95P - Implementation of TDM and PGx in mRCC patients treated with sunitinib to personalize drug dosing

Background

Sunitinib (SUN) is a tyrosine kinase inhibitor used in metastatic renal cell carcinoma (mRCC). It exhibits high variability in drug exposure (exp) and toxicity/response among patients (pts). Fixed SUN dosing may lead to under- or over-exposure in different pts, considering a literature proposed target ranges of 37.5-75 ng/mL for continuous dosing and 50-87.5 ng/mL for intermittent dosing. The implementation of Therapeutic Drug Monitoring (TDM) and pharmacogenetic (PGx) assessment can aid in optimizing treatment outcomes. We aimed to assess the feasibility and clinical utility of a pharmacological counselling using TDM and PGx, for SUN treatment in mRCC pts.

Methods

Patients were enrolled in the CRO-2022-14 trial conducted at CRO Aviano. Samples were collected at minimum steady-state plasma concentration (Cmin), and exp was determined by quantifying SUN and N-DES Cmin using a validated LC-MS/MS method. Polymorphisms in SUN-related cytochromes and cell-transporters were analyzed. Oncologists received a pharmacological counselling based on interpreted data.

Results

Eight SUN-treated pts were included in the study. At enrolment, pts were on treatment for a mean of 34 months, and received a SUN dose already reduced (6/8 pts) based on observed clinical toxicity. Six pts showed a mean Cmin ranging from 53 to 68 ng/mL, within the target range. One pt exhibited a mean Cmin of 84 ng/mL despite a dose reduction to 25 mg/day with G2 toxicity persistence, suggesting the need for possibly lower yet efficacious dosing. Another pt was treated at 25 mg/day (after dose reduction from 50 due to G3 toxicity), yielding a Cmin of 39 ng/mL. No further serious toxicities were observed, enabling consideration of higher dosing (37.5 mg/day) while maintaining exp within the target range. PGx analyses were conducted, yet the limited pt sample size precluded definitive conclusions.

Conclusions

Toxicity-driven dose adjustment led to uniform SUN Cmin exposure within the therapeutic range in a 34 months average treatment duration. A front-line TDM application could have optimized SUN dosing based on the Cmin target range in the earlier phases of the treatment, potentially improving tolerance and compliance while maintaining plasma concentration within the efficacy threshold.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Puglisi: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris, Daiichi Sankyo; Financial Interests, Personal, Other, travel grants: Amgen, AstraZeneca, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris, Daiichi Sankyo; Financial Interests, Personal, Research Grant: Amgen, AstraZeneca, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Italfarmaco, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, Viatris, Daiichi Sankyo; Financial Interests, Personal, Funding: AstraZeneca, Eisai, Roche. All other authors have declared no conflicts of interest.