596P - Dose-individualisation of fluoropyrimidines in <italic>DPYD</italic> wild-type patients: Final results from the Alpe2U study

Background

Although DPYD-based dosing has markedly improved the safety of fluoropyrimidine (FP) treatment, ∼23% of wild-type DPYD (DPYD _wt) patients still continue to experience severe toxicity. Previous studies linked pre-treatment uracil (U) levels to severe FP-related toxicity. In this prospective multicentre trial (NCT04194957), we investigated if U-based dose-individualisation for FP treatment can further improve safety in DPYD _wt patients.

Methods

Genotyping (DPYD*2A, *13, 2846A>T and 1236G>A), U levels (in fasted state between 8-10h AM) and DPD enzyme activity in peripheral blood mononuclear cells were measured prior to FP treatment. DPYD _wt patients with U levels > 16 ng/mL (U_high) received a 50% dose-reduction, as per French RNPGx guidelines. The incidence of CTCAE grade ≥ 3 FP-related toxicity in DPYD _wt/U_high patients was compared to DPYD _wt patients with U ≤ 16 ng/mL (U_normal) from this study and to a historical cohort of DPYD _wt/U_high patients (n = 14), both treated at full dose. Pharmacokinetic (PK) data was compared to a historical cohort (n = 20).

Results

Out of 911 patients enrolled, 27 were DPYD _wt/U_high. Dose-reduction of FPs in DPYD _wt/U_high patients had a significantly lower incidence of severe toxicity compared to full-dosing of FPs in historical DPYD _wt/U_high patients (20% vs. 43%, p =. 03). The incidence of severe toxicity during the first two treatment cycles was similar between 20 DPYD _wt/U_high and 554 DPYD _wt/U_normal patients from this study (10% vs. 11%, p = 1.0). PK analysis of 19 DPYD _wt/U_high patients treated at a 50% dose showed a substantially lower 5-fluorouracil (5-FU) exposure compared to historical DPYD _wt patients (177 vs. 381 ng*h/mL). Hereafter, five DPYD _wt/U_high patients were treated at full dose and showed comparable 5-FU exposure to the historical cohort (456 vs 381 ng*h/mL). No correlation (R =.006, p =.98) between U levels and DPD enzyme activity was observed.

Conclusions

While U-based dosing of FPs in DPYD _wt patients decreased severe toxicity, it also resulted in clinically relevant underexposure to 5-FU. This renders it unsuitable for dose-individualisation in DPYD _wt patients. Hence, we advise to reconsider the position of U-based dosing within the EMA guideline.

Clinical trial identification

NCT04194957.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Dutch Cancer Society (Alpe-d’HuZes/KWF-fund, NKI2013-6249).

Disclosure

H. Gelderblom: Financial Interests, Institutional, Local PI: Deciphera, Cytovation; Financial Interests, Institutional, Coordinating PI: Boehringer Ingelheim, AmMax Bio, Debiopharm, Abbisko. R.H. Mathijssen: Financial Interests, Institutional, Invited Speaker: Bayer, Novartis; Financial Interests, Institutional, Advisory Board: Servier, NaDeNo Nanoscience; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer-Ingelheim, Novartis, Nordic Pharma; Financial Interests, Institutional, Coordinating PI: Pamgene; Financial Interests, Institutional, Funding: Echo Pharmaceuticals, Deuter Oncology. All other authors have declared no conflicts of interest.