in clear-cell renal carcinoma leads to unregulated expression of proangiogenic factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor, and transforming growth factor alpha (TGF-), which have been implicated in disease progression.^5-7 Sorafenib is an oral agent that was developed as a Raf kinase inhibitor, but also inhibits the VEGF receptor family and the platelet-derived growth factor receptor.⁸ Sorafenib significantly increased progression-free survival of pretreated advanced renal cancer patients in a randomized, placebo-controlled study.²

Interferon alfa has been a long-standing treatment option for metastatic renal carcinoma. Although it has been associated with a low objective response rate, modest overall survival benefit has been suggested in two randomized studies.^9,10 The continued role of single-agent interferon therapy for advanced renal carcinoma is unclear, because superiority of new molecules has been demonstrated in randomized trials.^4,11 Although interferon's activity in renal carcinoma has often been attributed to its immunoregulatory activity, the agent also has effects on signal transduction, cell proliferation, and angiogenesis,^12,13 lending merit to exploring combination therapy with molecularly targeted agents with complementary mechanisms of action. Antiproliferative effects of interferon are enhanced in the presence of MEK/ERK (mitogen-activated protein kinase [MAPK]/extracellular regulated kinase) inhibitors, lending rationale to combination with an upstream Raf inhibitor such as sorafenib.¹⁴ Additionally, the antiangiogenic properties of interferon warrant testing in combination with VEGF receptor inhibitors.¹³

To explore the clinical activity of combined sorafenib and interferon therapy in advanced renal carcinoma, we performed a phase II study in patients with clear-cell histology and no prior systemic therapy. VHL gene status was evaluated from archival tumor specimens, and immunohistochemical analysis was performed for expression of activated markers downstream of Raf and related pathways.

	PATIENTS AND METHODS

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Eligibility
Patients were required to have metastatic or unresectable renal cell carcinoma with measurable disease, Zubrod performance status 0 to 1, and no prior systemic treatment for renal cell carcinoma. Tumors must have had a clear-cell histologic component, confirmed by the participating institutions. At least 28 days must have elapsed from any radiation or surgery and recovery from any adverse effects was required. Laboratory requirements included total bilirubin at or below institutional upper limit of normal (ULN), AST or ALT at or below 2.5x the ULN, and serum creatinine at or below ULN or calculated creatinine clearance of at least 60 mL/min (participants with prior nephrectomy must have had a serum creatinine 2 times the ULN). Patients with a history of brain metastases were not eligible; those with clinical suspicion of brain metastases must have undergone a brain computed tomography or magnetic resonance imaging negative for metastatic disease. Patients must not have had any ongoing requirement for systemic corticosteroid therapy and must not have been on drugs known to be potent inhibitors of the CYP3A4 enzyme. Pregnant or nursing women were not eligible, and both women and men of reproductive potential must have agreed to use an effective contraceptive method. Patients with other prior malignancy were ineligible, except for a history of adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or any adequately treated stage I or II cancer from which the patient had been disease free for 5 years. All participants gave written informed consent in accordance with institutional and federal guidelines.

Study Design
Treatment consisted of sorafenib 400 mg orally bid and interferon alfa-2b 10 MU subcutaneously on 3 nonconsecutive days weekly. Each 4-week treatment period was considered one cycle. Interferon delays and dose reductions (to 7.5 and 5.0 MU) were undertaken for grade 1 or higher elevations in liver function tests; grade 2 or higher neutropenia or thrombocytopenia; grade 2 or higher hypotension, diarrhea, or anorexia; and for attributable grade 3 to 4 nonhematologic toxicities. Dose interruption and up to two dose reductions of sorafenib (to 200 mg bid and 200 mg qd) were undertaken for sorafenib-associated grade 3 to 4 hematologic and nonhematologic toxicities and for grade 2 symptomatic hypertension or diastolic hypertension of at least 110 mmHg.

Baseline evaluation included a medical history and physical examination; assessment of performance status; biochemical profile; disease assessment with scans as needed for disease measurement; and bone scan, if clinically indicated. Participants underwent repeat history and physical examination every 2 weeks during the first two cycles, then at the beginning of each additional cycle. Biochemical profile and CBC were obtained throughout the study. Disease assessment was performed after every 2 cycles using scans as needed for disease measurement.

Study Evaluation and Statistical Methods
Version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events was utilized for toxicity assessment. Response Evaluation Criteria in Solid Tumors (RECIST) was used for response assessment.¹⁵ Confirmed partial response was defined as two or more documented objective statuses of partial response or better a minimum of 4 weeks apart. If only one documented objective status of partial response was obtained, this constituted an unconfirmed partial response.

The primary objective was assessment of the confirmed RECIST response rate of sorafenib and interferon. Secondary objectives included (1) assessment of the probability of treatment failure at 6 months and (2) overall survival; (3) evaluation of toxicity of the regimen; and (4) exploratory analyses of markers of Ras-Raf and related pathway signaling (p-MAPK, p-p38, and p-AKT) and VHL gene status. Response assessments were performed after the second, fourth, and sixth treatment cycles. Determination of response was made by investigator assessment. The same technique was required for baseline and follow-up tumor assessments. Treatment with sorafenib and interferon was continued until progression of disease, symptomatic deterioration, unacceptable toxicity, treatment delay for any reason more than 4 weeks or for hypertension more than 2 weeks, or withdrawal of consent.

Based on historical response rates of systemic therapy for advanced renal carcinoma, the regimen would be of considerable interest if the response rate were at least 25%, but would be of no further interest if the true response rate was at or below 10%. The null hypothesis that this regimen is of no further interest would be rejected if 10 or more responses were observed among 55 eligible patients using a one-stage phase II design. This study design has a power of 0.91 to detect a response rate of at least 25% in favor of a response rate of 10% or lower with a significance level of .04. Fifty-five patients are sufficient to estimate the RECIST response rate for patients receiving sorafenib and interferon to within 14% (95% CI). Overall and progression-free survival curves were plotted by the Kaplan-Meier method.¹⁶ All analyses are based on the data available as of October 17, 2006.

Immunohistochemistry
Pretreatment archival tumor tissue from consenting patients was evaluated by a pathologist blinded to the clinical data. Tumor was confirmed on histologic sections and each immunostained slide scored for reactivity by light microscopy. Immunohistochemistry was carried out using standard techniques as previously reported^17,18 using the following antibodies from Cell Signaling Technology Inc (Danvers, MA): phospho p38-MAPK Thr180/Tyr182 #4631 and phospho-Akt Ser473 #4051 and the anti-ACTIVE MAPK p antibody pTEpY (Promega Corp, Madison WI).

VHL Mutation Analysis
DNA was extracted from paraffin-embedded tissue after manual microdissection using the QIAamp DNA Mini Kit (Qiagen, Valencia, CA). Four different polymerase chain reaction (PCR) reactions were used to amplify VHL exons 1 to 3, with two separate groups of primers used to amplify exon 1; one pair (1A) includes the first 53 codons, whereas the second group (1B) encompasses the second initiation site. For each exon, 4.0 µL of DNA was amplified in a 24-µL reaction that included 1x PCR buffer, 20 µmol/L of deoxyribonucleotide triphosphate, 0.3 µmol/L primers and 2.0 U of Cloned Pfu polymerase (Stratagene, Cedar Creek, TX). For exon 1B and exon 2, 3% dimethyl sulfoxide was also used. See Table A1 (online only) for PCR conditions for each exon. After initial amplification, 2.0 µL of PCR product was reamplified under the same conditions. PCR products were run on a 2% agarose gel and stained with ethidium bromide. Bands were purified with the QIAquick Gel Extraction Kit (Qiagen), and sequenced using an ABI 3730 Capillary Electrophoresis Genetic Analyzer ABI with BigDye Terminator v3.1 Cycle Sequencing (Applied Biosystems, Foster City, CA). All PCR reactions were repeated and subsequently sequenced to verify results.

	RESULTS

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Patient Characteristics
The study was activated in September 2004 and completed accrual in May 2005. Of 67 enrolled patients, four were found to be ineligible (three because of unconfirmed clear-cell histology, one because of corticosteroid use). One patient withdrew consent before receiving any therapy. The remaining 62 participants were included in the efficacy and safety analyses. Baseline patient characteristics are shown in Table 1. Collection of data for Memorial Sloan-Kettering prognostic grouping¹⁹ was made mandatory in December 2004. These data were available for 74% of patients. No clear differences in outcome were noted between these patients and the 26% of patients for whom prognostic grouping was not available, suggesting that these data were missing at random. Among the patients for whom these data were available, the majority (67%) were categorized as intermediate risk.

Response
Response data are shown in Table 2. One complete response and 11 partial responses were observed, for an overall confirmed response rate of 19% (95% CI, 10% to 31%). Best response of stable disease or unconfirmed partial response was observed in 50% of patients. The median duration of confirmed responses was 8 months (range, 2 to 20+ months). Six patients were not assessable for response, and were assumed to be nonresponders.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier plots of (A) progression-free survival and (B) overall survival.

	DISCUSSION

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Single-agent treatment with tyrosine kinase inhibitors that target the VEGF axis has significant activity in renal carcinoma.^2-4 However, these treatments are not long-term solutions for patients with advanced disease, and progression is inevitable for the vast majority. Strategies to optimize treatment with these agents are needed. Combination therapy with agents harboring complementary mechanisms of action is one such potential strategy.

We observed a confirmed response rate of 19% (95% CI, 10% to 31%) with combined sorafenib and interferon therapy in a population of previously untreated patients with advanced clear-cell renal carcinoma. Similar to other studies with sorafenib, we observed a large percentage of patients with stable disease as the best response, including patients with unconfirmed partial responses or decreases in target lesions that did not meet RECIST definition of response. Given that confirmed RECIST response rates reported to date for single-agent sorafenib as well as for most studies with single-agent interferon have not exceeded 10%,^2,4,11 our results suggest that combination treatment with these two agents induces a higher incidence of protocol-defined responses than with either single agent alone. A second study of sorafenib and interferon in renal carcinoma has preliminarily reported a response rate of 42%, further suggesting increased antitumor activity of this combination.²⁰

Progression-free survival has recently been suggested as an end point for clinical trials using targeted small molecules in renal carcinoma, given that improvements in this measure have been shown in randomized studies despite relatively low RECIST response rates.^{2, 4} We observed a median progression-free survival of 7 months with sorafenib and interferon, albeit with a wide CI (95% CI, 4 to 11 months) because of the relatively small sample size of this phase II study. Although this median progression-free survival compares favorably with that reported with sorafenib as a single agent in the second-line setting (5.5 months)² or with single-agent interferon in the first-line setting (5 months),⁴ this finding must not be overinterpreted given the small sample size and nonrandomized nature of this study. It should be noted that a median progression-free survival of 11 months as first-line treatment was reported with the VEGF receptor inhibitor sunitinib in a phase III study, setting a new standard for future evaluations in this setting.⁴

We found the combination of sorafenib with interferon to be associated with significant adverse effects. All patients reported some adverse event with combined therapy, and 77% reported a grade 3 or greater adverse event. Although the most characteristic adverse effects of therapy with single-agent sorafenib include hand-foot syndrome, rash, diarrhea, and hypertension,^1,2 we observed a preponderance of adverse events commonly associated with interferon, including fatigue, anorexia, rigors, and fever. The full dose of interferon was not tolerated by most patients, and further investigations of the combination should consider a lower dose. We employed flat dosing of interferon at 10 MU rather than escalating to the target dose, which may partially explain the high rate of intolerance. A phase I study of sorafenib with interferon alfa-2a safely achieved equivalent dosing without dose-limiting toxicity.²¹ It is interesting to note that only 16% of patients in our study reported hand-foot syndrome, which has been reported in 30% to 62% of patients receiving sorafenib monotherapy.^1,2 Although the mechanism of sorafenib-induced acral erythema is unclear, modulation of keratinocyte proliferation by interferon could possibly explain the lower incidence of this cutaneous adverse effect.²²

We detected VHL mutations in four (22%) of 18 archival tumor specimens. This incidence is lower than other reports in which disruption of the VHL gene has been detected in approximately 34% to 57% of cases of sporadic renal carcinomas.^{5, 23-26} However, in this study, we did not assess the presence of promoter methylation or loss of heterozygosity. Although the small sample size of our study prevents formal statistical analysis, our findings with sorafenib and interferon are not inconsistent with a report that has suggested that certain VHL mutations (those that truncate or shift the reading frame) may be associated with longer progression-free survival among patients receiving VEGF-targeted therapy.²⁵

p-AKT overexpression has been suggested as both a positive and negative predictor of clinical outcome in other tumor types with other tyrosine kinase inhibitor therapy,^27,28 although some studies have not detected any correlation between p-AKT expression and outcome.²⁹ We found variable levels of p-AKT expression among the tumors tested, with two of three patients with absent p-AKT staining having a partial response. Our findings are not inconsistent with a hypothesis that higher p-AKT is associated with worse clinical outcome in advanced renal carcinoma patients receiving sorafenib and interferon, although none of the differences in outcome are statistically significant in this small sample size.

In the development of new combinations for renal carcinoma, any incremental clinical benefit achieved with combination therapy must be balanced with the potential increase in toxicity. It is not obvious that the increased response rate we observed with sorafenib plus interferon treatment justifies the relatively high toxicity profile of this regimen. Indeed, the clinical significance of achieving the arbitrary amount of tumor regression used to define a RECIST response has been questioned largely on the basis of experiences with sorafenib monotherapy, a treatment that induces some tumor regression in most patients with advanced renal carcinoma and prolongs progression-free survival, yet is associated with a very low objective response rate.^1,2 Further investigation of clinical and molecular markers that may help to predict those patients likely to achieve greater tumor response or longer progression-free survival should be pursued, and may help guide the design of future randomized studies of combination strategies.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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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: Christopher W. Ryan, Bayer-ONYX; Primo N. Lara Jr, Bayer-ONYX Stock: N/A Honoraria: Christopher W. Ryan, Bayer-ONYX; Primo N. Lara Jr, Bayer-ONYX Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Christopher W. Ryan, Primo N. Lara Jr, Tomasz M. Beer, Catherine M. Tangen, E. David Crawford

Administrative support: Primo N. Lara Jr, E. David Crawford

Provision of study materials or patients: Christopher W. Ryan, Primo N. Lara Jr, Chong-Xian Pan, Harry A. Drabkin

Collection and assembly of data: Bryan H. Goldman, Philip C. Mack, Catherine M. Tangen, Dianne Lemmon, Chong-Xian Pan, Harry A. Drabkin

Data analysis and interpretation: Christopher W. Ryan, Bryan H. Goldman, Philip C. Mack, Catherine M. Tangen

Manuscript writing: Christopher W. Ryan, Bryan H. Goldman, Philip C. Mack

Final approval of manuscript: Christopher W. Ryan, Bryan H. Goldman, Primo N. Lara Jr, Philip C. Mack, Tomasz M. Beer, Catherine M. Tangen, Dianne Lemmon, Chong-Xian Pan, Harry A. Drabkin, E. David Crawford

	Appendix

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	ACKNOWLEDGMENTS

 
We thank Regina Gandour-Edwards, MD, for interpretation of immunohistochemistry and William S. Holland for expert technical assistance.

	NOTES

 
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute: CA38926, CA32102, CA46441, CA42777, CA35176, CA58882, CA35178, CA63848, CA20319, CA35431, CA63844, CA45808, CA11083, CA35090, and CA35128.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and at the 5th International Kidney Cancer Symposium, September 22-23, 2006, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted February 26, 2007; accepted May 7, 2007.

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