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. 2024 Jul;63(7):1045-1054.
doi: 10.1007/s40262-024-01399-8. Epub 2024 Jul 16.

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort

Marinda Meertens  1 , Eline L Giraud  2 , Maud B A van der Kleij  3   4 , Kim Westerdijk  5 , Niels A D Guchelaar  4 , Roos F Bleckman  6 , Amy Rieborn  7 , Alex L T Imholz  8 , Hans-Martin Otten  9 , Annelie Vulink  10 , Maartje Los  11 , Paul Hamberg  12 , Winette T A van der Graaf  3 , Hans Gelderblom  13 , Dirk Jan A R Moes  7 , K Esther Broekman  6 , Daan J Touw  14 , Stijn L W Koolen  4   15 , Ron H J Mathijssen  4 , Alwin D R Huitema  1   16   17 , Nielka P van Erp  2 , Ingrid M E Desar  5 , Neeltje Steeghs  18   19 ; Dutch Pharmacology Oncology Group (DPOG)
Affiliations

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort

Marinda Meertens et al. Clin Pharmacokinet. 2024 Jul.

Abstract

Introduction and objective: Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing.

Methods: A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications.

Results: A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%).

Conclusion: TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

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Conflict of interest statement

MM, ELG, MBAvdK, KW, NADG, RFB, AR, ALTI, H-MO, AV, ML, PH, SLWK, DJARM, KEB, DJT, ADRH, and IMED declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. WTAvdG reports institutional research fees paid to the institute from Lilly and advisory compensation from Springworks, PTC Therapeutics, and Agenus, all outside the submitted work. RHJM reports research funding paid to the institute from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Deuter Oncology, Nordic Pharma, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier, all outside the submitted work. HG reports institutional research funding from Daiichi Sankyo, Deciphera Pharmaceuticals, Ipsen, and Novartis. ADRH is an Editorial Board member of Clinical Pharmacokinetics. ADRH was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. NPvE reports research funding paid to the institute from Astellas and Ipsen, all outside the submitted work. NS reports research grants paid to the institute from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, and Takeda, all outside the submitted work. NS provided consultation or attended advisory boards for Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma, Incyte, and Luszana.

Figures

Fig. 1
Fig. 1
Flowchart of inclusion and exclusion. DPOG-TDM Dutch Pharmacology Oncology Group-Therapeutic Drug Monitoring, NKI-AVL the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, PK pharmacokinetic, TDM therapeutic drug monitoring
Fig. 2
Fig. 2
Kaplan-Meier curves illustrating progression-free survival (a) and overall survival (b) stratified by the TDM-guided cohort and non-TDM-guided cohort. TDM therapeutic drug monitoring
Fig. 3
Fig. 3
Kaplan-Meier curve illustrating time on treatment stratified by the TDM-guided cohort and non-TDM-guided cohort. TDM therapeutic drug monitoring
Fig. 4
Fig. 4
Feasibility analysis. Cmin trough concentration, EOT end of treatment, PK pharmacokinetic
See this image and copyright information in PMC

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