phase ii study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma

Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma

  1. Nicholas J. Vogelzang
  1. From the Institut Gustave Roussy, Villejuif, France; Charité-Universitätsmedizin, Berlin; Klinikum rechts der Isar, Munich, Germany; Kantonsspital St Gallen, St Gallen, Switzerland; Karolinska University Hospital, Stockholm; Lund University Hospital, Lund, Sweden; Stanford University, Stanford, CA; Pfizer Global Research and Development, La Jolla, CA; Nevada Cancer Institute, Las Vegas, NV; Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; and the Papageorgiou Hospital, Thessaloniki, Greece.
  1. Corresponding author: Bernard Escudier, MD, Unité Immunothérapie, Institut Gustave Roussy; 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: bernard.escudier{at}igr.fr.

  1. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL, and at the 14th European Cancer Conference, September 23-27, 2007, Barcelona, Spain.

 
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Abstract

Purpose Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen.

Patients and Methods Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures.

Results One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM.

Conclusion Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

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INTRODUCTION

Approximately 210,000 new cases of renal cell carcinoma (RCC) are diagnosed annually worldwide with an estimated 102,000 deaths per year attributed to this disease.1 Up to 30% of RCC patients present with metastases.2,3 RCC is a heterogeneous disease comprising several subtypes, more than 85% of which are characterized by clear cell histology.4 Nonhereditary clear cell RCC, which accounts for the majority of kidney cancer, is caused in part by defects in the von Hippel–Lindau tumor-suppressor gene (VHL) in approximately 60% to 70% of cases.5 In healthy cells, the VHL protein inhibits the expression of hypoxia-inducible genes, such as those encoding vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). When the VHL protein is defective or absent, these genes' products are overexpressed, resulting in epithelial-cell proliferation and other proangiogenic processes integral to tumor growth, survival, and metastasis. Blocking activity of components of the VHL tumor-suppressor pathway is likely to reverse these effects, thus inhibiting tumor progression.

RCC is highly resistant to conventional chemotherapeutic agents. Until recently, cytokines were widely used as first-line RCC therapy, but because of low objective response rates (ORR; 5% to 20%),6–11 low median overall survival (OS; approximately 12 to 13 months)7,12–14 and significant toxicity,4 alternative treatments were sought. Recently, three new targeted therapies have been approved for advanced RCC: sorafenib (Nexavar; Bayer Healthcare Pharmaceuticals, Wayne, NJ, and Onyx Pharmaceuticals, Emeryville, CA), sunitinib malate (SUTENT; Pfizer, New York, NY), and temsirolimus (Torisel; Wyeth Pharmaceuticals, Philadelphia, PA). Sunitinib is an oral, selective multitargeted tyrosine kinase inhibitor of VEGF receptors (VEGFRs; -1, -2, and -3; data on file, Pfizer),15 PDGF receptors (PDGFRs-α and -β),15,16 as well as stem-cell factor receptor (KIT),16 glial cell-line derived neurotrophic factor (rearranged during transfection [RET]),17 colony-stimulating factor-1 receptor (CSF-1R),18 and FMS-like tyrosine kinase-3 (FLT-3).19

Sunitinib demonstrated robust clinical efficacy in two independent, open-label, phase II studies of patients with cytokine-refractory metastatic RCC (mRCC).20,21 These studies included 168 patients, total, who received intermittent therapy with sunitinib 50 mg/d administered in the morning on schedule 4/2 (4 weeks on treatment followed by 2 weeks off). The combined ORR was 42%, and a further 24% of patients had a best response of stable disease (SD) for ≥ 3 months.21 Median progression-free survival (PFS) in the two studies was 8.2 months (95% CI, 7.8 to 10.4 months), and median OS was 23.9 months (95% CI, 14.1 to 30.7 months) for patients in the second, pivotal study (n = 106).22 Treatment was generally tolerated with manageable adverse events (AEs), the most common of which were fatigue and diarrhea.20,21 Furthermore, in an international, multicenter, phase III randomized trial in first-line mRCC, treatment with sunitinib (on schedule 4/2) was found to be well-tolerated and associated with significantly longer PFS (11 v 5 months; P < .000001) and significantly higher ORR (47% v 12%; P < .000001) than interferon-alfa (IFN-α). Sunitinib also demonstrated a median OS of more than 2 years (26.4 months) compared to 21.8 months with IFN-α.23

Thus, sunitinib, dosed on schedule 4/2, is effective and well-tolerated, but as an alternative treatment regimen, continuous once-daily dosing may offer added convenience and flexibility. In addition, previous studies have only investigated the tolerability of sunitinib administered in the morning (AM). Sunitinib administered in the evening (PM) before sleep might reduce the incidence or severity of AEs, such as fatigue or nausea. The aim of this phase II study was to evaluate the antitumor activity and tolerability of sunitinib administered continuously at 37.5 mg/d, either in the AM or in the PM, before sleep, in patients with cytokine-refractory mRCC.

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PATIENTS AND METHODS

Patients

Patients age ≥ 18 years with histologically proven mRCC and evidence of measurable disease, based on Response Evaluation Criteria in Solid Tumors (RECIST),24 were eligible. Additional eligibility criteria included failure of one prior cytokine-based regimen in the metastatic setting (with IFN-α monotherapy administered ≥ 4 weeks); Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; adequate hematologic, hepatic, and renal function; and informed consent. Patients were excluded if they had prior treatment with any systemic RCC therapy, except for one cytokine-based therapy, or if they had any second malignancy within the past 3 years other than adequately treated basal cell carcinoma, squamous cell skin cancer, or in situ carcinoma. Additional exclusion criteria included a history of or known brain metastases, spinal cord compression or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease, as well as clinically significant cardiovascular disease, cardiac dysrhythmias, atrial fibrillation, prolongation of the QTc interval, or uncontrolled hypertension.

Baseline Evaluations

Baseline evaluations included medical history, physical examination, assessment of ECOG performance status, cardiac function (based on three 12-lead ECGs), laboratory parameters (hematology and clinical chemistry), and AEs, as well as tumor imaging (computed tomography [CT] scan or magnetic resonance imaging [MRI] of the chest, abdomen, pelvis, and other applicable disease sites, a bone scan, and a brain CT or MRI scan).

Assessment of Pharmacokinetic Parameters and Biomarkers

At the start of each cycle (day 1) and at the end of treatment, blood samples were collected from patients in the AM arm to determine trough (Cmin) plasma levels of sunitinib and its active metabolite SU12662. Plasma concentrations were determined using liquid chromatography/mass spectrometry at BASi (West Lafayette, IN), and the lower limit of detection was 0.1 ng/mL for each compound. In addition, samples were analyzed by enzyme-linked immunosorbent assay for relevant soluble proteins associated with angiogenesis.

Statistical Evaluation

A sample size of 100 patients was required to test the null hypothesis that the true response rate was ≤ 5% versus the alternative hypothesis that the true response rate was ≥ 15% with 90% power and an α level of .05. If ≥ 11 objective responses were observed, then the null hypothesis was rejected with a 5% target false positive error rate. Efficacy analyses included all patients that received ≥ 1 dose of sunitinib, had a baseline disease assessment, and had the correct histological cancer type. Analyses of safety results were summarized for all patients receiving ≥ 1 dose of sunitinib. For quality of life assessments, a baseline assessment for each questionnaire was required for each patient included in the analyses. The number and percent of patients experiencing a CR or PR was summarized along with the corresponding exact two-sided 95% CI. Time-to-event variables were summarized using the Kaplan-Meier method,27 with the median event time and two-sided 95% CI for the median provided for each variable.

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RESULTS

Patient Characteristics and Disposition

A total of 107 patients were enrolled between July 2005 and February 2006, with 54 patients randomly assigned to sunitinib in the AM and 53 in the PM (Fig 1). The majority had clear cell histology and underwent nephrectomy (Table 128); 89% had received prior treatment with IFN-α alone, or in combination with other agents, and 11% with interleukin-2 alone.

Fig 1.
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Fig 1.

Patient enrollment and outcomes.

View this table:
Table 1.

Baseline Patient Characteristics

Patients received sunitinib for a median of 8.3 months (range, 0.5 to 27.6 months) at a median average daily dose of 37.5 mg (range, 25.4 to 48.8 months; Table 2); 24 patients (22%) successfully completed the study as defined per the protocol (1 year on study) and transferred to a sunitinib treatment continuation protocol. Eighty-three patients (78%) discontinued treatment (Fig 1). The majority (65 patients [61%]) discontinued treatment because of disease progression (including one death) with 16 and two patients discontinuing because of AEs and consent withdrawal, respectively (Table 2). Sixty-nine patients (65%) experienced dose interruptions, and 46 (43%) experienced dose reductions to 25 mg/d, of whom 17 patients (16%) re-escalated to 37.5 mg. Thirty-one patients (29%) escalated dose to 50 mg/d as per the protocol; of those, 17 patients (16%) reduced back to 37.5 mg/d.

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Table 2.

Patient Disposition

Efficacy

Overall, 107 patients received ≥ one dose of sunitinib and were included in the efficacy analysis. One hundred two patients had at least one postbaseline tumor assessment and tumor shrinkage was reported in 87 patients (85%; Fig 2). Twenty-one patients had a confirmed PR, resulting in an ORR of 20% (95% CI, 12.8% to 28.9%), with a median DR of 7.2 months. An additional 53 patients (51%) had SD of whom 36 (34%) exhibited SD longer than 6 months, resulting in a clinical benefit response rate (PR + SD > 6 months) of 53%. Twenty-four patients (23%) had progressive disease with data unavailable or missing for seven (7%). Median PFS was 8.2 months (95% CI, 6.4 to 8.4 months; Fig 3A). Median OS was 19.8 months (95% CI, 16.2 to 24.9 months; Fig 3B). Thirty-nine patients remained alive at a median follow-up of 26.4 months. The probability of survival at 12 months was 72% (95% CI, 62.1% to 79.3%).

Fig 2.
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Fig 2.

Maximum percentage change in target lesions by patient (n = 102; five patients did not have postbaseline assessments). * Patients who discontinued prematurely due to toxicity, following an initial partial response, or for whom the initial response was not confirmed on repeat imaging, are not identified as patients with a partial response.

Fig 3.
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Fig 3.

Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival (N = 107).

Pharmacokinetics

After continuous once-daily dosing of sunitinib, mean Cmin plasma concentrations for sunitinib, its metabolite SU12662, and total drug were within 25.5 to 46.2 ng/mL, 11.1 to 18.4 ng/mL, and 37.3 to 64.6 ng/mL, respectively. Based on the dose-corrected Cmin plasma concentrations, the pharmacokinetics of sunitinib and its metabolite appeared to be similar between continuous once-daily dosing and intermittent schedule 4/2.20 No unexpected accumulation of sunitinib or SU12662 was observed throughout the study.

Biomarkers

Sunitinib treatment resulted in marked elevation in plasma VEGF and reduction in both plasma sVEGFR-2 and plasma sVEGFR-3, as observed previously in an intermittent dosing study of sunitinib in RCC.29 However, in contrast to this earlier result, and as expected with continuous dosing in the present study, the changes from baseline for each of these soluble proteins were sustained throughout sunitinib administration, with no evidence of a return towards baseline levels at any time point.

Safety

Most treatment-related AEs were mild or moderate (grade 1 or 2) in severity and did not interfere with treatment (data not shown). The most commonly reported grade 3 treatment-related AEs (occurring in ≥10% of patients) were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%; Table 3). Six treatment-related grade 4 AEs (hematemesis, renal failure, vertigo, dehydration, hyponatremia, and hemorrhagic gastritis) and one grade 5 AE (acute myeloblastic leukemia) were reported.

View this table:
Table 3.

Most Commonly Reported Treatment-Related Adverse Events in AM (n = 54) and PM (n = 53) Patients

Sixteen patients (15%) discontinued the study due to AEs, the most common being asthenia/fatigue (four patients), thrombocytopenia (two patients), and GI disturbances (three patients). Two patients discontinued treatment due to grade 3 brain edema (associated with unsteady gait and dizziness) and grade 3 congestive heart failure, respectively, both of which recovered on discontinuation of therapy. The most common AEs leading to dose reduction were asthenia/fatigue (13%), hand-foot syndrome (9%), and diarrhea (6%). The most common AEs leading to dose interruption were diarrhea, anorexia, hand-foot syndrome, and vomiting (each 8%).

The tolerability of AM and PM dosing was similar, overall, as reflected in the rates of AE-related discontinuations, dose interruptions, and dose escalations, although patients in the AM arm appeared to have slightly lower rates of dose reductions (Table 2). However, no statistical comparisons of treatment arms were performed.

Health-Related Quality of Life

Fifty-two patients in the AM group and 52 in the PM group provided baseline EQ-5D and FACIT-fatigue questionnaires, evaluating patient-reported general health status and fatigue, respectively. The compliance rate for returning both questionnaires at subsequent visits was generally similar for each treatment arm (> 95%).

Median baseline scores were identical in each treatment arm for the two EQ-5D measures assessed: EQ-5D Index, a population preference-based health state utility score (AM, 0.8; PM, 0.8) and, EQ-VAS, the patient's overall health state on a Visual Analog Scale (or thermometer; AM, 70; PM, 70). EQ-VAS was slightly lower than that of an age-matched sample of the general US population (age 55 to 74 years, score of 82), males (score of 83), or respondents with a chronic medical condition (score of 80).30 There was no evidence of a change in the EQ-5D Index or EQ-VAS scores from baseline through up to 29 cycles of treatment in either cohort and no statistically significant differences between cohorts (Fig 4A).

Median baseline scores on the FACIT-fatigue questionnaire were also similar for each treatment arm (AM, 43; PM, 42) to that of a nonanemic population of patients with cancer, but lower than that of a general US population.31 In general, there was no evidence of a decrease in median FACIT-fatigue scores from baseline in either cohort and no statistically significant differences between cohorts (Fig 4B). Previous studies have established the minimally important difference to be approximately 3 to 4 points in score changes.32,33 The change from baseline was intermittently greater than 3 points in both cohorts, but there was no evidence of a systematic change. fatigue was highest at the end of treatment; this result likely reflects disease progression or other disease processes at termination of the study.

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DISCUSSION

Targeting VHL pathway components, such as VEGFR, in RCC has been validated as an effective approach, first by studies with the anti-VEGF monoclonal antibody bevacizumab34,35 and later in phase II and III trials with intermittent sunitinib treatment.20–23 In this study, continuous once-daily administration of sunitinib 37.5 mg showed significant antitumor activity, with an ORR of 20%, a median PFS of 8.2 months, and median OS of 19.8 months.

Clinical studies of sunitinib administered in a continuous once-daily dosing regimen were also conducted in patients with gastrointestinal stromal tumors (GIST)36 and non–small-cell lung cancer (NSCLC).37 In both of those phase II studies, continuous once-daily dosing compared favorably with the approved intermittent dosing schedule: preliminary analysis of patients in the GIST study yielded a median PFS of 34.1 weeks compared with 24.1 weeks seen with intermittent dosing in a phase III GIST study of comparable patients.38 Similarly, preliminary analysis of patients in the NSCLC study yielded a median PFS of 12.3 weeks compared with 12.0 weeks for patients in the same study who received intermittent dosing39; in addition, patients receiving continuous dosing reported a lower rate of severe (grade 3 or 4) fatigue.

Pharmacokinetic results in those studies also demonstrated that expected therapeutic exposures can be achieved using either intermittent or continuous once-daily dosing, with total sunitinib drug Cmin concentrations for the latter consistent with that for repeated cycles without observed accumulation.

A meta-analysis of pharmacokinetic and efficacy data from all clinical studies with single-agent sunitinib in cytokine-refractory mRCC, using population pharmacokinetic-pharmacodynamic modeling, has shown that equivalent tumor size changes are anticipated with either dosing regimen; however, the probability of greater response and survival increases with higher exposure,40 which could explain the higher efficacy observed with sunitinib 50 mg/d on schedule 4/2. Nonetheless, the 95% CIs of both ORR (95% CI, 12.8% to 28.9%) and median OS (95% CI, 16.2 to 24.9 months) seen with continuous dosing in this study overlap with those observed with schedule 4/2: ORR (95% CI, 25% to 44%)21 and median OS (95% CI, 14.1 to 30.7 months).22

The safety profile of sunitinib administered continuously at 37.5 mg/d was similar to that in studies of patients with mRCC utilizing intermittent schedule 4/2.20–22 Tolerability was similar with AM and PM dosing, although patients in the AM arm generally experienced fewer grade 3 AEs; therefore, continuous dosing in the PM did not substantially reduce the incidence or severity of AEs compared to AM dosing, as was initially hypothesized. No difference in quality of life was reported between patients who took sunitinib in the AM versus PM, mirroring the similar tolerability profiles of the two dosing arms. The comparability of AM and PM dosing in terms of tolerability and quality of life enables greater dosing flexibility for the patient.

In conclusion, continuous once-daily administration of sunitinib 37.5 mg was generally well tolerated in patients with cytokine-refractory mRCC, with neither dose reduction nor treatment delay required in the majority of patients. Efficacy, tolerability, and quality- of-life results were similar between patients dosed in the AM or PM. Continuous once-daily administration of sunitinib 37.5 mg is, therefore, a useful alternative to intermittent treatment, providing flexibility in dose scheduling, which can be explored in future combination studies and which is useful in patients developing symptoms in the 2-week off-treatment period. The results of a phase II trial that will directly compare the efficacy and tolerability of continuous versus intermittent administration of sunitinib (the Randomized Phase II Study of the Efficacy and Safety of Sunitinib Malate Schedule 4/2 vs. Sunitinib Malate Continuous Dosing as First-Line Therapy for Metastatic Renal Cell Cancer [Renal EFFECT Trial])41 will be interesting in this respect.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. 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 or Leadership Position: Edna Chow Maneval, Pfizer (C); Isan Chen, Pfizer (C); Nicholas J. Vogelzang, Meso Foundation (U), Nevada Cancer Institute (C) Consultant or Advisory Role: Bernard Escudier, Bayer Pharma (C), Novartis (C), Roche (C); Jan Roigas, Pfizer (C), Bayer (C), Roche (C), Wyeth (C); Silke Gillessen, Pfizer (C); Sandhya Srinivas, Pfizer (C); Per Flodgren, Pfizer (C); Nicholas J. Vogelzang, Pfizer (C), Novartis (C), Onyx/Bayer (C) Stock Ownership: Edna Chow Maneval, Pfizer; Isan Chen, Pfizer Honoraria: Bernard Escudier, Bayer, Roche, Pfizer, Genentech, Novartis; Jan Roigas, Pfizer, Bayer, Roche, Wyeth; Silke Gillessen, Pfizer; Ulrika Harmenberg, Pfizer (Stockholm, Sweden); Sandhya Srinivas, Pfizer; Christian Peschel, Pfizer; Per Flodgren, Pfizer, Roche; Nicholas J. Vogelzang, Wyeth, Novartis Research Funding: Sandhya Srinivas, Pfizer; George Fountzilas, Pfizer; Christian Peschel, Pfizer; Nicholas J. Vogelzang, Glaxo Expert Testimony: None Other Remuneration: Ulrika Harmenberg, Pfizer (Stockholm, Sweden)

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AUTHOR CONTRIBUTIONS

Conception and design: Bernard Escudier, Edna Chow Maneval, Isan Chen

Administrative support: Edna Chow Maneval

Provision of study materials or patients: Bernard Escudier, Jan Roigas, Silke Gillessen, Ulrika Harmenberg, Sasja F. Mulder, George Fountzilas, Christian Peschel, Per Flodgren, Nicholas J. Vogelzang

Collection and assembly of data: Bernard Escudier, Silke Gillessen, Ulrika Harmenberg, Sandhya Srinivas, Sasja F. Mulder, George Fountzilas, Christian Peschel, Edna Chow Maneval

Data analysis and interpretation: Bernard Escudier, Sandhya Srinivas, Sasja F. Mulder, Edna Chow Maneval, Isan Chen

Manuscript writing: Bernard Escudier, Sandhya Srinivas, Sasja F. Mulder, Edna Chow Maneval, Isan Chen, Nicholas J. Vogelzang

Final approval of manuscript: Bernard Escudier, Jan Roigas, Silke Gillessen, Ulrika Harmenberg, Sandhya Srinivas, Sasja F. Mulder, George Fountzilas, Christian Peschel, Per Flodgren, Edna Chow Maneval, Isan Chen, Nicholas J. Vogelzang

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Acknowledgment

We thank all of the patients and their families for their participation in this study as well as all of the participating investigators, including Manfred Johannsen, MD, for his contributions. We also acknowledge the contributions of, and honor the memory of, our colleague Pieter H.M. de Mulder, MD, an investigator in this trial who died in 2007. Editorial assistance was provided by ACUMED (Tytherington, United Kingdom) and was funded by Pfizer Inc.

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Footnotes

  • Supported by Pfizer Inc.

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

  • Clinical Trials repository link available on JCO.org.

  • Clinical trial information can be found for the following: NCT00137423.

  • Received October 16, 2008.
  • Accepted March 17, 2009.
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  1. Published online before print August 3, 2009, doi: 10.1200/JCO.2008.20.5476 JCO vol. 27 no. 25 4068-4075
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