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Abstract

Sunitinib is a multitarget tyrosine kinase inhibitor endowed mainly by antiangiogenic effects, although an indirect inhibitory effect on tumor growth and, more recently, a complex activity on antitumor immune response has been described. From approval by the US Food and Drug Administration (FDA) in January 2006, sunitinib represents a key molecule in the treatment of metastatic renal cell carcinoma (mRCC) due to the peculiar molecular pathogenesis of this neoplasm. Over the past 10 years, clinical trials and real-world experiences helped clinicians to understand how, when and for how long to use sunitinib. Although a huge amount of data evidenced the relationship existing between sunitinib dose intensity and improved clinical outcome, the management of sunitinib-induced adverse events is often complex; thus, alternative schedules have been proposed over time which allow increased tolerability, without decreased daily sunitinib exposure, leading to improved clinical outcomes. To date, combinations of sunitinib with other approved targeted agents did not demonstrate any significant benefit over its single-agent use, mainly due to tolerability issues. Sunitinib has also been tested in the adjuvant setting, within the ASSURE and S-TRAC trials, with opposite results; indeed, equivocal risk-stratification criteria, as well as immature overall survival (OS) data prevent any definitive conclusion on this important issue. Despite being on the market for a long time, sunitinib still plays a role as the ‘comparator arm’ of a number of trials in the field of mRCC. Combinations with immune checkpoint inhibitors and vaccines look promising; once again, sunitinib can help us to optimize mRCC management.

Keywords

anti-angiogenic therapy kidney cancer renal cell carcinoma sunitinib tyrosine kinase inhibitor

Introduction

Sunitinib (SU011248) is a small molecule that inhibits several members of the split-kinase domain family of receptor tyrosine kinases (RTKs), including the vascular endothelial growth factor receptors (VEGFRs) types 1 and 2 (FLT1 and FLK1/KDR), the platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), the stem cell factor receptor c-KIT, as well as the FLT3 and RET kinases.¹

Inhibiting these RTKs blocks downstream signal transduction, thereby affecting tumor angiogenesis and growth. Although the relative contribution of the inhibition of each of the above RTKs to sunitinib antitumor activity is still poorly understood, it is clear that its antineoangiogenic properties represent its major mechanism of action.¹

It is thus not a surprise that sunitinib has been first developed in renal cell carcinoma (RCC), an extremely angiogenesis-dependent malignancy.²

In addition, sunitinib has been shown to have a direct inhibitory effect on tumor growth by promoting tumor apoptosis, as well as an indirect inhibitory effect on tumor growth by stimulating antitumor immune responses.³

The aim of this review is to summarize the sunitinib clinical development program in RCC, paying particular attention to more recent data, consequently trying to hypothesize further development steps within a rapidly changing therapeutic scenario.

Sunitinib clinical development program in renal cell carcinoma

Sunitinib was studied, within different phase I studies, using various schedules, including a 3-week cycle consisting of treatment for 2 weeks followed by a 1-week rest period (schedule 2/1), a 4-week cycle comprising treatment for 2 weeks followed by a 2-week rest period (schedule 2/2), or a 6-week cycle of treatment for 4 weeks followed by a 2-week rest period (schedule 4/2). These schedules explored both daily and every other day administration, and incorporated planned rest periods due to the prolonged half-life of the drug, and evidence of accumulation with continuous daily dosing.⁴ Ultimately, the fixed dose of 50 mg daily (sufficient to produce target plasma concentrations above 50 ng/ml required to inhibit the PDGFRs and VEGFR RTKs) and the 4 weeks on, 2 weeks off schedule were chosen for the subsequent development of the drug.

As far as RCC, two phase II studies were then conducted in cytokine-refractory RCC patients.^5–7 These studies not only showed an extremely high rate of objective responses (40% and 39%, respectively), but also yielded an unprecedentedly long time to progression (TTP) of 8.7 months, as well as an intriguing overall survival (OS) of 16.4 months. These results warranted both an accelerated approval by the US Food and Drug Administration (FDA), as well as the subsequent design of a pivotal, phase III.

In the pivotal randomized phase III trial, 750 previously untreated metastatic RCC patients were randomized to receive either sunitinib (administered according to the standard dose and schedule), or interferon (IFN)-α (given subcutaneously at a dose of 9 MU three times week), the primary endpoint of the study being progression-free survival (PFS), while OS was among the secondary endpoints.

The average PFS in the group of patients treated with sunitinib was significantly longer than that of patients treated with IFN-α (11 versus 5 months), corresponding to a hazard ratio (HR) of 0.42 (i.e. a reduction in the risk of progression or death of 58%).⁸ Notably, the advantage in terms of PFS in favor of sunitinib was then maintained in all three prognostic groups according to the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. As expected, based on the results of previous phase I and II studies, sunitinib induced objective responses in a high percentage of patients (31%).

Regarding tolerability, patients treated with sunitinib showed a higher incidence of diarrhea, vomiting, hypertension, hand–foot syndrome, and neutropenia, a safety profile consistent with what had been observed within earlier phase studies. Overall, a better quality of life was observed in sunitinib-treated patients, as compared with IFN-α^8,9 Regarding OS, although it was higher in patients treated with sunitinib compared with those treated with IFN-α (26.4 versus 21.8 months, respectively), this difference did not reach statistical significance.¹⁰ However, since the primary endpoint of the study was PFS (and not OS), and the p value for OS was close to statistical significance, it was obvious that the study was simply underpowered to show a significant benefit in terms of OS. Indeed, when patients who crossed over from IFN-α to sunitinib were censored within a nonpreplanned analysis, a statistically significant benefit was observed also in OS.¹¹

The activity and safety of sunitinib in an unselected, real world patient population was then confirmed by the results of its global expanded access program (EAP); furthermore, sunitinib activity in specific subpopulations of patients usually excluded, or under-represented in clinical trials (e.g. elderly, patients with brain metastases, patients with nonclear-cell histotypes, etc.) clearly emerged from this huge cohort of patients.^12–14

Sunitinib clinical development is summarized in Table 1.

Table 1.

Sunitinib clinical development program in RCC.

Study	Design	Patients n	Efficacy Results
Motzer et al.⁵	Phase II, cytokine-refractory mRCC (schedule 4/2)	63	ORR, 40%^a Median TTP, 8.7 months Median OS, 16.4 months
Motzer et al.⁶ Motzer et al.⁷	Phase II, cytokine-refractory mRCC (schedule 4/2)	106	ORR, 33%^a Median TTP, 8.8 months Median OS, 23.9 months
Motzer et al.⁸ Motzer et al.¹⁰	Phase III, treatment-naïve mRCC, sunitinib versus IFN (schedule 4/2)	750	ORR, 31% versus 6% (p < 0.001) Median PFS, 11 versus 5 months (HR, 0.42; p < 0.001)^a Median OS, 26.4 months (HR, 0.821; p = 0.051)
Gore et al.¹³	Expanded-access program, cytokine-refractory or treatment-naïve mRCC (schedule 4/2 and CDD)	4,543	ORR, 16% Median PFS, 9.4 months Median OS, 18.7 months

Primary endpoint.

CDD, 37.5 mg/day on a continuous daily dosing schedule; HR, hazard ratio; IFN, interferon-α;

mRCC, metastatic renal cell carcinoma; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; schedule 4/2, 50 mg/day on a 4-weeks-on/2-weeks-off schedule; TTP, time to tumor progression.

As soon as sunitinib became commercially available on a global scale, it assured as the standard of care for the treatment of metastatic RCC, and as such, it remained until pazopanib joined it in that position following the presentation of the results of the COMPARZ and PISCES studies.

Sharing a leading position with pazopanib

In the COMPARZ study¹⁵ 1110 patients with clear-cell, metastatic RCC, were randomized 1:1 to receive pazopanib (at a dose of 800 mg once daily, continuous dosing) or sunitinib (standard dose and schedule), its primary endpoint being PFS; the study was powered to show the non-inferiority of pazopanib versus sunitinib.

Pazopanib proved to be non-inferior to sunitinib with respect to PFS [HR: 1.05; 95% confidence interval (CI): 0.90–1.22], meeting the predefined non-inferiority margin (upper bound of the 95% CI: <1.25); also, OS was similar (HR: 0.91; 95% CI: 0.76–1.08). Furthermore, 11 of 14 health-related quality-of-life (QoL) domains favored pazopanib, when it came to QoL.¹⁵

On the other hand, the PISCES study¹⁶ had as its primary endpoint patients’ preference. In this innovative study, patients with metastatic RCC were randomized to pazopanib for 10 weeks, a 2-week washout, and then sunitinib for another 10 weeks, or the reverse sequence; doses and schedules were the usual ones for both agents. The primary endpoint, patient preference for a specific treatment, was assessed by a questionnaire at the end of the two treatment periods. Other endpoints and analyses included reasons for preference, Health Related Quality of Life (HRQoL) and physician’s preference.

Significantly more patients preferred pazopanib (70%) over sunitinib (22%), whilst 8% expressed no preference (p < 0.001); less fatigue and better overall QoL were the main reasons for preferring pazopanib, with less diarrhea as the main reason for their choice in those patients who preferred sunitinib.¹⁶ Again, adverse events were consistent with each drug’s known profile, but pazopanib proved to be superior to sunitinib in terms of QoL, thus corroborating the QoL results of the COMPARZ study.

Even though methodologically not faultless, these two important studies have put the two drugs on the same level (at least in terms of evidence-based medicine) as standard first-line treatments for metastatic RCC.

Sequential use of sunitinib and sorafenib

Sunitinib and the other multikinase inhibitor sorafenib were the very first targeted agents that reached patients’ bedsides in the field of metastatic RCC.

In retrospective studies, sequential use of sunitinib and sorafenib provided additional clinical benefit beyond the use of either agent alone.^17,18 SWITCH was the first prospective, randomized, phase III study aimed at testing the hypothesis that sequential therapy with sorafenib–sunitinib is superior to sunitinib–sorafenib in prolonging total PFS (defined as time from randomization to confirmed progression or death during second-line therapy).

No significant difference in either total PFS (median 12.5 versus 14.9 months; HR: 1.01; 90% CI: 0.81–1.27; p = 0.5 for superiority) and OS (median 31.5 and 30.2 months; HR: 1.00, 90% CI: 0.77–1.30; p = 0.5 for superiority) between sorafenib–sunitinib and sunitinib–sorafenib emerged.¹⁹ Ultimately, the results of this trial suggested a degree of noncross-resistance between sunitinib and sorafenib.

Sunitinib versus everolimus

More recently, a multicenter, randomized phase II trial (RECORD-3) was conducted to compare the standard sequence of first-line sunitinib followed by everolimus with the inverse sequence, the primary endpoint of the study being PFS non-inferiority of first-line everolimus compared with first-line sunitinib.²⁰ The primary endpoint of this study was not met, median PFS being 7.9 months for first-line everolimus versus 10.7 months for first-line sunitinib (HR: 1.4, 95% CI: 1.2–1.8). Among patients who discontinued first line, just 108 (45%) crossed over from everolimus to second-line sunitinib, and 99 (43%) crossed over from sunitinib to second-line everolimus, making the evaluation of the two-agents’ sequence almost impossible. However, the median combined PFS was 25.8 months for sequential sunitinib followed by everolimus versus 21.1 months for sequential everolimus followed by sunitinib (HR: 1.3, 95% CI: 0.9–1.7). As far as OS, it was 32.0 months for sequential sunitinib followed by everolimus versus 22.4 months for sequential everolimus followed by sunitinib (HR: 1.2, 95% CI: 0.9–1.6).²⁰

Trying to optimize treatment: dose, schedule and treatment duration

From the very beginning it was clear that at least in some patients, the antitumor activity of sunitinib can be hampered by its safety profile, which is often difficult to manage, especially for inexperienced physicians; indeed, real-world clinical data^21–23 confirmed the relationship between sunitinib exposure and clinical efficacy already evident in a huge population pharmacokinetic study,⁴ showing that unnecessary dose reduction and treatment interruptions do correlate with a poor treatment outcome.^21,22,23

Several researchers addressed the topic of sunitinib dose and schedule, as summarized in Table 2.

Table 2.

Treatment optimization trials.

Study name	Design	Number	Efficacy results
EFFECT, Motzer²⁴	Phase II, treatment-naïve advanced RCC (schedule 4/2 versus CDD)	292	ORR: 32.2% versus 28.1% (p = 0.444) Median TTP, 9.9 versus 7.1 months (HR: 0.77; p = 0.090)^a Median OS, 23.1 versus 23.5 months (HR: 1.09; p = 0.615)
Atkinson²⁵	Retrospective, mRCC [switch from schedule 4/2 due to toxicity to 2/1 (82% patients)]	88 pts in the 2/1 arm	Median PFS, 14.5 versus 4.3 months (p < 0.0001) Median OS, 33 versus 17.7 months (p < 0.0001)
RAINBOW, Bracarda²⁶	Retrospective, mRCC [switch from schedule 4/2 due to toxicity to 2/1 (83% patients)]	249 pts in 2/1 arm	Median PFS, 30.2 versus 9.7 months Median OS, not reached versus 27.8 months
Bjarnason²⁷	Retrospective, mRCC [switch from schedule 4/2 due to toxicity to 2/1 or 1/1 (78% patients)]	134 pts in 2/1 or 1/1 arm	Median PFS, 10.9 versus 5.3 months (p < 0.0001) Median OS, 23.4 versus 15.4 months (p = 0.03)
RESTORE, Lee²⁸	Prospective, phase II randomized	38 pts in 2/1 arm	Median TTP, 12.1 versus 10.1 months (NS) Median OS, 30.5 versus 28.4 months (NS)

Primary endpoint; HR, hazard ratio; NS, not significant; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; schedule 1/1, 50 mg/day on a 1-weeks-on/1-weeks-off schedule; schedule 2/1, 50 mg/day on a 2-weeks-on/1-weeks-off schedule; schedule 4/2, 50 mg/day on a 4-weeks-on/2-weeks-off schedule; TTP, time to tumor progression; RCC, renal cell carcinoma; mRCC, metastatic renal cell carcinoma.

A first attempt to optimize sunitinib dose and schedule and make it more tolerable without losing efficacy came with the renal EFFECT trial.²⁴

In this randomized phase II trial, the traditional sunitinib schedule (schedule 4/2, 50 mg/day on a 4-weeks-on/2-weeks-off schedule) was compared with a reduced (37.5 mg/day), but continuous daily dosing (CDD) schedule. The median TTP (primary endpoint) was numerically longer with schedule 4/2 than with CDD. In addition, schedule 4/2 was superior to the CDD schedule according to a composite endpoint of time to deterioration, which included death, disease progression, and progression of disease-related symptoms.

From a certain viewpoint, surprisingly, the CDD schedule not only proved to be less active, but also was not better tolerated, as initially expected.

Some retrospective studies^25–29 suggested that patients who experience intolerable toxicities on a 4/2 schedule could switch to a 2/1 schedule (50 mg/day on a 2-weeks-on/1-week-off schedule) to improve tolerability without compromising efficacy. The prospective randomized phase II RESTORE trial evaluated the efficacy and safety of the sunitinib 2/1 schedule versus the standard 4/2 schedule in 74 Asian patients with clear-cell metastatic RCC (mRCC). The 2/1 schedule resulted in a higher 6-month failure-free survival (the primary endpoint, 63% versus 44%) and median time to treatment failure (7.6 versus 6.0 months, HR: 0.57, p = 0.029). The 2/1 schedule was associated with lower toxicity in terms of neutropenia (all grades 61% versus 37%, p = 0.037) and fatigue (all grades 83% versus 58%, p = 0.017) and time-to-first-dose reduction (HR: 0.35, p = 0.014).²⁸ Additional prospective studies with larger sample size will eventually confirm the efficacy of the 2/1 schedule.

Furthermore, we do not yet know if a successful sunitinib treatment leading to a complete response or a long-lasting disease stabilization may be discontinued. Several small studies suggest that intermittent dosing of sunitinib (‘drug holidays’) may be better tolerated than standard fixed schedule without compromising efficacy.^30–32 A randomized multicenter phase III study is ongoing (STAR trial) that compares the conventional schedule of sunitinib 50 mg daily 4/2 weeks with a drug-free interval strategy, namely a treatment break after completion of at least four cycles and maximal radiological response until progressive disease (PD) and then a restart of sunitinib for a minimum of four cycles and maximal radiological response.³³

Sunitinib in nonclear-cell renal cell carcinoma

The evidence for sunitinib treatment in nonclear-cell RCC is available from several retrospective and prospective phase II trials, as well as from a subgroup analyses of the large EAP.^13,34

Only two randomized prospective phase II trials compared everolimus and sunitinib as first-line treatment in nonclear-cell RCC (Table 3). The results of the first trial (ESPN trial) showed no benefit for everolimus in terms of median PFS (sunitinib 6.1 months, everolimus 4.1 months) and median OS (sunitinib 16.2 months, everolimus 14.9 months), both agents showing only modest efficacy.³⁵ The second trial (ASPEN) showed a significant increase in the median PFS with sunitinib (8.3 months) versus everolimus (8.3 versus 5.6 months; HR: 1.41; p = 0.16), while the median OS was not different between the two groups.³⁶

Table 3.

Randomized controlled trials of sunitinib in nonclear-cell histologies.

Study name	Design	Number	Efficacy results
ESPN, Tannir³⁵	Prospective, phase II randomized (arm A: sunitinib; arm B: everolimus)	68 patients in total: 33 sunitinib arm; 35 everolimus arm	Median PFS^a (months), 6.1 sunitinib versus 4.1 everolimus (p = 0.6) Median OS (months), 16.2 sunitinib versus 14.9 everolimus (p = 0.18)
ASPEN, Armstrong³⁶	Prospective, phase II randomized open label (arm A: sunitinib; arm B: everolimus)	108 patients in total: 51 sunitinib arm; 57 everolimus arm	Median PFS^a (months), 8.3 sunitinib versus 5.6 everolimus (HR: 1.41; 80% CI: 1.03–1.92; p = 0.16) Median OS (months), 31.5 sunitinib versus 13.2 everolimus (HR: 1.12; 95% CI: 0.7–2.1; p = 0.60)

Primary endpoint. HR, hazard ratio; OS, overall survival; PFS, progression-free survival, HR, hazard ratio; CI, confidence interval.

The results of a recent systematic review and meta-analysis showed a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and OS compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached.³⁷ The relative benefits and harms of these treatments remain uncertain. A randomized controlled trial with sufficient power to detect potential differences between treatments, is needed, although one should acknowledge that for rare cancers, specific trial designs are badly needed.³⁸

Given available data, sunitinib is still recommended as an option for first-line treatment in nonclear-cell RCC in current guidelines, especially for patients with good MSKCC risk scores.^39,40

Neoadjuvant sunitinib therapy

Presurgical targeted molecular therapy may be considered for a subset of patients with bulky/central renal tumors for whom partial nephrectomy would not be readily feasible and in patients with metastatic RCC having a low relative volume of disease in the primary tumor. The integration of surgery and targeted therapy is relatively safe, with low overall morbidity in most patients.⁴¹

The favorable outcomes reported in several retrospective reviews and case studies have provided sufficient rationale for ongoing prospective phase II clinical trials evaluating the efficacy of sunitinib in the neoadjuvant setting. Preliminary results from one such study (56 patients with metastatic RCC) show a 5% response in the primary tumor according to RECIST standards, with no local progression. Nearly, 20% of patients, however, showed progression of systemic disease prior to surgery. Overall, 71% of patients underwent nephrectomy with 20% experiencing surgical complications including one death.⁴² However, randomized, controlled, long-term studies are desperately needed to provide substantial evidence of the neoadjuvant effectiveness of sunitinib.

Sunitinib in the adjuvant setting: two-faced Janus

The adjuvant treatment of RCC has traditionally been a significant unmet need: several adjuvant strategies, including cytokine therapy, radiotherapy, and hormone therapy, have been explored to decrease the rate of relapse in RCC, but none were successful.⁴³

As always happens in oncology, sunitinib activity in the metastatic setting prompted many researchers to move it in the adjuvant setting, in the attempt of reducing the risk of relapse in radically resected patients at high risk of disease recurrence.

To date, the results of two large trials have been published, which yielded conflicting results; indeed, while the ECOG ASSURE trial⁴⁴ failed, the S-TRAC trial⁴⁵ succeeded, (although OS data of this study are not mature enough).

ASSURE was a double-blind, placebo-controlled, randomized, phase III trial in which 1943 patients from the United States and Canada were randomized (1:1:1) to receive 54 weeks of sunitinib 50 mg per day, 4 weeks on and 2 weeks off, sorafenib 400 mg twice per day CDD or placebo.

Unfortunately, no significant differences in disease-free survival (DFS), the primary endpoint of the study, were observed between the three treatment arms: median DFS was 5.8 years for sunitinib (HR: 1.02; 97.5% CI: 0.85–1.23; p = 0.8038), 6.1 years for sorafenib (HR: 0.97; 97.5% CI: 0.80–1.17; p = 0.7184), and 6.6 years for placebo. The most common adverse events leading to dose reduction were hand–foot syndrome (grade ⩾ 3: sunitinib arm 15%, sorafenib arm 33%, placebo arm 1%), hypertension (grade ⩾ 3: sunitinib arm 17%, sorafenib arm 16%, placebo arm 4%) and fatigue (grade ⩾ 3: sunitinib arm 18%, sorafenib arm 7%, placebo arm 3%). Despite the reduction in starting dose, the proportion of grade ⩾ 3 adverse events still exceeded 55% in both the sunitinib and sorafenib groups.⁴⁴

Given these negative results (which indeed were coupled with a not-so-strong biologic rationale), somewhat surprisingly, the S-TRAC, which compared 1 year of sunitinib versus 1 year of placebo, yielded positive results; indeed, the median duration of DFS (the primary endpoint of the study) was 6.8 years (95% CI: 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI: 3.8–6.6) in the placebo group (HR: 0.76; 95% CI: 0.59–0.98; p = 0.03).⁴⁵

The selection of patients with different degrees of risk of relapse due to the use of different and equivocal (Table 4) risk-stratification criteria, has been advocated to justify the different results of these two trials.⁴⁶

Table 4.

Key inclusion criteria of adjuvant trials of sunitinib.

Study name, ClinicalTrials.gov identifier	Design	Clear-cell histology mandatory?	Key staging inclusion criteria
ASSURE, NCT00326898	Sunitinib versus sorafenib versus placebo	No	Using 2002 AJCC TNM staging, patients must be one of the following: (1) pT1b, G3−4, N0 (or pNX where clinically N0), M0 (2) pT2, G any, N0 (or pNX where clinically N0), M0 (3) pT3, G any, N0 (or pNX where clinically N0), M0 (4) pT4, G any, N0 (or pNX where clinically N0), M0 or (5) T any, G any, N+ (fully resected), M0 Patients with microvascular invasion of the renal vein of any grade or stage (as long as M0) are also eligible Clinical evidence of lymph node positivity requires removal of all clinically positive nodes; surgeons should designate extent of node dissection; all surgical specimens must have negative margins; patients with positive renal vein margins are eligible unless there is invasion of the renal vein wall at the margin (provided no other margins are positive) Only excluded histologies were collecting duct and medullary carcinomas
S-TRAC, NCT00375674	Sunitinib versus placebo	Yes	High-risk renal cancer per modified UISS criteria: (1) pT2, N0, M0 (grades 3–4) or (2) pT3−4, N0, M0 or (3) pTx, N1, M0 Subjects must have histologically confirmed preponderant clear-cell RCC Subjects must have no evidence of macroscopic residual disease or metastatic disease; subjects having evidence for microscopic disease (R1) are acceptable

AJCC, American Joint Committee on Cancer; TNM classification for Renal Cell Carcinoma: T (primary tumors), N (regional lymph node), M (distant metastasis); N0: no regional lymph node metastasis, NX: regional lymph nodes cannot be assessed, N+ or N1: metastasis in regional lymph node(s); G: nuclear grading; UISS, UCLA Integrated Staging System.

None of the recently completed or ongoing adjuvant trials with targeted agents has been already prospectively implemented with genetic analyses such as the genetic recurrence score.⁴⁷ Thus, one could speculate if this score could help us to understand why sunitinib, as an adjuvant treatment failed in the ECOG ASSURE trial, while succeeding in the S-TRAC one.

Given this discrepancy between the two studies, the possibility that in S-TRAC, sunitinib has just delayed relapse (in the absence of OS data) and the issue of toxicity (with potentially cured patients less prone, as compared with metastatic ones, to tolerate treatment-related adverse events), it appears clear that the amount of uncertainty regarding the present place, if any, of sunitinib as an adjuvant to radical surgery remains quite high, and our judgement should be postoponed at least till the availability of S-TRAC OS data.⁴⁶

Sunitinib-based combinations

Several studies have investigated sunitinib in combinations with other targeted agents.⁴⁸ The combinations sunitinib plus INF-α, sunitinib plus bevacizumab, sunitinib plus everolimus, sunitinib plus temsirolimus, were tested in phase I studies in patients with advanced RCC. These trials were terminated early due to dose-limiting toxicity.

In a single-arm phase II study (39 patients), the combination of sunitinib with the cytotoxic chemotherapy gemcitabine appeared to be more efficacious than either therapy alone in patients with sarcomatoid or poor-risk mRCC (ORR: 26% and 24% for patients with sarcomatoid RCC and poor- risk RCC, respectively).⁴⁹

RCC is a potentially immunogenic tumor: the immunologic dysfunctions described in this tumor are numerous, being evident even in the presence of localized and not-yet metastatic disease.⁵⁰ Given this feature, attempts to combine sunitinib with different forms of immunotherapy (from cytokines to novel checkpoint inhibitors and vaccines) have been tested over the years, with somewhat conflicting results.⁵¹

Two different types of vaccines have been tested in both cases in combination with sunitinib. In a recently published phase II trial, AGS-003, an autologous dendritic cell-based immunotherapy was tested in combination with sunitinib in patients with intermediate and poor-risk mRCC.⁵² Given the promising results of this trial (ORR was 43%, the median PFS was 11.2 months), an international phase III randomized trial ADAPT [ClinicalTrials.gov identifier: NCT01582672] of AGS-003 plus standard treatment in advanced RCC is ongoing.

The cancer vaccine IMA901, comprises 10 synthetic tumor-associated peptides expressed by the majority of RCCs with demonstrated antigenicity. IMA901 with sunitinib had already proved able to lower both myeloid suppressor cells, as well as Treg lymphocytes.⁵³ However, a consequent phase III study of IMA901 plus sunitinib versus sunitinib alone showed a detrimental effect of the vaccine-plus-sunitinib combination on the survival of treated patients, particularly evident for patients with an intermediate prognosis.⁵⁴ Indeed, although median OS did not differ significantly between the groups [33.17 months (95% CI: 27.81–41.36) in the sunitinib plus IMA901 group versus not reached (33.67 to not reached) in the sunitinib monotherapy group], the resulting HR was 1.34 (0.96–1.86; p = 0.087).

More recently, preliminary results from a phase I trial, Checkmate 016 [CA209-016, ClinicalTrials. gov identifier: NCT01472081], using sunitinib or pazopanib and nivolumab [anti-programmed-death 1 (anti-PD-1) antibody, starting dose: 2 mg/kg intravenously every 3 weeks, with the expectation of increasing to 5 mg/kg] in pretreated mRCC have been published and show evidence of activity for the combination (ORR 52% for nivolumab plus sunitinib and 45% for nivolumab plus pazopanib) with a prominent safety profile.⁵⁵ The most common grade 3 or 4 adverse events were an elevation of alanine aminotransferase (ALT) (18%) and hypertension and hyponatremia (15% each); in 8 of 33 patients (24%), treatment-related adverse events led to permanent discontinuation of the treatment.

Sunitinib rechallenge

Treatment guidelines recommend sequential treatment of mRCC in order to offer patients the longest survival possible; after disease progression on one agent, treatment with another targeted agent generally controls the disease, giving additional PFS. Recent retrospective analysis of the International mRCC Database Consortium (IMDC) database found that patients who received multiple targeted-therapy lines lived substantially longer than those treated with only one.⁵⁶

Several retrospective studies and case reports have shown that reintroduction of sunitinib after progression with other treatments can result in additional clinical benefit,^22,23 indicating further research is warranted to improve our understanding of sunitinib rechallenge therapy.

The mixed retrospective and prospective REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study has evaluated the efficacy, as measured by PFS, and safety of sunitinib rechallenge in mRCC patients who received first-line sunitinib, then one or more lines of different targeted treatments, followed by further sunitinib.⁵⁷ A total of 28 patients (54% of 52 patients eveluated) had a complete (n = 1) or partial response (PR) with first-line sunitinib, and 8 patients (15%) achieved a PR upon sunitinib rechallenge. Median PFS with first-line sunitinib was 18.4 months (95% CI: 12.5–23.7) and 7.9 months (95% CI: 5.4–13.2) with sunitinib rechallenge.

Two ongoing prospective phase II studies (an Italian study, RETRY, EudraCT 2012-000473-23 and a Dutch study, NTR3711) will provide further information on this topic.

Sunitinib and radiotherapy

Preclinical studies show the feasibility of combining sunitinib with radiotherapy (RTx) for RCC treatment. This strategy involves different mechanisms, including vascular normalization, modulation of cell growth and apoptosis, as well as the alterations of the immune response.⁵⁸

Instigated by the promising results of preclinical research, several phase I and II clinical studies have been performed to assess the feasibility of combining sunitinib with radiotherapy in cancer patients. A phase II trial in olimetastatic RCC patients showed a local control rate of 75%, and distant control of 52% with the sunitinib–radiotherapy combination. The median time until progression was 9.5 months, and at the end of the study, 18 patients were alive, 11 of whom without disease.⁵⁹ By several case reports, encouraging results were also observed in patients with mRCC who received either sunitinib combined with single-fraction stereotactic radiosurgery⁶⁰ or high-dose hypofractionated RTx.⁶¹ Overall, the toxicities of the concurrent combination of RTx and sunitinib appear to depend on the duration and dose of sunitinib treatment, on the concurrent dose of RTx, but also on previous treatments and type of metastases.

To translate preclinical findings into clinically relevant treatment, protocols are needed to establish the clinical benefit of combination with additional studies.

Future perspectives

mRCC is a highly angiogenic-dependent neoplasm, as well as a potentially immunogenic one: combining molecularly targeted agents with different forms of immunotherapy thus makes a lot of sense.

Novel immune checkpoint inhibitors (i.e. anti-PD1 or anti-programmed-death ligand-1 agents) have just started to reach patients’ bedsides and their combination with molecularly targeted agents is presently under clinical evaluation, although the only trial presented in detail (ASCO 2014), but not yet published in extenso, is the phase I CA209-016 study, discussed above.

Several phase III trials are presently comparing immunotherapy combinations against sunitinib, as the standard first-line treatment for metastatic RCC (Table 5).

Table 5.

Combination of vascular endothelial growth factor receptor inhibitors with immune checkpoint inhibitors: main ongoing studies.

Study	ClinicalTrials.gov identifier	Description
W029637	NCT02420821	A phase III, open-label, randomized study of atezolizumab (anti-PD-L1 antibody) in combination with bevacizumab versus sunitinib in patients with untreated advanced renal cell carcinoma
JAVELIN renal 101	NCT02684006	A phase III, multinational, randomized, open-label, parallel-arm study of avelumab (MSB0010718C) in combination with axitinib (Inlyta) versus sunitinib (Sutent) monotherapy in the first-line treatment of patients with advanced renal cell carcinoma
2000249	NCT02014636	An open-label, two-part study of pazopanib with or without MK 3475 (pembrolizumab) in treatment-naïve subjects with advanced renal cell carcinoma Part 1 consists of a phase I dose escalation of pazopanib + MK 3475 followed by an expansion cohort to determine the maximum tolerated regimen and the recommended phase II dose; part 2 is a randomized three-arm phase II study to evaluate the clinical efficacy and safety of pazopanib + MK 3475 as compared with single-agent pazopanib and single-agent MK 3475

PD-L1, programmed death ligand 1.

Combinations of sunitinib together with immune checkpoint inhibitors are definitely promising, but cumulative toxicity remains a potential issue. Toxicity aside, doubts also remain over the effect of different immunologic targeted agents and therefore the ability to rationally combine any of these agents with different immunotherapeutics.⁵¹

Concluding remarks

Sunitinib has revolutionized the treatment of mRCC over the past 10 years so far. Large-scale studies have demonstrated sound and reproducible benefits (across all activity and efficacy endpoints) assigning to sunitinib a leadership position in this setting.

Available data also support an evolving role of sunitinib in the adjuvant setting. However, all the knowledge acquired in the advanced stage setting may not be enough to select the ideal patient for adjuvant therapy. Indeed, more accurate and reproducible clinical and, hopefully, also molecular tools would be needed to identify patients with radically resected RCC who are at high risk for recurrence following potentially curative nephrectomy.

Combinations of sunitinib with novel immunotherapeutics (either vaccine or immune checkpoint inhibitors) hold promise, but cumulative toxicity seems to remain an issue.

Finally, biomarker-driven clinical trials are needed to stratify patients and to evaluate novel immunotherapy-based combination regimens in selected advanced RCC patients.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

Chow

Eckhardt

Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007; 25: 884–896.

Kaelin

The von Hippel-Lindau tumour suppressor protein and clear cell renal carcinoma. Clin Cancer Res 2007; 13: 680s–684s.

Jaini

Rayman

Cohen

. Combination of Sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy. Int J Cancer 2004; 134: 1695–1705.

Houk

Bello

Poland

. 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: 357–371.

Motzer

Michaelson

Redman

. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 16–24.

Motzer

Rini

Bukowski

. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 295: 2516–2524.

Motzer

Michaelson

Rosenberg

. Sunitinib efficacy against advanced renal cell carcinoma. J Urol 2007; 178: 1883–1887.

Motzer

Hutson

Tomczak

. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–124.

Cella

Yount

. Development and validation of the functional assessment of cancer therapy-kidney symptom index (FKSI). J Support Oncol 2006; 4: 191–199.

10.

Motzer

Hutson

Tomczak

. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584–3590.

11.

Motzer

Escudier

Bukowski

. Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer 2013; 108: 2470–2477.

12.

Gore

Szczylik

Porta

. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009; 10: 757–763.

13.

Gore

Szczylik

Porta

. Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma. Br J Cancer 2015; 113: 12–19.

14.

Sternberg

Calabrò

Bracarda

. Safety and efficacy of sunitinib in patients from Italy with metastatic renal cell carcinoma: final results from an expanded-access trial. Oncology 2015; 88: 273–280.

15.

Motzer

Hutson

Cella

. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 8369: 722–731.

16.

Escudier

Porta

Bono

. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol 2014; 32: 1412–1418.

17.

Porta

Procopio

Cartenì

. Sequential use of sorafenib and sunitinib in advanced renal-cell carcinoma: an Italian multicentre retrospective analysis of 189 patient cases. BJU Int 2011; 108: E250– E257.

18.

Stenner

Chastonay

Liewen

. A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma. Oncology 2012; 82: 333–340.

19.

Eichelberg

Vervenne

De Santis

. SWITCH: a randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-sunitinib versus sunitinib-sorafenib in the treatment of metastatic renal cell cancer. Eur Urol 2015; 68: 837–847.

20.

Motzer

Barrios

Kim

. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2014; 32: 2765–2772.

21.

Heng

Xie

Regan

. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicentre study. J Clin Oncol 2009; 27: 5794–5799.

22.

Porta

Paglino

Grunwald

Sunitinib re-challenge in advanced renal-cell carcinoma. Br J Cancer 2014; 111: 1047–1053.

23.

Porta

Levy

Hawkins

. Impact of adverse events, treatment modifications, and dose intensity on survival among patients with advanced renal cell carcinoma treated with first-line sunitinib: a medical chart review across ten centers in five European countries. Cancer Med 2014; 3: 1517–1526.

24.

Motzer

Hutson

Olsen

. 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: 1371–1377.

25.

Atkinson

Kalra

Wang

. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol 2014; 191: 611–618.

26.

Bracarda

Iacovelli

Boni

. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol 2015; 26: 2107–2113.

27.

Bjarnason

Khalil

Hudson

. 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: 480–487.

28.

Lee

Kim

Park

. 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: 2300–2305.

29.

Bracarda

Negrier

Casper

. How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma. Expert Rev Anticancer Ther. Epub ahead of print 3 January 2017. DOI: 10.1080/14737140.2017.1276830.

30.

Johannsen

Staehler

Ohlmann

. Outcome of treatment discontinuation in patients with metastatic renal cell carcinoma and no evidence of disease following targeted therapy with or without metastasectomy. Ann Oncol 2011; 22: 657–663.

31.

Albiges

Oudard

Negrier

. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol 2012; 30: 482–487.

32.

Rini

Wood

Elson

. A phase II study of intermittent sunitinib (S) in previously untreated patients (Pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2013; 31(Suppl.): abstract 4515.

33.

Collinson

Gregory

McCabe

. The STAR trial protocol: a randomized 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.

34.

Ravaud

Oudard

De Fromont

. First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG). Ann Oncol 2015; 26: 1123–1128.

35.

Tannir

Jonasch

Albiges

. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicentre phase 2 trial. Eur Urol 2015; 69: 866–874.

36.

Armstrong

Halabi

Eisen

. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomized phase 2 trial. Lancet Oncol 2016; 17: 378–388.

37.

Fernandez-Pello

Hofmann

Tahbaz

. A systematic review and meta-analysis comparing the effectiveness and adverse effects of different systemic treatments for non-clear cell renal cell carcinoma. Eur Urol. Epub ahead of print 7 December 2016. DOI: 10.1016/j.eururo.2016.11.020.

38.

Porta

How to identify active novel agents in rare cancers and then make them available: a need for a paradigm shift. Eur Urol 2012; 62: 1020–1021.

39.

NCCN Panel Members. NCCN Guidelines Kidney Cancer. Version 1.2017, www.nccn.org/patients.

40.

Escudier

Porta

Schmidinger

. ESMO Clinical Practice Guidelines. Renal cell carcinoma: guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27(Suppl. 5): v58–v68.

41.

Lane

Derweesh

Kim

. Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma. Urol Oncol 2015; 33: 112, e15–e21.

42.

Powles

Kayani

Blank

. The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer. Ann Oncol 2011; 22: 1041–1047.

43.

Massari

Bria

Maines

. Adjuvant treatment for resected renal cell carcinoma: are all strategies equally negative? Potential implications for trial design with targeted agents. Clin Genitourin Cancer 2013; 11: 471–476.

44.

Haas

Manola

Uzzo

. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016; 387: 2008–2016.

45.

Ravaud

Motzer

Pandha

. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016; 375: 2246–2254.

46.

Porta

Chiellino

. ASSURE vs. S-TRAC: conflicting results of adjuvant treatments for kidney cancer in the era of targeted agents and genomics. Ann Transl Med 2016; 4(Suppl. 1): S14.

47.

Rini

Goddard

Knezevic

. A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol 2015; 16: 676–685.

48.

Michaelson

MD.

Combination of targeted agents in metastatic renal cell carcinoma: a path forward or a dead-end street. Cancer 2012; 118: 1744–1746.

49.

Michaelson

McKay

Werner

. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 2015; 121: 3435–3443.

50.

Porta

Bonomi

Lillaz

. Renal cell carcinoma-induced immunosuppression: an immunophenotypic study of lymphocyte subpopulations and circulating dendritic cells. Anticancer Res 2007; 27: 165–173.

51.

Porta

Toscani

Czarnecka

. Immuno-oncology for renal cell carcinoma treatment: future perspectives for combinations and sequences with molecularly targeted agents. Expert Opin Biol Ther 2016; 29: 1–12.

52.

Amin

Dudek

Logan

. Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J Immunother Cancer 2015; 3: 14.

53.

Finke

Rini

Ireland

. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 2008; 14: 6674–6682.

54.

Rini

Stenzl

Zdrojowy

. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 2016; 17: 1599–1611.

55.

Amin

Elizabeth

Plimack

. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2014; 32(Suppl.): abstract 5010.

56.

Choueiri

Rini

. First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC. Br J Cancer 2014; 110: 1917–1922.

57.

Oudard

Geoffrois

Guillot

. Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma. Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study. Eur J Cancer 2016; 62: 28–35.

58.

Faivre

Demetri

Sargent

. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007; 6: 734–745.

59.

Tong

Sung

. Phase II trial of concurrent sunitinib and image-guided radiotherapy for oligometastases. PLoS One 2012; 7: e36979.

60.

Staehler

Haseke

Nuhn

. Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma. BJU Int 2011; 108: 673–678.

61.

Staehler

Haseke

Stadler

. Feasibility and effects of high-dose hypofractionated radiation therapy and simultaneous multi-kinase inhibition with sunitinib in progressive metastatic renal cell cancer. Urol Oncol 2012; 30: 290–293.

Sunitinib in the treatment of renal cell carcinoma: an update on recent evidence

Abstract

Keywords

Introduction

Sunitinib clinical development program in renal cell carcinoma

Sharing a leading position with pazopanib

Sequential use of sunitinib and sorafenib

Sunitinib versus everolimus

Trying to optimize treatment: dose, schedule and treatment duration

Sunitinib in nonclear-cell renal cell carcinoma

Neoadjuvant sunitinib therapy

Sunitinib in the adjuvant setting: two-faced Janus

Sunitinib-based combinations

Sunitinib rechallenge

Sunitinib and radiotherapy

Future perspectives

Concluding remarks

Footnotes

Funding

Conflict of interest statement

References