Pavlos Msaouel, MD, PhD
The University of Texas MD Anderson Cancer Center
Nizar M. Tannir, MD
Professor, Department of GenitourinaryMedical 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
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 real-world 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 receptors α and β (PDGFRα and PDGFRβ). 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 PDGFRβ 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 “week-off” 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).
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 primary 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 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 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 ‘stop-and-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 randomized 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 (to view a larger version of this Table, click here), 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.
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, et al. Real-world use of sunitinib in Japanese patients with advanced renal cell carcinoma: efficacy, safety and biomarker analyses in 1689 consecutive patients. Jpn J Clin Oncol. 2015;45:576-83.
3. Crumbaker M, Guminski A, Gurney H, Sabanathan D, Wong S, Pavlakis N. Real-world experience of the feasibility and tolerability of the 2/1 dosing schedule with sunitinib in the treatment of patients with advanced renal cell carcinoma in Australia. Asia Pac J Clin Oncol. 2017.
4. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol. 2017;35:591-7.
5. Escudier B, Tannir NM, McDermott DF, Frontera OA, Melichar B, Plimack ER, et al. LAB5 – CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. . ESMO 2017.
6. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25-35.
7. Faivre S, Demetri G, Sargent W, Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov. 2007;6:734-45.
8. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-24.
9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol. 2010;66:357-71.
10. Kalra S, Rini BI, Jonasch E. Alternate sunitinib schedules in patients with metastatic renal cell carcinoma. Ann Oncol. 2015;26:1300-4.
11. Schwandt A, Wood LS, Rini B, Dreicer R. Management of side effects associated with sunitinib therapy for patients with renal cell carcinoma. Onco Targets Ther. 2009;2:51-61.
12. Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol. 2012;30:1371-7.
13. George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, Deprimo SE, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009;45:1959-68.
14. Rovithi M, de Haas RR, Honeywell RJ, Poel D, Peters GJ, Griffioen AW, et al. Alternative scheduling of pulsatile, high dose sunitinib efficiently suppresses tumor growth. J Exp Clin Cancer Res. 2016;35:138.
15. Bjarnason GA, Khalil B, Hudson JM, Williams R, Milot LM, Atri M, et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol. 2014;32:480-7.
16. Bjarnason GA. Can individualized sunitinib dose and schedule changes optimize outcomes for kidney cancer patients? Can Urol Assoc J. 2016;10:S252-S5.
17. Khosravan R, Motzer RJ, Fumagalli E, Rini BI. Population Pharmacokinetic/Pharmacodynamic Modeling of Sunitinib by Dosing Schedule in Patients with Advanced Renal Cell Carcinoma or Gastrointestinal Stromal Tumor. Clin Pharmacokinet. 2016;55:1251-69.
18. Atkinson BJ, Kalra S, Wang X, Bathala T, Corn P, Tannir NM, et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol. 2014;191:611-8.
19. Najjar YG, Mittal K, Elson P, Wood L, Garcia JA, Dreicer R, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer. 2014;50: 1084-9.
20. Kondo T, Takagi T, Kobayashi H, Iizuka J, Nozaki T, Hashimoto Y, et al. Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma—comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off. Jpn J Clin Oncol. 2014;44:270-7.
21. Ezz El Din M. Sunitinib 4/2 Versus 2/1 Schedule for Patients With Metastatic Renal Cell Carcinoma: Tertiary Care Hospital Experience. Clin Genitourin Cancer. 2017;15:e455-e62.
22. Bracarda S, Iacovelli R, Boni L, Rizzo M, Derosa L, Rossi M, et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol. 2015;26:2107-13.
23. Miyake H, Miyazaki A, Harada K, Fujisawa M. Assessment of efficacy, safety and quality of life of 110 patients treated with sunitinib as first-line therapy for metastatic renal cell carcinoma: experience in real-world clinical practice in Japan. Med Oncol. 2014;31:978.
24. Basso U, Maruzzo M. More on sunitinib 2 weeks on/1 week off schedule: the Rainbow analysis. Ann Oncol. 2016;27:202-3.
25. Pan X, Huang H, Huang Y, Liu B, Cui X, Gan S, et al. Sunitinib dosing schedule 2/1 improves tolerability, efficacy, and health-related quality of life in Chinese patients with metastatic renal cell carcinoma. Urol Oncol. 2015;33:268 e9-15.
26. Lee JL, Kim MK, Park I, Ahn JH, Lee DH, Ryoo HM, et al. RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type Renal cell carcinoma: RESTORE trial. Ann Oncol. 2015;26:2300-5.
27. Bracarda S, Negrier S, Casper J, Porta C, Schmidinger M, Larkin J, et al. How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2017; 17:227-33.
28. Guida FM, Santoni M, Conti A, Burattini L, Savini A, Zeppola T, et al. Alternative dosing schedules for sunitinib as a treatment of patients with metastatic renal cell carcinoma. Crit Rev Oncol Hematol. 2014;92: 208-17.
29. Johannsen M, Florcken A, Bex A, Roigas J, Cosentino M, Ficarra V, et al. Can tyrosine kinase inhibitors be discontinued in patients with metastatic renal cell carcinoma and a complete response to treatment? A multicentre, retrospective analysis. Eur Urol. 2009;55:1430-8.
30. Ornstein MC, Wood LS, Elson P, Allman KD, Beach J, Martin A, et al. A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol. 2017;35:1764-9.
31. Collinson FJ, Gregory WM, McCabe C, Howard H, Lowe C, Potrata D, et al. The STAR trial protocol: a randomised multi-stage phase II/III study of Sunitinib comparing temporary cessation with allowing continuation, at the time of maximal radiological response, in the first-line treatment of locally advanced/metastatic renal cancer. BMC Cancer. 2012;12:598. KCJ
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: firstname.lastname@example.org