Annals of Oncology Advance Access published February 21, 2015
review
Annals of Oncology 00: 1–5, 2015 doi:10.1093/annonc/mdv030
Alternate sunitinib schedules in patients with metastatic renal cell carcinoma S. Kalra1, B. I. Rini2 & E. Jonasch1* 1 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston; 2Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA
Received 27 October 2014; revised 30 December 2014; accepted 7 January 2015
introduction The VHL–HIF pathway is pivotal to the pathobiology of clearcell renal cell carcinoma (RCC), and insights into its dysregulation have been crucial for the development of targeted agents that include vascular endothelial growth factor (VEGF) receptor inhibitors and antibodies to circulating VEGF [1]. Inhibitors of the mammalian target of rapamycin molecule, which is downstream of the phosphoinositide 3-kinase and protein kinase B pathways, have also demonstrated a role in the treatment of metastatic renal cell carcinoma (mRCC). These new agents have dramatically changed the therapeutic landscape of mRCC, and are now considered standard of care for patients with mRCC [2, 3]. Despite their efficacy, these agents continue to be the focus of ongoing investigation, attempting to identify ways to maximize response and minimize toxicity. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor exhibiting antiangiogenic activity. Sunitinib demonstrated superior median progression-free survival (PFS) when compared with interferon-α in a large phase III study of patients with mRCC [4]. Sunitinib was FDA approved in 2006, after which it became a standard of care in front-line treatment of mRCC. Although the therapeutic goal in the treatment of mRCC is prolongation of survival, it is equally important to keep the
*Correspondence to: Dr Eric Jonasch, Department of Genitourinary Medical Oncology, U. T. MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1374, Houston, TX 77030, USA. Tel: +1-713-563-7232; Fax: +1-713-563-7215; E-mail: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
review
treatment-related toxicities to a minimum to maximize drug adherence, and overall time on treatment. Maintenance of sunitinib dose intensity can be challenging due to treatment-related adverse events (AEs) such as fatigue, hypertension, hand–foot syndrome (HFS) and diarrhea. In the original phase III trial of sunitinib, 38% and 32% patients in the sunitinib arm underwent dose interruptions and reductions, respectively, because of drug toxicity [4]. In clinical practice, it is often noted that AEs increase throughout each cycle, and tend to be worst in the final 2 weeks of treatment cycle [5]. The impact of treatment-related toxicities on patients can be significant and, for some patients, living longer may not always equate with living better. Although sunitinib was administered on a continuous daily dose schedule in preclinical studies, the 4-week on followed by 2-week off schedule (4/2 schedule) was designed from the collective results of a few studies. Bone marrow and adrenal toxicities were noted in preclinical studies, but were not frequently observed in phase II clinical trials. In a study assessing the 4/2 schedule with doses of sunitinib between 50 and 100 mg, daily dosing for 28 days led to a 3- to 5.5-fold accumulation of sunitinib and a 7- to 15-fold accumulation of SU-12662, when compared with levels on day 1 of treatment [6, 7]. With a rising concern over drug accumulation, additional studies assessed sunitinib administered every other day and once daily on 2-week on and 2-week off and 4-week on and 2-week off schedules [8]. Pharmacokinetics for these studies were similar to those in the first study: accumulation of sunitinib and SU-12662 was noted after 14 days of continuous dosing, with a decline in the concentration to predose
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 17, 2015
Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor exhibiting antiangiogenic activity. Sunitinib demonstrated improved outcomes in comparison to interferon-α in a large phase III study of treatment naïve patients with metastatic renal cell carcinoma. Maintaining patients on sunitinib treatment is essential for a sustained disease control as higher exposure to sunitinib has been associated with an improved overall response rate, progression-free survival and overall survival. Various studies have compared the outcomes of patients undergoing sunitinib therapy based on modifications from their standard dose and schedule. Several studies have shown that switching to an alternate schedule with more frequent dose interruptions without affecting dose density over a 6-week cycle is associated with improved outcomes and increased tolerability. Key words: sunitinib, renal cell carcinoma, drug administration schedule, alternate schedule
review
methods A literature search was carried out in the Medline database using terms renal cell carcinoma, RCC, sunitinib, pharmacokinetics, pharmacodynamics and endothelial cells between January 2000 and June 2014. The Medline search was supplemented by searches of the published abstracts of major meetings of the American Society of Clinical Oncology and European Society of Medical Oncology. The search was limited to English language articles. The studies that were included assessed the efficacy of continuous daily dosing (CDD) of sunitinib and administration of sunitinib on alternate schedule. The studies that reported phase I trials and retrospective cohorts with
review
Annals of Oncology 00: 1–5, 2015 doi:10.1093/annonc/mdv030
Alternate sunitinib schedules in patients with metastatic renal cell carcinoma S. Kalra1, B. I. Rini2 & E. Jonasch1* 1 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston; 2Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, USA
Received 27 October 2014; revised 30 December 2014; accepted 7 January 2015
introduction The VHL–HIF pathway is pivotal to the pathobiology of clearcell renal cell carcinoma (RCC), and insights into its dysregulation have been crucial for the development of targeted agents that include vascular endothelial growth factor (VEGF) receptor inhibitors and antibodies to circulating VEGF [1]. Inhibitors of the mammalian target of rapamycin molecule, which is downstream of the phosphoinositide 3-kinase and protein kinase B pathways, have also demonstrated a role in the treatment of metastatic renal cell carcinoma (mRCC). These new agents have dramatically changed the therapeutic landscape of mRCC, and are now considered standard of care for patients with mRCC [2, 3]. Despite their efficacy, these agents continue to be the focus of ongoing investigation, attempting to identify ways to maximize response and minimize toxicity. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor exhibiting antiangiogenic activity. Sunitinib demonstrated superior median progression-free survival (PFS) when compared with interferon-α in a large phase III study of patients with mRCC [4]. Sunitinib was FDA approved in 2006, after which it became a standard of care in front-line treatment of mRCC. Although the therapeutic goal in the treatment of mRCC is prolongation of survival, it is equally important to keep the
*Correspondence to: Dr Eric Jonasch, Department of Genitourinary Medical Oncology, U. T. MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1374, Houston, TX 77030, USA. Tel: +1-713-563-7232; Fax: +1-713-563-7215; E-mail: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
review
treatment-related toxicities to a minimum to maximize drug adherence, and overall time on treatment. Maintenance of sunitinib dose intensity can be challenging due to treatment-related adverse events (AEs) such as fatigue, hypertension, hand–foot syndrome (HFS) and diarrhea. In the original phase III trial of sunitinib, 38% and 32% patients in the sunitinib arm underwent dose interruptions and reductions, respectively, because of drug toxicity [4]. In clinical practice, it is often noted that AEs increase throughout each cycle, and tend to be worst in the final 2 weeks of treatment cycle [5]. The impact of treatment-related toxicities on patients can be significant and, for some patients, living longer may not always equate with living better. Although sunitinib was administered on a continuous daily dose schedule in preclinical studies, the 4-week on followed by 2-week off schedule (4/2 schedule) was designed from the collective results of a few studies. Bone marrow and adrenal toxicities were noted in preclinical studies, but were not frequently observed in phase II clinical trials. In a study assessing the 4/2 schedule with doses of sunitinib between 50 and 100 mg, daily dosing for 28 days led to a 3- to 5.5-fold accumulation of sunitinib and a 7- to 15-fold accumulation of SU-12662, when compared with levels on day 1 of treatment [6, 7]. With a rising concern over drug accumulation, additional studies assessed sunitinib administered every other day and once daily on 2-week on and 2-week off and 4-week on and 2-week off schedules [8]. Pharmacokinetics for these studies were similar to those in the first study: accumulation of sunitinib and SU-12662 was noted after 14 days of continuous dosing, with a decline in the concentration to predose
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 17, 2015
Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor exhibiting antiangiogenic activity. Sunitinib demonstrated improved outcomes in comparison to interferon-α in a large phase III study of treatment naïve patients with metastatic renal cell carcinoma. Maintaining patients on sunitinib treatment is essential for a sustained disease control as higher exposure to sunitinib has been associated with an improved overall response rate, progression-free survival and overall survival. Various studies have compared the outcomes of patients undergoing sunitinib therapy based on modifications from their standard dose and schedule. Several studies have shown that switching to an alternate schedule with more frequent dose interruptions without affecting dose density over a 6-week cycle is associated with improved outcomes and increased tolerability. Key words: sunitinib, renal cell carcinoma, drug administration schedule, alternate schedule
review
methods A literature search was carried out in the Medline database using terms renal cell carcinoma, RCC, sunitinib, pharmacokinetics, pharmacodynamics and endothelial cells between January 2000 and June 2014. The Medline search was supplemented by searches of the published abstracts of major meetings of the American Society of Clinical Oncology and European Society of Medical Oncology. The search was limited to English language articles. The studies that were included assessed the efficacy of continuous daily dosing (CDD) of sunitinib and administration of sunitinib on alternate schedule. The studies that reported phase I trials and retrospective cohorts with
