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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