Abstract:
High interindividual variability in pharmacokinetics coupled with
concentration-effect relationship make sunitinib an ideal candidate for
therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib
in patients with metastatic renal cell carcinoma (mRCC) was evaluated in
this prospective observational study. Seventy patients with mRCC treated
with sunitinib 50mg OD were enrolled. Total trough levels (TTL) of
sunitinib and N-desethyl sunitinib were measured between days 10-14 of
cycle 1. The discriminatory potential of TTL of sunitinib for the
prediction of responders and occurrence of grade ≥3 toxicity was
determined using receiver operating characteristic (ROC) curve.
Threshold concentrations obtained from ROC analysis showed that TTL
≥60.75ng/mL was associated with higher response rates and TTL ≥82.3ng/mL
was associated with higher incidence of grade ≥3 toxicity compared with
lower exposures (31/34 versus 5/12, P=0.001 and 9/24 versus 4/36;
P=0.024 respectively). More than 50% of patients in our cohort attained
TTL outside the optimal range of 60.75-82.3 ng/mL demonstrating the
feasibility of TDM.
Introduction:
Sunitinib malate was the standard first-line treatment for metastatic
renal cell carcinoma (mRCC) globally till recently. Even today, in
several low and middle income countries where immunotherapies are
ill-afforded, it continues to be the standard of care. The
pharmacokinetics of sunitinib is highly variable with a reported
inter-patient coefficient of variation (CV) of up to 60% for various
pharmacokinetic parameters1. Moreover, there is an
excellent concentration-efficacy/toxicity relationship seen with
sunitinib in patients of mRCC2,3. For these reasons,
sunitinib is an ideal candidate for therapeutic drug monitoring (TDM)
rather than using a fixed dose of 50 mg that is currently in vogue.
Maintaining a total target trough plasma concentration of sunitinib and
its active metabolite (N-desethyl sunitinib, SU12662) in the range of
50–100 ng/mL has been proposed based on several clinical and
non-clinical studies2,3,4. Higher sunitinib exposure
is associated with an increased risk of severe adverse events,
indicating a narrow therapeutic index. The threshold value of plasma
composite (sunitinib+SU12662) exposure predicting grade 3–4 toxicities
remains to be determined in routine clinical practice. In a
retrospective study involving 59 patients, 23(39%) patients required
dose interruption or dose delay while 12(20%) patients required dose
modification due to toxicity5. Recent studies have
indicated that PK guided dosing can optimize sunitinib therapy compared
to standard fixed dose and can decrease the frequency of dose
interruption. This study was planned to evaluate the feasibility of TDM
of Sunitinib in patients with mRCC in a real world setting.
Material & Methods:
The prospective observational study was conducted at Tata Memorial
Centre, Mumbai. The study was approved by the Institutional Ethics
Committee of Tata hospital. All trial participants provided written
informed consent prior to their enrolment. The study was carried out in
accordance with the Declaration of Helsinki and International Conference
on Harmonization—Good Clinical Practice (ICH‐GCP) guidelines. A steady
state trough plasma sample was collected between days 10-14 of the first
cycle. Sunitinib and SU12662 concentrations were measured simultaneously
using ultra-high-performance liquid chromatography as described
previously6. Sunitinib administration was continued
until disease progression, intolerable adverse events or patient’s
refusal to take the drug for any reason. All adverse events were graded
according to Common Terminology Criteria for Adverse Effects (CTCAE)
version 4.03. All response assessments, until disease progression, were
collated and the best response was determined as either complete
response (CR), partial response (PR), stable disease (SD) or progressive
disease (PD) as per RECIST 1.17. The optimal cut-off
value of sunitinib concentration for the prediction of the response and
the occurrence of grade≥3 toxicity was identified using the receiver
operating characteristic (ROC) curve. Time to event endpoints were
analysed using Kaplan-Meier plots and compared between groups using
log-rank test. All computations were performed with the SPSS Version
25.0.
Result and
Discussion:
Seventy patients aged 18 years or older with histologically or
cytologically confirmed mRCC receiving sunitinib at 50 mg dose daily
were enrolled in the study. Recently the RESTORE trial, a phase II
randomized trial compared the 4-week on/2-week off (4/2) schedule vs a
2-week on/1-week off (2/1) schedule. This study concluded that the
administered 2/1 schedule is associated with less toxicity and higher
failure-free survival (FFS) at 6 months than the 4/2 schedule, without
compromising the efficacy in terms of objective response rate (ORR) and
time to progression (TTP)8. Sixteen patients received
sunitinib for 4/2 regimen in a six week cycle and 54 patients received
2/1 regimen.
The patient characteristics are summarized in table 1. The number of
patients included in each analysis is summarized in Supplementary fig 1.
Total trough levels of sunitinib (sunitinib + SU12662) (TTL) was
determined for 60 out of 70 patients. The median TTL, trough sunitinib
and SU12662 concentrations were 75.2 (24.5-209.4), 56.5 (16.5-129.4) and
19.8 (6.9-48.4) ng/mL respectively. The TTL of sunitinib was highly
variable (CV=46.3%) (Supplementary fig 2).
A total of 60 patients were evaluable for the analysis of the
association between TTL of sunitinib and toxicity whereas 46 of the 70
patients were evaluable for the analysis of the association between TTL
of sunitinib and response. During cycle 1 of treatment, toxicity of any
grade was observed in 50 out of 60 patients (83.3%). Grade ≥3 toxicity
were observed in 12 patients. Grade ≥3 toxicities attributed to
sunitinib treatment included hypertension, fatigue, hyponatremia,
thrombocytopenia and hand-foot syndrome (HFS). The ability of TTL to
predict grade ≥3 toxicity and response (having SD or better as best
response) is shown in the ROC curve analysis in Figure 1A and 1B
respectively. TTL of 82.3ng/mL was found to be discriminatory for the
prediction of grade ≥3 toxicity (AUC: 0.678, 95% CI: 0.516-0.839,
Sensitivity: 69.23%, Specificity: 68.09%, p=0.05) whereas TTL of
60.75ng/mL was discriminatory for the prediction of responders (AUC:
0.797, 95% CI: 0.618-0.977, Sensitivity: 86.11%, Specificity: 70%,
p=0.004). The best overall response for all the patients is presented in
supplementary figure 3. The incidence of grade ≥3 toxicity was observed
in 4/36 (11.1%) patients in the low-exposure group (TTL
<82.3ng/mL) compared with 9/24 (37.7%) patients in the
high-exposure group (TTL ≥82.3ng/mL) (p=0.024). On the other hand an
objective response was observed in only 5/12 patients (41.6%) in the
low-exposure group (TTL <60.75ng/mL) compared with 31/34
patients (91.1%) in the high-exposure group (TTL ≥60.75ng/mL)
(p=0.001).
On similar lines, analysis of association of toxicity/ response and TTL
of sunitinib was done for 54 patients who received the 2/1 regimen of
sunitinib. Forty six patients were included in this analysis of toxicity
whereas 36 were included in analysis of response (Supplementary fig 1).
The ROC curve showed that the concentration of 82.3ng/mL and 60.75ng/mL
was discriminatory for the prediction of grade ≥3 toxicity (AUC: 0.688,
95% CI: 0.435-0.940, Sensitivity: 83.33%, Specificity: 72.50%,
p=0.142) and responders (AUC: 0.818, 95% CI: 0.746-1.000, Sensitivity:
85.19%, Specificity: 88.89% and p: 0.001) respectively (Figure 2A &
2B). The incidence of grade≥3 toxicity was observed in 1/30 (3.33%)
patients in the low-exposure group (TTL < 82.3ng/mL) compared
with 5/16 patients (31.25%) in the high-exposure group (TTL ≥82.3ng/mL)
(p=0.015). An objective response was observed in 4/12 patients (33.3%)
in the low-exposure group (TTL <60.75 ng/mL compared with
23/24 patients (95.8 %) in the high-exposure group (TTL ≥60.75ng/mL)
(p<0.001).
The median follow-up for all patients was 29.2 (22-34.4) months while it
was 29 (18-40) months for the patients receiving 2/1 regimen. The
probability of 2 years survival was 13.4% in the low-exposure group
(TTL <60.75ng/mL) as compared to 38.8% in the high-exposure
group (TTL ≥60.75 ng/mL) for all patients (Figure 1C), whereas, for
patients receiving 2/1 dose regimen of sunitinib the probability of 2
years survival was 7% in the low-exposure group as compared to 40.8%
in the high-exposure group (Figure 2C).
Previous PK/PD data in a mouse xenograft model and phase I trials
indicate that optimal target range for TTL is
50-100ng/mL2,3,4. Previously Noda et al. has shown
that dose reduction is needed, when the total sunitinib concentration is
>100ng/mL, to avoid unnecessary early discontinuation of
treatment9. Uemura et al also have shown that
sunitinib was effective at TTL of 50ng/mL in patients with
mRCC10. Our findings corroborate these observations
albeit at slightly different threshold concentrations, indicating a TTL
range of 60.75-82.3ng/ml is ideal for optimal therapeutic effect.
However, it may not be possible to maintain trough concentration within
this narrow range, particularly through fixed oral dosing. Therefore,
for practical reasons, the TTL range of 60-100ng/mL may be most
appropriate for our setting considering treatment failure rates
increased dramatically in patients who did not achieve TTL of
60.75ng/mL.
It has been reported that severe sunitinib-induced acute toxicities can
impact the quality of life (QoL) and lead to early treatment
discontinuation11. Collecting longitudinal QOL data
would have given better understanding of the state of health leading to
continuation or discontinuation of sunitinib at various stages of
treatment. It would have allowed us to study the association between
drug levels and QoL and could have complimented the strategy for optimal
dosing of sunitinib in mRCC.
To conclude, although scattered evidence favors exposure-monitored
dosing, TDM has not been adopted into routine practice because of the
absence of high level evidence in the form of large randomized
controlled trials or systematic reviews. Here, we could show that
patients with mRCC may benefit from TDM based dosing, and we were able
to ascertain the therapeutic range in our population. A randomized trial
of TDM based dosing versus conventional dosing is underway at our centre
to conclusively establish the role of TDM in improving the safety and
efficacy of sunitinib in mRCC.
Acknowledgement:
The authors gratefully acknowledge the Indian Council of Medical
Research for partially funding this study through the Centre for
Advanced Research and Excellence (ICMR-CARE) in Clinical Pharmacology
(Grant No. 55/4/13/CARE-CP/2018-NCD-II). The authors acknowledge Mr.
Sharath Kumar HJ for extending his help in making figures.
Conflict of interest statement .
None