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Proffered paper session - Gastrointestinal tumours, colorectal

1777 - DPYD genotype-guided dose individualization of fluoropyrimidine therapy: A prospective safety and cost-analysis on DPYD variants DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A

Date

22 Oct 2018

Session

Proffered paper session - Gastrointestinal tumours, colorectal

Presenters

Linda Henricks

Citation

Annals of Oncology (2018) 29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Authors

L.M. Henricks1, C.A.T.C. Lunenburg2, F.M. de Man3, D. Meulendijks4, G.W.J. Frederix5, E. Kienhuis3, G.M. Creemers6, A. Baars7, V.O. Dezentjé8, H. Rosing9, J.H. Beijnen9, E. van Werkhoven10, A.B.P. van Kuilenburg11, R.H.N. van Schaik12, R.H.J. Mathijssen13, J.J. Swen14, H. Gelderblom2, A. Cats15, H. Guchelaar14, J.H.M. Schellens16

Author affiliations

  • 1 Department Of Clinical Pharmacology, Division Of Medical Oncology, The Netherlands Cancer Institute, 1066CX - Amsterdam/NL
  • 2 Department Of Medical Oncology, Leiden University Medical Center, 2300 RC - Leiden/NL
  • 3 Department Of Medical Oncology, Erasmus MC Cancer Institute, 3015 CE - Rotterdam/NL
  • 4 Dutch Medicines Evaluation Board, CBG-MEB, Utrecht/NL
  • 5 Julius Center For Health Sciences And Primary Care, University Medical Center Utrecht, Utrecht/NL
  • 6 Department Of Medical Oncology, Catharina Hospital, 5602 ZA - Eindhoven/NL
  • 7 Department Of Internal Medicine, Hospital Gelderse Vallei, 6710 HN - Ede/NL
  • 8 Department Of Internal Medicine, Reinier de Graaf Hospital, Delft/NL
  • 9 Department Of Pharmacy & Pharmacology, The Netherlands Cancer Institute, 1066CX - Amsterdam/NL
  • 10 Department Of Biometrics, The Netherlands Cancer Institute, Amsterdam/NL
  • 11 Laboratory Genetic Metabolic Diseases, Department Of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam/NL
  • 12 Department Of Clinical Chemistry, Erasmus Medical Center, Rotterdam/NL
  • 13 Department Of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam/NL
  • 14 Department Of Clinical Pharmacy And Toxicology, Leiden University Medical Center, Leiden/NL
  • 15 Department Of Gastrointestinal Oncology, Division Of Medical Oncology, The Netherlands Cancer Institute, 1066 CX - Amsterdam/NL
  • 16 Department Of Clinical Pharmacology, Division Of Medical Oncology, The Netherlands Cancer Institute, Amsterdam/NL
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Abstract 1777

Background

Fluoropyrimidines are generally well tolerated drugs, but can result in severe, potentially fatal toxicity in up to 30% of patients. The major cause of toxicity is reduced activity of the key metabolizing enzyme dihydropyrimidine dehydrogenase (DPD), most often the result of genetic DPYD variants. In this prospective clinical trial we determined whether toxicity of fluoropyrimidine treatment can be reduced by upfront screening for 4 relevant DPYD variants and DPYD genotype-guided dosing.

Methods

Prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A was performed in patients prior to start of fluoropyrimidine-based therapy. Heterozygous DPYD variant carriers received an initial dose reduction of 25% (c.2846A>T, c.1236G>A) or 50% (DPYD*2A, c.1679T>G). Incidence of severe (grade ≥3) toxicity in DPYD variant carriers was compared to a historical cohort of DPYD variant carriers treated with full dose.

Results

A total of 1,103 evaluable patients was enrolled, of whom 85 were heterozygous DPYD variant carriers (7.7%). In DPYD variant carriers the overall frequency of grade ≥3 toxicity was 39%. When comparing to the historical cohort, DPYD genotype-guided dosing markedly reduced the risk of grade ≥3 toxicity for DPYD*2A and c.1679T>G carriers, moderately reduced risk for c.2846A>T carriers, and resulted in a similar risk for c.1236G>A carriers. Pharmacokinetic analyses showed that fluoropyrimidine exposure after dose reductions in DPYD variant carriers was comparable to wild-type patients. A cost-analysis showed that the reduced risk in toxicity resulted in average total treatments costs per patient that were even lower for the screening strategy (€2599) compared to non-screening (€2650).

Conclusions

Upfront DPYD genotyping improves patient safety during fluoropyrimidine chemotherapy, is feasible in routine practice, and is cost saving. For heterozygous DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction is recommended. For c.1236G>A and c.2846A>T carriers the applied dose reductions of 25% in this study were not enough to lower the risk of severe toxicity in this group, so more cautious dose reductions of 50% are recommended.

Clinical trial identification

NCT02324452.

Legal entity responsible for the study

The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Funding

Dutch Cancer Society (Alpe d'HuZes/KWF-fund).

Editorial Acknowledgement

Disclosure

C.A.T.C. Lunenburg: Unrestricted grant: Roche Pharmaceuticals. R.H.J. Mathijssen: Research support: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi; Consultation fees: Novartis, Servier; Travel support: Astellas, Pfizer. All other authors have declared no conflicts of interest.

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