Optimizing Sunitinib Dosing: Balancing Efficacy and Tolerability Pavlos Msaouel, MD, PhD Oncology Fellow, The University of Texas MD Anderson Cancer Center Houston, Texas In what might be described as “real-world” data meeting clinical trial results, guidelines for the optimal use of sunitinib reflect the manner in which clinical practice has kept pace with and even supplanted some of the evidence-driven recommendations. More specifically, there has been a move from the 4- weeks-on / 2-weeks-off towards the 2-weeks-on / 1-week-off schedule. New studies, albeit mostly retrospective or single-arm prospective, provide key insights as to how exposure to the drug can be maximized while solving the riddle of adverse effects that often stand in the way of treatment compliance. If there is a textbook example of how oncologists modify the indicated dosing of oral anticancer drugs to coincide with what is happening in “real-world” clinical practice, then look no further than how the rules are changing for the scheduling of sunitinib in metastatic renal cell carcinoma (mRCC). And yet, there is still significant controversy surrounding the optimal approach to the use of sunitinib. The most commonly used sunitinib dosing regimens are the traditional 50 mg by mouth 4-weeks-on / 2- weeks-off (4/2) and the alternative schedule of 50 mg by mouth 2-weeks-on / 1-week-off (2/1). Until we obtain further prospective data from head-to-head trials of the safety and efficacy of these two widely used strategies, the conundrum will remain: what is the sunitinib dosing schedule that delivers the optimal benefit-risk balance for patients with mRCC? Despite the growing evidence from numerous trials addressing sunitinib dosing, one of the most intriguing aspects of the analyses and meta-analyses is that realworld 66 Kidney Cancer Journal experience from many centers around the globe has emerged as a driving force frequently determining, or at least influencing, the dosing choice.1-3 However, to accept a strategy as the standard of care we need to examine a number of questions before reaching a consensus, before a truly evidenced based approach is validated. Recent reports are elucidating much of this needed information and they point toward a time when we will be able to more accurately predict which patients are most likely to benefit from a specific dosing strategy while ensuring that more patients are started on the optimal dose of sunitinib. The use of sunitinib in the first-line setting is being challenged in numerous Phase III studies testing other tyrosine kinase inhibitors (TKIs), the combination of immune checkpoint inhibitors with TKIs, or the combination of two immune checkpoint inhibitors.4,5 It remains to be seen what the impact of these studies will be on first-line choices, and how the use of the 4/2 and 2/1 schedules of sunitinib will have relative merit. It is indeed important to delineate the optimal schedule for sunitinib before designing a fair comparison of this drug with newer agents. Pharmacokinetics and Antitumor Activity of Sunitinib Initial preclinical and clinical data elucidated the pharmacokinetics and pharmacodynamics of sunitinib in patients with advanced malignancies, and ultimately determined the recommended dose and tolerability that served as the basis for sunitinib’s approval. In their report more than 10 years ago, Faivre et al6 delineated the profile of sunitinib, a novel at that time, oral, multitargeted TKI with antitumor and antiangiogenic activities. Earlier reports identified the drug as a potent inhibitor of Vascular Endothelial Growth Factor Receptors -1 and -2 (VEGFR-1 and VEGFR-2), fetal liver tyrosine kinase receptor 3 (FLT3), KIT, Platelet Derived Growth Factor re- Keywords: sunitinib, dosing schedules, pharmacokinetics, RESTORE trial, RAINBOW trial, dose modification, VEGF blockade, adverse effects. Corresponding Author: Pavlos Msaouel, MD, UT MD Anderson Cancer Center, 1400 Holcombe Blvd., Unit 463, Houston, TX 77030. Email: pmsaouel@mdanderson.org Nizar M. Tannir, MD Professor, Department of Genitourinary Medical Oncology Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and Deputy Department Chair Department of Genitourinary Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas
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