Population Pharmacokinetic/Pharmacodynamic Modeling of Sunitinib by Dosing Schedule in Patients with Advanced Renal Cell Carcinoma or Gastrointestinal Stromal Tumor

Sunitinib is an orally administered, multi-targeted tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity [1]. The advent of sunitinib and other antiangiogenic therapies has revolutionized the therapeutic landscape for patients with advanced renal cell carcinoma (RCC) or imatinib-resistant/intolerant gastrointestinal stromal tumors (GIST), considerably improving outcomes compared with previous management paradigms [2‐4]. For any therapeutic agent, a key challenge is to achieve efficacy while minimizing treatment-related adverse events (AEs), so that both therapy compliance and on-treatment time are maximized [5]. It is recommended that sunitinib (50 mg once daily) be administered for 4 consecutive weeks followed by 2-weeks-off treatment (‘Schedule 4/2’) in RCC and GIST patients, as was employed in the pivotal phase III trials in these indications [2, 6]. However, due to drug toxicity, 28–38 and 11–32 % of sunitinib-treated patients in these trials experienced dose interruptions and reductions, respectively [2, 6], instigating efforts to optimize the dosing schedule to improve tolerance. In an open-label, phase II trial of cytokine-refractory metastatic RCC patients, continuous daily dosing (CDD) with 37.5 mg displayed a manageable safety profile [7]. However, no difference in AE incidence between this regimen and Schedule 4/2 was observed in a randomized, phase II trial that directly compared these regimens as first-line therapy in patients with advanced RCC. Furthermore, time to tumor progression (TTP) was numerically longer on Schedule 4/2 than CDD [8]. In patients with imatinib-resistant/intolerant GIST, an open-label, phase II trial showed CDD with 37.5 mg to be active, with an acceptable safety profile [9]. These results were broadly similar to those of the phase III trial of sunitinib in GIST [2, 9].

A previous pharmacokinetic/pharmacodynamic (PK/PD) meta-analysis of data from studies in patients with solid tumors, including RCC and GIST, predicted that increased sunitinib exposure was associated with improved efficacy but increased AE risk [10]. With the aim of preserving sunitinib efficacy while minimizing treatment-related toxicity, the utility of a 2-weeks-on/1-week-off schedule (‘Schedule 2/1’) in RCC has been investigated in clinical practice. Retrospective reports suggest that with Schedule 2/1 dosing, the efficacy of sunitinib was preserved and the toxicity profile was more manageable than Schedule 4/2 [11‐14]. Data comparing the efficacy and safety of Schedule 4/2 with Schedule 2/1 in GIST patients are currently lacking [15].

It has been previously shown that the efficacy and toxicity of sunitinib could be predicted by PK/PD modeling [10, 16]. Our objective was to develop PK and PK/PD models that took into account the effects of important covariates by pooling data from 10 prospective clinical studies in adult patients with RCC or GIST. The models were used to make predictions with respect to the PK, safety, and efficacy of sunitinib in these patients on Schedule 2/1 compared with Schedule 4/2.

In this analysis, PK/PD models predicting the effects of sunitinib on the efficacy endpoint SLD and on several safety endpoints were generated. The models predicted that, in patients with advanced RCC or GIST, sunitinib Schedule 2/1 dosing would have the same efficacy as Schedule 4/2, despite some differences in the PK profiles of the two schedules. The models also predicted that, in both indications, sunitinib-related thrombocytopenia would be less severe on Schedule 2/1 versus Schedule 4/2. The findings from our study are supported by several retrospective studies [11‐14] and by prospective studies [26, 27]. In addition, a prospective phase II trial of sunitinib Schedule 4/2 versus Schedule 2/1 as first-line therapy in metastatic RCC is ongoing (NCT02398552) and, once completed, could support the findings of the PK/PD modeling.

However, one of the limitations of these types of PK/PD models was that they required continuous safety measures/endpoints; therefore, categorical safety endpoints, such as hand–foot syndrome, fatigue, nausea, vomiting, or diarrhea, could not be included in the PK/PD modeling analyses. In addition, considering the similarities in the dose, total dose, the average and steady-state plasma exposures over any cycle (i.e. 6-week period) between the two dosing schedules, the empirical models such as time to event models or Markov-type models, would not be able to differentiate between the two dosing schedules and hence could not be utilized with respect to these categorical safety endpoints. That said, prospective clinical studies have shown that other categorical AEs, including fatigue, hand–foot syndrome, stomatitis, and dysgeusia, improved by changing from Schedule 4/2 to Schedule 2/1 [11, 27]. Another limitation of the model was that efficacy was evaluated in patients with advanced RCC using the target tumor SLD rather than PFS or overall survival. However, SLD has been shown to be a reliable predictor of outcome in RCC patients receiving vascular endothelial growth factor-targeted therapies [28, 29].

The models generated here were based on a clinical dataset with few patients treated on sunitinib Schedule 2/1 or 2/2. Therefore, for the covariate analyses, with respect to the effect of dosing schedule on different PK or PK/PD parameters, intermittent Schedules 2/2, 2/1, and 4/2 were grouped together and compared with CDD schedules. Grouping of the intermittent dosing schedules was also supported by the diagnostic plots, which indicated a lack of consistent noticeable differences in key PK or PK/PD parameters for Schedule 2/1 or 2/2 versus Schedule 4/2. The advantage of NONMEM analysis is that it enables the pooling of patients bearing different characteristics because the covariates (tumor, sex, schedule, etc.) are integrated into the model. The PK and PK/PD models were indeed verified and validated by VPC using both the working and validation datasets, bootstrapping techniques, and plotting of predicted population values versus observed population values. The PK/PD models used were mainly semi-mechanistic PK/PD models with TCSFL or mechanism-based IDR models as described by Danhof et al. [30]. These models offer the advantage of including target-site distribution, target binding and activation, PD interactions, transduction, and homeostatic feedback mechanisms.

PK parameter values for sunitinib and its metabolite estimated by the models used in this study agree well with values estimated by other PK models in the literature [31] and those reported in clinical studies in healthy volunteers [32]. Trough plasma concentrations of sunitinib of approximately 50 ng/mL were predicted by the models for the two schedules and are in broad agreement with measured trough plasma concentrations previously reported [33, 34]. The higher CL/F and V _c/F values in GIST patients compared with RCC patients is mostly likely due to the lower bioavailability of sunitinib in GIST patients compared with RCC patients. This lower bioavailability in GIST could be caused by the fact that the site of disease in GIST is potentially impacting the absorption of sunitinib from the GI tract. The covariates identified for CL/F and V _c/F in the sunitinib final PK model, as well as the SU012662 final model, were plausible and relevant and most have been previously reported by Houk et al. [31].

Similarly, the majority of the covariates identified for key parameters in the final PK/PD models for different endpoints appeared to be plausible and relevant. For example, for the efficacy endpoint SLD, it is highly plausible that patients with poor performance status (i.e. ECOG PS ≥ 1) will have a greater target tumor SLD at baseline. Similarly, the fact that the EC₅₀ for efficacy was higher in patients on Schedule CDD versus the intermittent dosing schedule was also consistent with the clinical data indicating lower PFS and ORR in patients on Schedule CDD compared with patients on Schedule 4/2 [8]. Furthermore, the EC₅₀ for efficacy (i.e. the SLD) was significantly higher for GIST compared with RCC (i.e. 177 vs. 30.5 ng/mL), consistent with a lower observed PFS and ORR in GIST compared with RCC following sunitinib therapy.

Although the intersubject variability in PK was low to moderate, there was a large degree of intersubject variability associated with the EC₅₀ for efficacy, as well as the safety endpoints, indicating that establishing a universal therapeutic window or target plasma concentration for therapeutic drug monitoring purposes would not be feasible. Therefore, the curent approach to start patients with the 50 mg dose and then allow for dose adjustments (i.e. incremental dose increase or decrease) based on individual patient safety tolerability appears to be an appropriate and practical approach and ensures that every patient achieves optimal plasma exposures.

Our model predicted that sunitinib, regardless of schedule, reduced target lesion SLD. Likewise, sunitinib was predicted to induce neutropenia, a small reduction in LVEF, lymphocytopenia, and fluctuating ALT, AST, and DBP, all known AEs associated with sunitinib [2, 6, 16]. In a pivotal trial comparing sunitinib versus interferon-α as first-line treatment in patients with advanced RCC, sunitinib was administered on Schedule 4/2 [6]; however, due to drug toxicity, more than 35 % of patients in this trial underwent dose interruptions, and more than 30 % had dose reductions. Subsequently, research efforts have been undertaken to identify optimal dosage schedules, and a number of retrospective reports regarding the efficacy and safety of Schedule 2/1 in RCC have been published. For example, Miyake et al. [27] and Najjar et al. [14] showed that, in RCC patients switched from Schedule 4/2 to Schedule 2/1, the incidence of AEs decreased after the switch. In both studies, sunitinib-induced thrombocytopenia-related AEs of grade 3 or higher were experienced in a significantly smaller proportion of patients on Schedule 2/1 than Schedule 4/2 [14, 27]. Grade 3 or higher AEs related to leukopenia and hypertension associated with sunitinib treatment, were experienced by a similar number of patients administered at either of the two schedules [27]. In the study of Najjar et al. [14], leukopenia-related AEs were experienced by fewer sunitinib-treated patients on Schedule 2/1, but this difference did not reach statistical significance. Two other retrospective studies reported no loss of efficacy with sunitinib in patients switched from Schedule 4/2 to Schedule 2/1 due to AEs [11, 12]; however, given the design of these studies, their results must be interpreted with caution. In another retrospective comparison of the two sunitinib schedules, Kondo et al. [13] observed that, with Schedule 2/1, fewer patients required dose interruptions due to AEs, and ORR and PFS were similar between the two schedules. In that same study, fewer patients experienced thrombocytopenia-related AEs of grade 3 or higher when on Schedule 2/1, but this was not statistically significant.

Good agreement was observed between our model predictions and reported clinical data in patients with advanced RCC treated with sunitinib on Schedule 4/2 or 2/1. Similar findings were also observed in patients with GIST, although clinical data for Schedule 2/1 in GIST are lacking. Sunitinib Schedule 2/1 dosing offers a potential alternative to Schedule 4/2 as it allows for management of toxicity without loss of efficacy.