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Poster session 01

70P - Fluoropyrimidine (FP) dose individualization based on pretreatment uracil levels: Safety and pharmacokinetic (PK) analysis from the Alpe2U study

Date

10 Sep 2022

Session

Poster session 01

Topics

Translational Research;  Genetic and Genomic Testing, Counseling

Tumour Site

Breast Cancer;  Gastric Cancer;  Pancreatic Cancer;  Colon and Rectal Cancer;  Head and Neck Cancers

Presenters

Mirjam De With

Citation

Annals of Oncology (2022) 33 (suppl_7): S27-S54. 10.1016/annonc/annonc1037

Authors

M. De With1, J. Knikman2, A. Baars3, G.M. Creemers4, H.J. Droogendijk5, E. Fiets6, A.L.T. Imholz7, L.B.J. Valkenburg-van Iersel8, F.J.F. Jeurissen9, C.M.P.W. Mandigers10, R.H.N. Van Schaik11, B.J.C. van den Bosch12, H. Rosing13, J.H. Beijnen14, J.J. Swen15, H. Gelderblom16, J.H.M. Schellens17, R.H. Mathijssen18, H. Guchelaar15, A. Cats19

Author affiliations

  • 1 Depts. Of Medical Oncology And Clinical Chemistry, Erasmus MC Cancer Institute, 3015 GD - Rotterdam/NL
  • 2 Pharmacy And Pharmacology Departments, Netherlands Cancer Institute, 1006 BE - Amsterdam/NL
  • 3 Medical Oncology Department, Hospital Gelderse Vallei, 6716 RP - Ede/NL
  • 4 Medical Oncology Department, Catharina Hospital Eindhoven, 5602 ZA - Eindhoven/NL
  • 5 Internal Medicine Department, Bravis Ziekenhuis-Roosendaal, 4708 AE - Roosendaal/NL
  • 6 Internal Medicine Department, Medical Center Leeuwarden, 8934 AD - Leeuwarden/NL
  • 7 Medical Oncology Department, Deventer Ziekenhuis, 7416 SE - Deventer/NL
  • 8 Medical Oncology Department, Maastricht Universitair Medisch Centrum, 6229 HX - Maastricht/NL
  • 9 Internal Medicine Department, HMC - Haaglanden Medisch Centrum - Westeinde, 2512 VA - Den Haag/NL
  • 10 Internal Medicine Department, Canisius Wilhelmina Hospital, 6532 SZ - Nijmegen/NL
  • 11 Clinical Chemistry Department, Erasmus University Medical Center, 3015 GD - Rotterdam/NL
  • 12 Clinical Genetics Department, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL
  • 13 Pharmacy & Pharmacology Department, titute, 1066 CX - Amsterdam/NL
  • 14 Pharmacy & Pharmacology Department And Pharmacoepidemiology And Clinical Pharmacology Division, Netherlands Cancer Institute and Utrecht University, 1006 BE - Amsterdam/NL
  • 15 Clinical Pharmacy And Toxicology Department, Leiden University Medical Center and Leiden Network for Personalised Therapeutics, 2333 ZA - Leiden/NL
  • 16 Medical Oncology Department, Leiden University Medical Center, 2300 RC - Leiden/NL
  • 17 Pharmaceutical Sciences Department, Utrecht University - Faculty of Pharmaceutical Sciences, 3584 CG - Utrecht/NL
  • 18 Medical Oncology, Erasmus MC Cancer Institute, 3015 GD - Rotterdam/NL
  • 19 Gastrointestinal Oncology Department, Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
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Abstract 70P

Background

Risk of severe adverse events (AEs) during FP treatment can be significantly reduced through dose reduction in patients (pts) with dihydropyrimidine dehydrogenase (DPD) deficiency, the main FP metabolizing enzyme. Hence, in 2020 EMA stated that screening for DPD deficiency should be performed before FP treatment by DPYD genotyping, or by DPD phenotyping using plasma uracil (U) levels. Based on previous studies, pts with U >16 ng/ml are considered DPD deficient. However, a specific dosing strategy for these pts is missing. The Alpe2U study (NCT04194957) is the first prospective multicenter trial studying FP dose individualization based on combined DPYD genotype and U levels.

Methods

Genotyping for DPYD*2A, 2846A>T, 1679T>G and 1236G>A, measuring U levels (in fasting state between 8-10h AM) and DPD enzyme activity in peripheral blood mononuclear cells were performed prior to FP based treatment. DPYD wild type pts (WTs) with U >16 ng/mL and heterozygous DPYD variant carriers received an initial 50% dose reduction and were uptitrated guided by safety. In addition, PK sampling was performed during the 1st treatment cycle. A pre-planned interim analysis was done at 50% inclusion of the required 36 WTs with U >16 ng/mL in which safety and PK data were compared with a reference cohort of 20 WTs receiving full dose FPs (Deenen, CCP 2015).

Results

A total of 645 pts were enrolled in 14 Dutch hospitals. 18 WTs with U >16 ng/mL who received 50% FP dose were evaluable for analysis. Mean (range) U was 19.6 (16.2-29.3) ng/mL. In these pts, the mean dose-corrected area under the curve of 5-fluorouracil (5-FU) was 167 ng*h/mL, compared to 381 ng*h/mL (reference cohort). Mean DPD enzyme activity was 10.8 nmol/mg protein/h (range: 2.9-19.3), with 8.7-24.4 as range for normal DPD enzyme activity. Safety demonstrated low occurrence of severe AEs (18% vs. 43%).

Conclusions

WTs who received a 50% dose reduction based on U >16 ng/mL showed 56% lower AUC of 5-FU than expected and coinciding low FP-associated AEs. This suggests that FP dose individualization based on U levels may be accompanied with high risk of underdosing. Clinicians should be aware of this risk and the use of U levels for dose individualization of FPs should be reconsidered.

Clinical trial identification

The Alpe2U-study NCT04194957.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Alpe d’Huzes/KWF Program Grant, Dutch Cancer Society (NKI 2013-6249).

Disclosure

L.B.J. Valkenburg-van Iersel: Financial Interests, Personal, Advisory Role: Servier, Roche, Pierre Fabre. R.H.N. Van Schaik: Non-Financial Interests, Personal, Other, Board: European Society Pharmacogenomics and Personalized Therapy; Non-Financial Interests, Personal, Other, Chair: Utch Clinical Pharmacogenetics Network. J.H. Beijnen: Financial Interests, Personal, Full or part-time Employment, Part time employee (0,1): Modra Pharmaceuticals BV; Financial Interests, Personal, Stocks/Shares, Co-founder: Modra Pharmaceuticals BV; Financial Interests, Personal, Other, Co-inventor on a patent: Modra Pharmaceuticals BV; Financial Interests, Institutional, Other, Financial compensation for laboratory work: PharmaMar, Astex. H. Gelderblom: Financial Interests, Institutional, Invited Speaker: Daiichi, Deciphera, Novartis, Boehringer Ingelheim, AmMax Bio, Debiopharm, Cytovation. J.H.M. Schellens: Financial Interests, Personal, Full or part-time Employment: Modra Pharmaceuticals BV, Byondis BV; Financial Interests, Personal, Other, CMO: Modra Pharmaceuticals BV; Financial Interests, Personal, Member of the Board of Directors, and CMO: Byondis BV; Financial Interests, Personal, Stocks/Shares: Modra Pharmaceuticals BV; Financial Interests, Personal, Other, Consultant: Debiopharm Switzerland. R.H. Mathijssen: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Other, Patent pending: Pamgene; Financial Interests, Institutional, Other, Investigator-initiated research: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Servier. All other authors have declared no conflicts of interest.

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