Figure 3. Dose-limiting toxicities (DLT) according to the average of first 3 trough (Cmin) concentration of pazopanib (n=118).
DISCUSSION
The pivotal PALETTE trial (6) showed a clinical benefit of pazopanib compared to placebo in STS patients treated with 800 mg/day. However, a large interindividual variability in response to pazopanib is observed in STS patients in daily clinical practice, both in terms of efficacy and toxicity. Different clinical and biological parameters can contribute to this variability, especially in unselected STS patients treated outside a clinical trial. In the present study, different parameters such as PS, tumour grade, bone or node metastasis, BMI and NLR were identified as risk factors for 3-month progression. These results are in accordance with those of PALETTE trial.
The main finding of this observational study is that a PAZ Cmin < 27 mg/L at day 15 was an independent risk factor of 3-month PFS while a daily start dosing lower than 800 mg/day was not. A threshold of 20.5 mg/L was previously explored by Verheijen R.B et al and was found significantly associated with PFS in RCC patients but not in STS patients (9,16). This discrepancy could be related to the lower efficacy of pazopanib in STS patients compared to RCC. We also observed OS tended to be shorter in patients with PAZ Cmin < 27 mg/L, but the difference was not statistically significant. In the PALETTE trial, none of all explored factors were found to be significantly associated with OS (23).
The safety profile of pazopanib in our real-life cohort is generally consistent with previous studies (5,6). In the present study, the univariate analysis identified PS and BMI as risk factors of DLT onset. Regarding PK/PD analysis, a higher risk was observed in patients with increased plasma Cmin over the first 3 months of treatment (p=0.01). In RCC patients (n=205), Suttle et al. showed an increased frequency of hypertension, diarrhea, hepatic cytolysis, and stomatitis in the fourth quartile PAZ Cmin (36-85 mg/L) (9). In the present,study, we did not investigate any PK/PD relationship for these specific adverse events because our study was not statistically designed to address this issue. However, we tested the threshold value of 50 mg/L proposed for DLT onset in RCC patients (16,24,25), but it was not statistically significant (data not shown). This threshold is probably less than 50 mg/L in sarcoma patients owing to their higher fragility compared to RCC patients. Further studies are warranted to clearly identify a threshold value of PAZ Cmin able to predict DLT onset in sarcoma patients.
The poor tolerance profile of several TKI, especially in patients with poor PS, has led to evaluate the use of a lower daily dose at the initiation with a secondary increase according to tolerance. Such strategies have been validated with regorafenib and afatinib (26,27). but need close clinical monitoring that is not always feasible in daily practice. The use of therapeutic drug monitoring (TDM) could be an alternative approach to ensure therapeutic plasma exposure over the whole treatment course. In case of suboptimal exposure, a dose escalation strategy should be conducted whether the safety profile is favourable to it. However, it is noteworthy to underline that daily of PAZ above 800 mg exhibits a saturation of its intestinal absorption (11). Therefore, splitting the dose into 400 mg twice is strongly recommended to enhance the bioavailability in underexposed patients treated with 800 mg/day (21,28).
The major strength of this study is its sample size, which is the largest about pazopanib pharmacokinetics in sarcoma. Moreover, both survival and tolerance data from this “real-life” study are consistent with the literature. However, the present study also presents several drawbacks, including the monocentric design and the numerous treatment interruption within the first three months that could interfere with PK/PD analysis.
In patients treated with oral targeted anticancer drug, TDM has been recognized as a powerful tool to individualize drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates (29). Several PK/PD studies showed the relevance and feasibility of TDM in patients treated with angiogenesis inhibitors such as sorafenib or sunitinib (14,15,30–32). The presents study suggests the clinical benefit to practice early TDM in STS patients under pazopanib, as previously proposed in RCC patients (10). Some clinically drug-drug interactions are also relevant indications for TDM in STS patients treated with PAZ. For example, coadministration of proton pump inhibitors is known to decrease by 40% plasma exposure, which results in significantly shortened PFS and OS (33). Thereby, TDM may be helpful for the clinical management of most patients. Overall, early TDM strategy could be helpful to both prevent early treatment failure and DLT onset.
In conclusion, the present study confirms PAZ Cmintarget >27 mg/L in a large cohort of STS patients to optimize efficacy. In today’s era of personalized medicine, early TDM could be helpful to optimize response to pazopanib in these patients, as previously reported in RCC patients. In this context, any STS or RCC patient treated with PAZ should have access to TDM.
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