The relationship between sunitinib exposure and both efficacy and toxicity in real‐world patients with renal cell carcinoma and gastrointestinal stromal tumour

Abstract

Aim Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Because of the large interpatient pharmacokinetic variability and established exposure‐response and exposure‐toxicity relationships in clinical trial patients, therapeutic drug monitoring (TDM) seems promising for optimizing sunitinib exposure. We aimed to investigate the relationship between sunitinib exposure and treatment outcome in a real‐world patient cohort. Methods We performed a retrospective observational cohort study in 53 patients with metastatic RCC and 18 patients with metastatic GIST treated with sunitinib and receiving TDM‐guided dosing. Time on treatment – as a surrogate for progression‐free survival – in patients who achieved adequate sunitinib exposure was compared with patients who did not. Additionaly, the median sunitinib exposure was compared in patients with or without sunitinib‐induced toxicity leading to dose reduction. Results The median time on treatment in patients with RCC who achieved adequate sunitinib exposure (n = 39) was 32 weeks, compared to 15 weeks in patients who did not achieve adequate sunitinib exposure (n = 12) (P = 0.244). In 29 patients (41%) with toxicity leading to dose reduction, sunitinib sum plasma trough concentration (Ctrough) until dose reduction was significantly higher compared to patients without toxicity leading to dose reduction (median 60 ng/mL vs 44 ng/mL; P < 0.001) and reduced to comparable levels after dose reduction (44 ng/mL; P = 0.488). Conclusion In our real‐world patient cohort, patients with sunitinib‐induced toxicity requiring dose reduction had significantly higher sunitinib exposure compared to patients without toxicity. The threshold for toxicity, however, was lower compared to that previously described in clinical trials.

Pharmacokinetically guided dosing has the potential to improve real‐world outcomes of pazopanib

“…Among the remaining 6 patients for whom proposed interventions were not implemented, the reasons for no dose adjustment included toxicity ( n = 4, 67%) and clinical response despite subtherapeutic drug exposure ( n = 2, 33%). These results of dose interventions were generally comparable to those in previous studies with sunitinib as well as pazopanib 13,14 . PK‐guided dosing significantly increased median time‐to‐treatment discontinuation (252 vs 74 days, P = .012) and improved OS (not reached vs 313 days, P = .002) relative to conventional dosing in the control group (Figure 1B and C).…”

Population Pharmacokinetic Analysis of Pazopanib in Patients and Determination of Target AUC

“…This approach makes it possible, in clinical practice, to personalize the medical treatments administered and therefore offers patients the best possible treatment. Monitoring plasma concentrations, or other parameters, in order to suggest dose adjustments, is a modern approach of medicine that gives patients access to high-quality health care, and therapeutic drug monitoring is an effective tool to optimize treatment by continuously ensuring its efficacy and preventing side effects [ 13 , 17 , 19 ].…”

“…A C trough > 20.5 mg·L −1 is correlated with the progression-free survival for metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma. Regarding toxicity, the standard of proof remains lower, but some studies demonstrate correlation or trends between C trough and dose-limiting toxicity [ 7 , 17 ].…”

Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors

“…6, 8, 20). In fact, a lower toxicity threshold of 60 ng/mL was suggested in a more recent analysis (43). Overall, these findings translate into favoring PD biomarkers over PK ones for dose individualization of sunitinib in GIST.…”