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Phase II Trial of Sorafenib Plus Interferon Alfa-2b As First- or Second-Line Therapy in Patients With Metastatic Renal Cell Cancer

Jared A. Gollob, W. Kimryn Rathmell, Tina M. Richmond, Christine B. Marino, Elizabeth K. Miller, Gayle Grigson, Catharine Watkins, Lin Gu, Bercedis L. Peterson, John J. Wright

From the Division of Medical Oncology, Department of Medicine, and Departments of Biostatistics and Bioinformatics, Duke University Medical Center, Durham; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; and Investigational Drug Branch, National Cancer Institute, Bethesda, MD

Address reprint requests to Jared A. Gollob, MD, Duke University Medical Center, DUMC 3441, Durham, NC 27710; e-mail: jared.gollob{at}duke.edu

	ABSTRACT

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Purpose We undertook this study to determine the activity and tolerability of sorafenib administered with interferon alfa-2b (IFN--2b) as first- or second-line therapy in metastatic renal cell cancer (RCC).

Patients and Methods Between November 2004 and October 2006, 40 patients at two sites were enrolled onto a phase II trial of sorafenib plus IFN--2b. Treatment consisted of 8-week cycles of sorafenib 400 mg orally bid plus IFN--2b 10 million U subcutaneously three times a week followed by a 2-week break. Patients were eligible to receive additional cycles of therapy until disease progression. Dose reduction of both drugs by 50% was permitted once for toxicity.

Results The response rate was 33% (95% CI, 19% to 49%; 13 of 40 patients), including 28% partial responses (n = 11) and 5% complete responses (n = 2). Responses were seen in treatment-naïve and interleukin-2 (IL-2) –treated patients within the first two cycles. The median duration of response was 12 months. With a median follow-up time of 14 months, median progression-free survival time was 10 months (95% CI, 8 to 18 months), and median overall survival time has not yet been reached. Fatigue, anorexia, anemia, diarrhea, hypophosphatemia, rash, nausea, and weight loss were the most common toxicities. Grade 3 toxicities were uncommon but included hypophosphatemia, neutropenia, rash, fatigue, and anemia. Dose reductions were required in 65% of patients.

Conclusion The combination of sorafenib and IFN--2b has substantial activity in treatment-naïve and IL-2–treated patients with RCC. The toxicity exceeded that of either drug alone, but dose reductions and breaks between cycles allowed for chronic therapy. A larger, randomized trial would determine whether there is any advantage to this regimen compared with sorafenib alone.

	INTRODUCTION

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The treatment of metastatic renal cell cancer (RCC) has recently evolved from being predominantly cytokine based to being grounded now in the use of drugs that target the dysregulated vascular endothelial growth factor (VEGF) and platelet-derived growth factor beta (PDGFß) pathways that are characteristic of clear cell RCC with loss of von Hippel-Lindau protein.^1,2 Sorafenib (Nexavar; Bayer Pharmaceuticals Corp, Wayne, NJ, and Onyx Pharmaceuticals Inc, Emeryville, CA) is a multikinase inhibitor targeting VEGF receptors 1 to 3, PDGFß receptor, and the Raf kinase^3,4 that was approved by the US Food and Drug Administration in December 2005 for the treatment of advanced RCC. In a randomized phase III trial comparing sorafenib with placebo as second-line therapy in RCC,⁵ the investigator-assessed partial response (PR) rate to sorafenib was 10%, and the median progression-free survival (PFS) was doubled in the sorafenib arm (5.5 v 2.8 months, respectively). Although sorafenib is clearly an advance in the treatment of RCC and has demonstrated a highly significant improvement in PFS with a strong trend toward improvement in overall survival (OS), it is not a curative therapy.^5,6

Interferon alfa (IFN-) has a 5% to 10% response rate in RCC^7,8 and is one of only two drugs shown to modestly improve OS in RCC,^9,10 the other being the mammalian target of rapamycin inhibitor temsirolimus.¹¹ However, in a first-line randomized phase III trial, the multikinase inhibitor sunitinib was superior to IFN- with regard to response rate and PFS,⁸ and in a randomized phase III trial in poor-risk RCC, temsirolimus was superior to IFN- with regard to PFS and OS.¹¹ Given these results, there is little remaining rationale for IFN- monotherapy in RCC.

Combination therapy with IFN- in RCC has involved using it together with interleukin-2 (IL-2), fluorouracil, retinoic acid, and/or thalidomide; none of these studies has shown any consistent improvement in outcome over IFN- monotherapy.^7,12-14 However, in addition to its immunomodulatory effects, IFN- has direct antitumor¹⁵ as well as antiangiogenic activity,^16,17 including the inhibition of VEGF and basic fibroblast growth factor expression, that could enhance the antitumor and antiangiogenic effects of sorafenib mediated by its inhibition of Raf and VEGF receptor/PDGFß receptor, respectively.¹⁸ Therefore, we initiated a phase II trial of sorafenib plus IFN--2b to assess the activity and safety of this combination regimen in RCC.

	PATIENTS AND METHODS

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Patient Selection
All patients were adults with histologically confirmed RCC that was metastatic or unresectable and measurable according to Response Evaluation Criteria in Solid Tumors; patients with all subtypes of RCC were eligible. Patients were required to have an Eastern Cooperative Oncology Group performance status of 2, absolute neutrophil count 1,500/µL, platelet count 100,000/µL, creatinine 1.5x the upper limit of normal, and total bilirubin less than 1.5 mg/dL. Patients were allowed to have received prior radiation therapy to nonindex lesions and/or one prior biologic response modifier regimen but were excluded if they were previously treated with IFN-. Patients with brain metastases, potentially life-threatening autoimmune disorders, or severe depression or on therapeutic anticoagulation were excluded from the study.

Study Design
The study was a National Cancer Institute (NCI) Cancer Therapy Evaluation Program–sponsored, open-label, nonrandomized, multicenter, phase II trial (NCI protocol No. 6553) approved by the Institutional Review Boards at Duke University Medical Center (Durham, NC) and the University of North Carolina at Chapel Hill (Chapel Hill, NC). Written informed consent was obtained from each patient. Sorafenib was supplied by NCI Cancer Therapy Evaluation Program (Bethesda, MD). The primary end points of the trial were response rate and tolerability of sorafenib plus IFN--2b. Given the favorable toxicity profile of sorafenib, the abundant published experience with IFN- in RCC, and the lack of overlapping potentially life-threatening toxicities between sorafenib and IFN--2b, an initial phase I dose-finding study with the combination of sorafenib and IFN--2b was not deemed necessary.

Treatment consisted of 8-week cycles of sorafenib dosed at 400 mg orally bid on a continuous basis plus IFN--2b (INTRON A; Schering-Plough, Kenilworth, NJ) 10 million U subcutaneously three times a week. Patients were evaluated for tumor response during week 8, and patients with an objective response or stable disease (SD) could receive additional cycles until disease progression. A break between cycles of up to 2 weeks was permitted for resolution of treatment-related toxicity. Patients were permitted to premedicate with acetaminophen and/or naprosyn before each IFN- dose, and other supportive measures included antiemetics, antidiarrheals, antihypertensives, phosphate supplements, appetite stimulants (including megestrol acetate and dronabinol), and emollients and/or pyridoxine for hand-foot reaction, as needed. Patients were seen on weeks 1, 5, and 8 of each cycle and had blood tests to check renal and hepatic function, electrolytes, and blood counts on weeks 1, 3, 5, and 7 of cycle 1 and on weeks 1 and 5 of all subsequent cycles. Pancreatic enzymes were checked at the start of each cycle.

Toxicity was assessed using the NCI Common Toxicity Criteria (version 3.0). Grade 2 nonhematologic toxicities were managed by holding both drugs until resolution to grade 1 and then resuming without a dose reduction. Exceptions could include grade 2 fatigue, skin rash, weight loss, or hypophosphatemia. If the patient experienced a second grade 2 nonhematologic toxicity requiring another dose interruption, both drugs were dose-reduced by 50%. Grade 3 or 4 hematologic and nonhematologic toxicities were managed through dose interruption followed by 50% dose reduction of both drugs. Exceptions could include grade 3 or 4 lymphopenia or grade 3 fever/chills, hyperlipasemia, hyperamylasemia, or hypophosphatemia. In addition, grade 3 neutropenia, rash, and fatigue were managed as grade 2 nonhematologic toxicities. Only one dose reduction was permitted; if a second dose reduction was required, treatment was permanently discontinued. Treatment was also discontinued if a grade 3 or 4 toxicity did not resolve within 3 weeks. The dosing period during an 8-week cycle was not extended to compensate for interruptions in study treatment.

Assessment of Tumor Response
Tumor measurements were obtained by computed tomography scan before treatment and during week 8 of each cycle. Magnetic resonance imaging or computed tomography scan of the brain was performed before treatment and during week 8 of each even-numbered cycle. Response and progression were assessed by the treating physicians, who performed their evaluation on the basis of the Response Evaluation Criteria in Solid Tumors.

Statistical Methods
Under the intent-to-treat principle, this report provides a summary of patient characteristics and outcome of therapy on all 40 enrolled patients. With an accrual goal of 40 patients, the trial used a single-stage design to test the null hypothesis that the response rate is 0.10 versus the alternative hypothesis that the response rate is 0.25. If seven patients (17.5%) or more responded, the null hypothesis would be rejected. This design yielded type I and II error rates of 10%.

Toxicities are tabulated by type and grade. Complete response (CR) + PR rate is reported with its exact 95% CI. Four patients who did not complete at least one cycle are assumed to be nonresponders. Response duration was defined among the responders from time of first response (either PR or CR) until progression. PFS was defined as the time from enrollment to progression or death, whichever came first. Survival probabilities for PFS, OS, and response duration were estimated using the Kaplan-Meier method. The SEs for these estimates were obtained using the variance estimate of Peto.¹⁹

	RESULTS

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Patient Characteristics
Forty patients were enrolled between November 2004 and October 2006, including 28 at Duke University Medical Center and 12 at University of North Carolina's Lineberger Comprehensive Cancer Center. As shown in Table 1, the majority of patients had an Eastern Cooperative Oncology Group performance status of 0, had clear cell RCC, and underwent prior nephrectomy. Using the Memorial Sloan-Kettering Cancer Center criteria, the majority of patients fell into the favorable (40%) or intermediate (50%) risk groups.²⁰ Sixty-three percent of patients had no prior systemic therapy; among those with prior therapy, most had received high-dose IL-2. The most common sites of metastasis were lungs, pleura, and nodes, and the majority of patients had two or more sites of metastasis.

Clinical Responses
Thirty-six patients completed at least one cycle of therapy and were assessable for response. The four patients who were not assessable for response stopped treatment before completing the first cycle for reasons unrelated to treatment toxicity, and only one of these four patients came off early for disease progression. All 40 patients were used to calculate response rate (intent-to-treat analysis), and all 40 patients were used for the survival analysis. Major responses occurred in 33% of patients (95% CI, 19% to 49%), including 28% PRs and 5% CRs (Table 3). Forty-five percent of patients had SD for at least one cycle, and 12% had progressive disease (PD). Responses occurred quickly, with the majority of tumor regression observed after the first one to two cycles. Although the most common sites of response were lungs and nodes (Table 4), dramatic responses were also seen in patients with bulky disease in the pleura (Fig 1), liver (Fig 2), and pancreas. The median response duration among the 13 responders, six of whom have experienced progression, was 12 months (95% CI, 6 to 13 months). Among the two patients who achieved a CR, one patient had node-only disease and experienced relapse in nodes 4 months later, whereas the second patient with lung metastases remains without evidence of disease 9 months to date and is currently off therapy.

View larger version (49K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Clinical responses to sorafenib plus interferon alfa (IFN-) in renal cell cancer. The computed tomography images show tumor response in the pleura in a patient after the first two cycles of therapy. (A) Pretreatment; (B) post-cycle 2 sorafenib plus IFN-.

View larger version (52K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Clinical responses to sorafenib plus interferon alfa (IFN-) in renal cell cancer. The computed tomography images show tumor response in the liver in a patient after the first two cycles of therapy. (A) Pretreatment; (B) post-cycle 2 sorafenib plus IFN-.

The median follow-up time among the censored patients was 14 months (range, 2 to 24 months). Median PFS time was 10 months (95% CI, 8 to 18 months; Fig 3A), with 23 patients having experienced progression and 48% of patients progression free at 1 year (95% CI, 31% to 63%). Median OS time has not yet been reached (Fig 3B); 11 patients have died, and 73% were alive at 1 year (95% CI, 55% to 85%).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier curves for (A) progression-free survival and (B) overall survival in renal cell cancer patients treated with sorafenib plus interferon alfa (N = 40).

	DISCUSSION

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Sorafenib and sunitinib were approved by the US Food and Drug Administration for use in RCC based on their ability to improve PFS in cytokine-refractory and untreated patients, respectively.^5,8 However, based on the sorafenib data, it seems as though a high major response rate is not a prerequisite to multikinase inhibitors having an impact on PFS in RCC. Therefore, if the IFN-/sorafenib combination is capable of eliciting more major responses than sorafenib alone, which our trial suggests, this may not necessarily translate into improved PFS compared with sorafenib alone. The median PFS of 10 months on our trial compares favorably with the 5.5-month median PFS seen with sorafenib alone in cytokine-refractory patients.⁵ However, our trial comprised both untreated and cytokine-refractory RCC patients, and the improvement in PFS may have been more a result of this fact than a result of the addition of IFN- to sorafenib. There is an ongoing randomized phase II trial of sorafenib versus IFN- in untreated RCC patients²²; if the median PFS of sorafenib-treated patients in that trial is substantially less than 10 months, it would suggest that the IFN-/sorafenib combination may improve both response rate and PFS compared with sorafenib alone.

Although the only unexpected serious adverse event that occurred with the combination was a small stroke in one patient, the toxicity of the regimen was not insignificant. The 2-week breaks between cycles were necessary for resolution of toxicity and thereby permitted the administration of multiple cycles of therapy. Although the observed toxicities were typical for either IFN-^7,8 or sorafenib,^5,23 the incidence of some toxicities were higher with the combination than expected. For instance, there was more fatigue, anorexia, anemia, and diarrhea with the combination than expected for either agent alone. The incidence of hypophosphatemia and rash was also higher than expected for sorafenib alone. Conversely, there was less hand-foot reaction than expected with sorafenib alone (incidence reported as 30% to 62% in two studies,^5,23 including 7% to 13% grade 3 or 4). The lower incidence of hand-foot reaction with the combination may have been a result of the high incidence of sorafenib/IFN- dose reductions on the study, which occurred in 65% of patients.

The requirement for dose reductions in 65% of patients shows that full doses of both drugs were not tolerated by the majority of patients, most of whom had an excellent performance status at the start of therapy. Although this study required that both agents be dose reduced for toxicity, in hindsight, it is likely that dose reduction of only the IFN- would have sufficed to mitigate most of the constitutional toxicities and neutropenia. Whether a strategy that minimizes sorafenib dose reductions would improve the outcome with IFN- plus sorafenib remains to be determined. In addition to starting with a lower dose of IFN- and/or preferentially dose reducing the IFN-, another strategy to be considered to lessen toxicity is using the IFN-/sorafenib combination until the response plateaus (which usually occurs within the first two cycles) and then continuing with sorafenib alone. Further studies with the combination of IFN- and sorafenib, including a larger randomized phase III trial, will be necessary to determine whether this regimen can benefit RCC patients to a greater degree than sorafenib alone.

	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: Jared A. Gollob, Bayer, Onyx; W. Kimryn Rathmell, Bayer, Onyx Stock: N/A Honoraria: Jared A. Gollob, Bayer, Onyx, Schering-Plough; W. Kimryn Rathmell, Bayer, Onyx; Elizabeth K. Miller, 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 REFERENCES

 
Conception and design: Jared A. Gollob, Bercedis L. Peterson, John J. Wright

Administrative support: Jared A. Gollob, W. Kimryn Rathmell, Tina M. Richmond, Christine B. Marino, Elizabeth K. Miller, Gayle Grigson, Catharine Watkins, John J. Wright

Provision of study materials or patients: Jared A. Gollob, W. Kimryn Rathmell, Tina M. Richmond, Christine B. Marino, Elizabeth K. Miller, Gayle Grigson, Catharine Watkins

Collection and assembly of data: Jared A. Gollob, W. Kimryn Rathmell, Tina M. Richmond, Christine B. Marino, Gayle Grigson, Catharine Watkins

Data analysis and interpretation: Jared A. Gollob, Lin Gu, Bercedis L. Peterson

Manuscript writing: Jared A. Gollob

Final approval of manuscript: Jared A. Gollob, W. Kimryn Rathmell, Bercedis L. Peterson, John J. Wright

	NOTES

 
Supported by National Institutes of Health Grants No. K23RR15541 and U01-CA-099118.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and the 3rd International Congress on Kidney and Bladder Cancer, August 4-6, 2006, Orlando, FL.

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

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Submitted January 19, 2007; accepted April 9, 2007.

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