707P - Personalised dosing of oral targeted therapies in oncology: The era of therapeutic drug monitoring

Background

Although oral targeted therapies used in oncology demonstrate high interpatient variability in pharmacokinetics (PK), resulting in overdosing (>15%) and underdosing (30%) of patients (pts), a standard fixed dose for all pts is still used. This could lead to unnecessary toxicity and decreased efficacy, considering the established exposure–response and –toxicity relationships for many of these drugs. Personalised dosing through therapeutic drug monitoring (TDM) – individual dose adjustments based on measured PK–levels – could improve treatment outcomes. Results of 600 pts were published last year (Groenland et al, Ann Oncol. 1071-82, 2022 Oct). We hereby provide results of additional enrolment up to a 1000 pts, longer follow–up and newly reviewed cohorts.

Methods

This ongoing prospective study focusses on the feasibility, efficacy and tolerability of TDM of multiple oral targeted therapies in oncology. PK–levels are measured at 4–8–12 weeks after start of treatment and every 12 weeks thereafter. Recommendations are given based on established efficacy targets. Recommended interventions include dose adjustments, intake with food, split of intake moments, emphasize compliance and adjustment of interacting medication. An intervention is considered successful if there is a PK–level above target after intervention and if there is no dose limiting toxicity observed within one month.

Results

As of May 1^st 2023, this study includes 1006 pts from 14 hospitals using one of 24 different oral targeted therapies. The largest cohorts are abiraterone (n = 189), imatinib (n = 165), sunitinib (n = 112) and pazopanib (n = 106). Among 916 evaluable pts, 41.3% (n = 378) had all PK–levels above target, while 58.7% (n = 538) had ≥1 PK–level below target. A PK-guided intervention was possible in 55.4% (n = 298), and was successful in 69.1% of cases. Of all pts with a PK-level below target, intervention was successful in 38.3%. As a result, there was a 22.5% gain in pts with PK-levels above target, reaching a total of 63.8% (n = 584).

Conclusions

The results of this study support the feasibility of TDM of oral targeted therapies in oncology. Before implementation, efficacy of TDM still requires further evaluation. For the largest cohorts this evaluation will be performed.

Clinical trial identification

Netherlands Trial Register NTR6866, Release date: 6 December 2017.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute-Antoni van Leeuwenhoek.

Funding

Unrestricted Research Grants from Ipsen, GSK, Merck, Novartis, Pfizer, Roche.

Disclosure

P. Hamberg: Financial Interests, Personal, Advisory Board: Astellas, MSD, Pfizer, AstraZeneca, BMS, Ipsen. H. Gelderblom: Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, Deciphera, Novartis, Boehringer Ingelheim, AmMax Bio, Debiopharm, Cytovation. A.K.L. Reyners: Financial Interests, Institutional, Other, Member of the board: Dutch Society of Medical Oncology; Financial Interests, Institutional, Invited Speaker, FIRST study; coordinator for the Netherlands: Tesaro; Financial Interests, Institutional, Invited Speaker, Local PI GCT1015-05 study: Genmab; Financial Interests, Institutional, Invited Speaker, Local PI for the RUBY study: Tesaro; Financial Interests, Institutional, Invited Speaker, Local PI of the R2810 study: Regeneron; Financial Interests, Institutional, Invited Speaker, PI of MK3475-C93 trial: Merck; Non-Financial Interests, Leadership Role, Chairperson of the group that advises the Dutch Society of Medical Oncology whether EMA authorised medication should be common practice in the Netherlands (cieBOM): Dutch Society of Medical Oncology. N.P. Van Erp: Financial Interests, Institutional, Invited Speaker: Wad 'n Workshop; Financial Interests, Institutional, Invited Speaker, IDS: Ipsen, Astellas. R.H. Mathijssen: Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer-Ingelheim, Novartis; Financial Interests, Institutional, Invited Speaker: Pamgene. N. Steeghs: Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma, Luszana; Financial Interests, Institutional, Invited Speaker: AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Crescendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GSK, 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, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer, Deciphera, GSK, Merck, Novartis, Pfizer. All other authors have declared no conflicts of interest.