ceptors �� and �� (PDGFR�� and PDGFR��). In vitro data showed that sunitinib was metabolized by cytochrome CYP3A4, thus forming a major pharmacologically active metabolite, SU12662.7 Subsequent pharmacokinetic studies in animal models extended this line of evidence: target plasma concentrations of sunitinib plus SU12662 ranging from 50-100 ng/mL successfully inhibited the phosphorylation of PDGFR and VEGFR-2.7 These earlier studies led to the Phase I dose-escalation trial that determined the recommended dose, tolerability, basic pharmacokinetics and antitumor effects of sunitinib when given orally daily for a 4-week on, 2-week off schedule (4/2) in patients with advanced malignancies.6 The recommended dose of 50mg/day led to the desired plasma concentration of 50-100 ng/mL, the maximum plasma concentration occurred ~5 hours after administration, and half-life ranged from 41 to 86 hours. This 50 mg 4/2 schedule became the standard that was used in the subsequent pivotal phase III trial that led to the FDA approval of sunitinib.8 Alternative Sunitinib Schedules: Improving Outcomes and Increasing Tolerability Higher exposure to sunitinib results in improved overall response rate, progression-free survival and overall survival. 9 Thus, maintaining drug adherence and maximizing drug exposure can result in improved outcomes. The main obstacle, however, is treatment-related adverse effects (AEs) such as fatigue, hypertension, hand-foot syndrome, and diarrhea. Numerous completed and ongoing trials are exploring whether alternative sunitinib doses and schedules provide a better balance between efficacy and tolerability than the traditional 50 mg 4/2 schedule.10 AEs generally tend to increase throughout the active drug period of each treatment cycle, and improve during the “weekoff” period.11 Indeed, patients on the 4/2 schedule report the lowest quality of life scores after the 4 weeks on treatment, and the highest scores following the 2-week break.12 Continuous daily administration of sunitinib at a lower dose is not preferred after a randomized prospective phase II trial showed that sunitinib 37.5 mg daily continuously with no “weeks off” does not provide any safety benefit and may produce slightly worse outcomes compared with the standard 50 mg 4/2 schedule.12 Phase II data in patients with gastrointestinal stromal tumors have shown no difference in morning vs evening administration of sunitinib.13 On the other hand, preclinical data suggest that pulsatile high dose sunitinib at doses of 200 mg once weekly or higher may produce a potent direct antitumor effect,14 and this approach is now studied in a phase I trial (NCT02058901 at clinicaltrials.gov). Furthermore, given the data suggesting that patients who develop less toxicity to sunitinib can have inferior disease response,15,16 it is possible that the cause of disease progression in at least some patients on the 50 mg 4/2 (or 2/1) regimens is underdosing. This hypothesis is being tested in a phase II trial of sunitinib dose escalation up to 75 mg 2/1 (NCT01499121 at clinicaltrials.gov). 68 Kidney Cancer Journal Comparisons Between the 4/2 and 2/1 Schedules The theoretical advantages of the 2/1 schedule vs 4/2 include the shorter duration of both the “on treatment” and “treatment break” periods while maintaining the same overall dose exposure over each 6-week period.17 Population pharmacokinetic and phamacodynamic modeling predicted that the 2/1 regimen produces comparable efficacy to 4/2 with a less severe toxicity profile.17 Sunitinib plus SU12662 reach steady-state concentrations and optimally suppress vascular perfusion within 14 days, while additional days of therapy do not produce substantial changes in pharmacokinetics.10 Furthermore, longer treatment break durations provide more time for both tumor and vascular endothelial cells to recover and proliferate.10 These considerations, along with the potentially more favorable toxicity profile and emerging efficacy data, have prompted clinicians to often favor the 2/1 over the FDA-recommended 4/2 schedule.1 A number of single center retrospective studies have suggested a favorable toxicity profile for the 2/1 schedule. 15, 18-21 These data were further corroborated by the RAINBOW analysis, a large multicenter, retrospective analysis of 3 separate patient groups: one group was switched to the 2/1 schedule after developing significant AEs with the 4/2 format; the second group used the 2/1 schedule from the beginning; the third group served as a 4/2 control.22 Switching from 4/2 to 2/1 reduced the overall incidence of grade 3-4 AEs from 45.7% to 8.2%.22 These AEs, including fatigue, hypertension, hand-foot syndrome, and thrombocytopenia, are the greatest deterrent to the continued use of the 4/2 regimen both in clinical trials and in real-world practice.2,8,23 As expected, patients who switched to the 2/1 regimen achieved a long treatment duration, at least in part explained by the lower incidence of unmanageable toxicities.22 There was also evidence of increased efficacy in the 4/2-to-2/1 group compared with the 4/2 control.22 However, this finding may have been influenced by selection bias.24 Despite such limitations, the RAINBOW analysis showed that a switch from 4/2 to 2/1 can ameliorate the toxicity of sunitinib. It would be reasonable to speculate that such an improved safety profile may translate into a survival benefit, as it allows higher and more prolonged drug exposure. A retrospective analysis of patients from 2 hospitals in China corroborated the results of the RAINBOW analysis by finding that switching from 4/2 to 2/1 reduces toxicity. Of note, however, median progression-free survival (PFS) was significantly longer for patients who were initiated on 2/1 compared with those that started on 4/2 and then switched to 2/1.25 A retrospective review of the ‘real-world’ experience with 2/1 in four Australian cancer centers showed that almost 1/3 of patients starting on 50 mg 2/1 required subsequent dose reductions but very few (6%) discontinued sunitinib due to toxicity, and there were no treatment-related deaths or grade 4 toxicities.3 The RESTORE trial was the first multicenter, randomized, phase II trial comparing 4/2 with 2/1 in mRCC, and used 6-month failure-free survival (FFS) rate as the pri
30114GA
To see the actual publication please follow the link above