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.
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).
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%).
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.
Legal entity responsible for the study
Alpe d’Huzes/KWF Program Grant, Dutch Cancer Society (NKI 2013-6249).
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.