mary endpoint.26 It found that the 6-month FFS rates were higher in the 2/1 (63%) vs the 4/2 group (44%). In addition, patients in the 2/1 group achieved an objective response rate (ORR) of 47% with a median time to progression (TTP) of 12.1 months compared with ORR 36% and median TTP 10.1 months in the 4/2 group. Furthermore, AEs such as fatigue and neutropenia were more common in the 4/2 group.26 Due to its open-label design, it is possible that some patients in the 4/2 group may have crossed-over to 2/1 if they were aware of the potentially better tolerability of this schedule. FFS is a composite outcome that can be difficult to interpret since the published results do not specify how many failures were due to disease progression, treatment toxicity, patient refusal, or death. Furthermore, the small sample size hindered the detection of differences in more established outcomes such as PFS and overall survival (OS). Nevertheless, the RESTORE trial added to the growing number of data showing that the 2/1 schedule can reduce toxicity without a substantial compromise in efficacy. The abundance of mainly retrospective information published on alternative dosing schedules for sunitinib may leave the clinician without a consensus. Despite the doubts cast on the traditional 4/2 schedule, it still has the highest level of evidence and is used in most clinical trial protocols. It is therefore still deeply rooted in many practices and at least some skepticism surrounds the decision to switch to the 2/1 schedule despite the clear trend in this direction. A group of European experts recently critically reviewed27 the data of the RESTORE “Despite the growing evidence from numerous trials addressing sunitinib dosing, one of the most intriguing aspects of the analyses and meta-analyses is that 'real world' experience from many centers around the globe has emerged as a driving force frequently determining, or at least influencing, the dosing choice.” trial26 and of three retrospective published studies18,19,22 comparing 4/2 with 2/1. Although their analysis supported the large consensus that the 2/1 schedule improves tolerability compared with 4/2, the low level of evidence regarding the comparative efficacy of 2/1 vs 4/2 precluded the authors from endorsing the use of 2/1 in all patients with mRCC. They thus suggested a strategy incorporating both schedules, echoing the RAINBOW analysis: all patients should be started on 4/2 but then be switched to 2/1 if they develop dose-limiting toxicities during weeks 3-4 of the 4/2 cycle. This reasonable recommendation, favoring a switch in schedules instead of a dose-reduction, will need to be readdressed as higher level data are published comparing 4/2 with 2/1. The best test will be a randomized clinical trial comparing the safety, tolerability, and efficacy of switching from 4/2 to 2/1 vs dose-reducing but maintaining the 4/2 schedule in patients who develop AEs. Such a phase II trial is currently underway (NCT02689167 at clinicaltrials.gov). Withholding and Re-initiating Sunitinib: The ‘Stop and Go’ Strategy One of the strategies receiving attention is called the ‘stop 70 Kidney Cancer Journal and go’ approach, so called because sunitinib is ‘stopped’ when a prespecified response endpoint has been reached and only reinitiated upon predefined disease progression. 28 Initial retrospective data in small cohorts indicated that disease control can be achieved by the reintroduction of sunitinib in cases where the drug was held after a complete response.29 A phase II single-arm study conducted at the Cleveland Clinic tested the efficacy of ‘stopand go’ sunitinib in 20 patients. Sunitinib was initially dosed at the standard 50mg 4/2 schedule for 4 cycles (24 weeks total) and then the treatment was held if there was a �� 10% reduction in tumor burden. The patients were closely monitored and sunitinib was restarted if there was a �� 10% increase in tumor burden. Treatment would then be held again if there was a �� 10% reduction in tumor burden. This intermittent dosing scheme was followed until there was disease progression or unacceptable toxicity. 30 The major limitations of this trial include its small size, lack of comparator arm, and use of feasibility as the primary endpoint, defined as the proportion of eligible patients who underwent the ‘stop and go’ strategy on trial. Thus, this small trial was not designed to test whether the ‘stop-and-go’ approach produced better efficacy or lower toxicity compared with the standard 4/2 approach. Nevertheless, its results indicated that the ‘stop-and-go’ strategy is feasible, tolerable, and low-cost as patients can spend prolonged time periods off therapy without major compromises in clinical efficacy.30 A variation of this approach is currently being tested in the random- ized multi-stage phase II/III STAR trial (ISRCTN06473203) which is investigating whether temporary discontinuation of first-line sunitinib or pazopanib is non-inferior compared with conventional dosing in terms of 2-year overall survival (OS) and quality adjusted life year (QALY).31 Future Directions: Ongoing Trials Search for the Elusive Prospective Data While the 2/1 schedule is gaining more traction in the ‘real-world’ a number of ongoing trials, listed in the Table, are seeking the prospective evidence to guide optimal sunitinib dosing. At the same time, however, upcoming results from studies of novel drug regimens may completely change the treatment landscape of mRCC within the next 1-2 years, and substantially reduce the role of sunitinib as a first-line agent. Nevertheless, sunitinib will still be used as a salvage regimen or as part of combination strategies, and these decisions should be guided by data on how to best balance efficacy and tolerability. References 1. Conter H. Practical first-line management of renal cell carcinoma in a community practice. Can Urol Assoc J. 2016;10:S239-S41. 2. Akaza H, Naito S, Ueno N, Aoki K, Houzawa H, Pitman Lowenthal S,
30114GA
To see the actual publication please follow the link above