Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma

Sunitinib malate, an oral multi-targeted tyrosine kinase inhibitor (TKI) is considered to be one of the standard first-line therapeutic options in metastatic renal cell cancer (mRCC) [1]. It is a small molecule indolinone [2] which binds directly to the kinase domain of receptor tyrosine kinases (RTKs) within an adenosine triphosphate (ATP) binding pocket between two lobes of the KIT kinase domain, preventing phosphorylation and activation [3‐5]. It selectively targets RTKs, which are important in RCC. Sunitinib has direct anti-tumor effects via binding the unactivated conformation of KIT and via platelet-derived growth factor receptor alpha polypeptide (PDGFRA) inhibition. The dual inhibitor activity against vascular endothelial growth factor receptors 1 and 3 (VEGFR 1 and VEGFR3), and platelet-derived growth factor receptor beta polypeptide (PDGFRB) on endothelial and pericyte membranes enhances anti-angiogenesis [6].

Sunitinib has been approved by the regulatory authorities after it had been demonstrated to improve progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and quality of life compared with interferon-alpha in previously untreated metastatic RCC patients [1, 7‐9]. According to the international guidelines (e.g., NCCN, ESMO, EAU), sunitinib can be used as first-line treatment in patients with advanced or metastatic dominantly clear cell histological type RCC whose condition has good or intermediate prognosis [10‐12]. Sunitinib has become the gold standard first-line therapy of mRCC in the past decade, and it has been used worldwide in this patient population in wider indications as well [10‐16].

The therapeutic administration of sunitinib and the dedicated patient population for this drug would be changing and would be refined in the near future. The preliminary results of the presented Checkmate-214 phase 3 trial with respect to mRCC, in which sunitinib was the comparator of the investigated drugs [17], the survival rates were more favorable in case of the immune checkpoint inhibitor nivolumab and ipilimumab combination compared to sunitinib administered alone, in poor and intermediate risk groups.

The standard treatment schedule of sunitinib is 50 mg for 28 days with a 14-day break [13‐15]. Alternate scheduling (2 weeks on/1 week off) can also be used to manage toxicity, but currently no robust data are available supporting it [16]. The dose can be adjusted according to the patient’s response to the treatment, but it should be kept within the range of 25 to 75 mg [18]. At higher sunitinib doses, the direct anti-cancer effect of the drug may be predominant.

Despite the efficacy of sunitinib therapy, the condition of initially responding patients may progress due to the acquired resistance. The underlying mechanisms for that may be the continuous VEGF axis activation via upstream or downstream effectors [19‐22], b-fibroblast growth factor (bFGF), c-met, interleukin-8 (IL-8), and angiogenic cytokine pathways [23], altered pharmacokinetics, drug sequestration [24], and epithelial to mesenchymal transition [25]. Drug resistance is associated with a transient increase in tumor vasculature and epigenetic changes in histone proteins in the chromatin, which contribute to tumor angiogenesis by inactivating the anti-angiogenic factors [26]. However, the drug-induced resistance can be overcome by sunitinib dose escalation [26]. If patients tolerate the standard regimen, the increased sunitinib exposure is associated with longer PFS, OS, and a higher response rate [27, 28].

The aim of our study was to analyze the maximal efficiency and the side-effects of escalated dose sunitinib for metastatic RCC in the everyday practice.

Sunitinib is one of the most frequently applied first line therapies in patients with metastatic ccRCC with MSKCC good and moderate prognoses.

The role of cytoreductive nephrectomy seems to be equivocal in the era of tyrosine-kinase inhibition. The results of the SURTIME study were presented by Bex et al. last year, in which the overall survival and post surgical complication rates were better with deferred versus immediate cytoreductive nephrectomy, while progression rates at 16 and 28 weeks were not significantly different between both sequences [32]. The ongoing CARMENA study (NCT00930033) may give an answer to this issue in the near future.

According to the recent knowledge, nephrectomy is recommended to be performed in patients in good general condition before the systemic therapy; however, randomized studies analyzing survival data have been performed only in combination with INFα therapy [33‐35]. In our study, nephrectomy was performed in 84.8% of the cases, and PFS and OS results of these patients were more favorable. Each patient with SP in the Study group (period 2) underwent nephrectomy (which means that the patients were fit enough for this operation). It might have been a potential selectional bias of the compared cohorts. However, the other parameters and the comorbidities of the patients in the two cohorts were not significantly different.

In our study, PFS was longer than in the registration study [8]; however, patients with MSKCC poor prognosis were excluded from our study, but the PFS of our patients was similar to the excellent international data [36, 37]. Nowadays, the median OS of patients with metastatic RCC is longer than 2 years [1], as it can be seen in our results as well.

One of the most important things in case of a successfully optimized medical therapy is appropriate dosing: the individually titrated, tolerable dose, with the administration of the maximum daily dose. It is important to choose the most suitable dosing scheme after taking comorbidities into consideration [38]. The recommended starting dose for sunitinib malate is 50 mg daily for 28 days followed by a 14-day break. Although individualized sunitinib therapy improves the outcome, poorer outcomes in patients tolerating the standard schedule treatment without significant toxicity [1, 14] may be the result of underdosing [27]. Several authors [39, 40] have reported that both PFS and OS are significantly higher in patients with at least grade 2 hypertension. As on-target side effects determine the drug effect, toxicity profile can be used to optimize dosing and treatment schedules individually [41]. According to the meta-analysis of Houk et al. [28], escalated sunitinib exposure (area under the curve) is associated with improved clinical outcomes as well as with an increased risk of adverse effects. The appropriate management of adverse events is necessary for effective sunitinib treatment, which requires the active contribution of the satisfactorily informed patient. Based on the above mentioned data, dose escalation has been applied after the summer of 2013 in cases with slight progression, when RECIST 1.1 results confirmed a stable disease if any clinically relevant side effects occurred. Our idea was to achieve the optimal titration of sunitinib until the appearance of on target side effects depending on the tolerable off target adverse events. The rate of CR according to RECIST in our studied population was relatively high (7.1%) compared to pivotal phase III trials of sunitinib [8], which might reflect an outstanding benefit from sunitinib mainly in patients with low tumor volume in our studied cohort. After an initial favor tumor response evolving slight progression can be stopped or be reversible with dose escalation and adequate titration has been hypothesized. Drug toxicity and efficacy may depend on the interindividual differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics [42, 43]; however, Motzer et al. [14] have not found correlation between sunitinib pharmacokinetic values and the toxicity profile. Adelaiye et al. [26] have detected an increase in sunitinib plasma concentration in animals treated with escalated dose TKI in the drug resistant group, and also a trend for decreased plasma concentration after prolonged sunitinib exposure. Gotink et al. [24] have found 1.7 to 2.5-fold increase in sunitinib concentration in resistant tumor cells due to the increased lysosomal drug sequestration, which was reversible after the removal of sunitinib from the cell culture. Blood levels of sunitinib reach a steady state at 10 to 14 days, and a maximum value on day 14 [27], and disease progression usually occurs during treatment interruption [44, 45]. In the retrospective analysis of Bjarnason et al. [27], an individualized treatment strategy and shorter treatment break (14 days on and 7 days off) have resulted in improved PFS and OS as compared to the standard sunitinib schedule, and the PFS detected in patients with ccRCC has been one of the best reported for any TKI. Modified sunitinib schedule is well tolerated and induces optimal drug exposure [46].

Based on our results, PFS and OS results can be improved by sunitinib dose escalation as by dose scheme modification in case of patients poorly tolerating the therapy. As the two patient populations are not the same, their effects can be considered independent. Dose escalation can be performed in case of patients with good general condition, who do not have any relevant adverse effects. In case of these patients, based on the prognostic values, the survival rate is potentially better. Therefore, we compared the two (almost similar) groups regarding dose escalation, so selection of patients with better prognosis could not have queried the results. The effect of dose escalation on PFS and OS was confirmed during the comparison of the two groups. No significant difference was found among the number of the subsequent therapies and mOS after sunitinib was equal in two groups as well, which may be because in our country the availability of more active new regimens was very limited during our study period.

The rate of adverse events (AE) in our real world dose escalated patients is lower in the selected cohort than the AE rate in patients administered the standard dose in the pivotal trials [8, 9]. It might be partly explained by the favorable VEGFR inhibitor tolerability and the better proactive management of toxicity, which may improve the tolerability of the drug.

Acquired resistance to sunitinib therapy, driven by several likely mechanisms, is a central issue in the treatment of metastatic RCC patients. However, drug resistance may be reversible, and gradual dose escalation may restore tumor sensitivity to sunitinib, as reported in preclinical and clinical studies as well. Adelaiye et al. [26] have treated mice with patient-derived xenografts 5 days/week with a 40–60-80 mg/kg sunitinib dose increase schedule, and they have found selected intrapatient dose escalation safe, resulting in prolonged PFS due to a greater and longer effect on tumor regression. Although xenografts initially responsive to 40 mg/kg sunitinib developed drug resistance, it could be overcome by incremental dose escalation. In metastatic RCC patients on standard schedule sunitinib with early disease progression, Adelaiye et al. [26] could increase sunitinib dose from 50 to 62.5 and 75 mg daily, with a 14-day on and 7-day off treatment scheme to some type of grade 2 toxicity, and they observed clinical benefit in the majority of the patients. As reported by Mitchell et al. [47], the daily dose of sunitinib can be safely up-titrated to 87.5 mg. According to Gotink et al. [24] and Zama et al. [48], sunitinib rechallenging in previously resistant patients also has a therapeutic value. Drug resistance is also associated with epigenetic changes in histone proteins in the chromatin, which may be reversible upon DE; thus, epigenetic therapies could be successful in ccRCC patients [26].

The limitations of our study are, on the one hand, its retrospective design, that is, an explorative retrospective analysis of a prospective RCC register, and on the other hand, the relatively small number of patients involved.

In conclusion, an individual escalated sunitinib therapy optimized by toxicity profile in metastatic RCC patients prolongs PFS and OS, and it is a safe treatment option with a moderate increase in adverse effects. Based on our data, dose escalation in 12.5 mg steps may be recommended for properly educated patients with slight progression, when RECIST 1.1 results confirm a stable disease in case any clinically relevant adverse effects occurred.