Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Due to large interpatient pharmacokinetic variability and an established exposure-response and exposure-toxicity relationship 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.
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 (PFS) - 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.
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 versus 44 ng/ml; P<0.001) and reduced to comparable levels after dose reduction (44 ng/ml; P=0.488).
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 previously described in clinical trials.
British journal of clinical pharmacology. 2020 May 01 [Epub ahead of print]
Kim Westerdijk, Stefanie D Krens, Winette T A van der Graaf, Sasja F Mulder, Carla M L van Herpen, Tineke Smilde, Nielka P van Erp, Ingrid M E Desar
Department of Medical Oncology Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands., Department of Medical Oncology, Jeroen Bosch Hospital, 's Hertogenbosch, Netherlands.