To Test or Not to Test—That Is the Question: DPD Deficiency and Weighing Potential Harms

January 16, 2025
Bethesda, Maryland

WORKSHOP CO-CHAIRS

Patricia M. LoRusso, DO, PhD (hc), FAACR, 2024-2025 President, American Association for Cancer Research
Jennifer Gao, MD, Associate Director for Education, Oncology Center of Excellence, U.S. Food and Drug Administration

workshop agenda speaker bios

OVERVIEW

The U.S. Food and Drug Administration (FDA) Oncology Center of Excellence and the American Association for Cancer Research (AACR) collaborated to host a one-day hybrid public workshop to explore the considerations for dihydropyrimidine dehydrogenase (DPD) deficiency testing before chemotherapy with fluoropyrimidines.

Fluoropyrimidine drugs, including 5-Fluorouracil (5-FU) and capecitabine (Xeloda), are frequently used to treat various solid tumors and remain the backbone of many combination therapies. The DPD enzyme plays a vital role in the breakdown of these drugs into non-toxic products, and individuals with certain genetic variants in the DPYD gene may have complete or partial DPD deficiency, which can lead to an increased risk of severe adverse reactions. As a result, more standardized approaches to testing for DPD deficiency could improve patient safety. In 2022, the FDA product labeling for Xeloda (capecitabine) was updated to include new information on DPD deficiency, and 5-FU product labeling was similarly updated in 2024. In conjunction with the 2022 labeling revisions for Xeloda, FDA also issued its response to a Citizen’s Petition requesting labeling revisions recommending pre-treatment testing be considered to identify patients with DPD deficiency.

The purpose of this workshop is to provide an interdisciplinary forum to examine the existing information and evidence surrounding DPD deficiency testing, consider the potential clinical implications of requiring testing, including potential unintended consequences, and to discuss the regulatory considerations for modifying FDA product labeling to require testing.

PROGRAM

Welcome and Fireside Chat

• Richard Pazdur, MD, U.S. Food and Drug Administration
• Patricia M. LoRusso, DO, PhD (hc), FAACR, 2024-2025 President, American Association for Cancer Research

Session 1: CURRENT LANDSCAPE—DPD DEFICIENCY TESTS AND FDA PRODUCT LABELING

Moderator: Michael Pacanowski, PharmD, MPH, U.S. Food and Drug Administration, Silver Spring, Maryland

• The importance of dihydropyrimidine dehydrogenase in 5-FU treatment
  Robert Diasio, MD, Mayo Clinic, Rochester, Minnesota
• AMP’s recommendations for clinical DPYD genotyping allele selection
  Victoria Pratt, PhD, Agena Bioscience, Indianapolis, Indiana
• Fluoropyrimidine and DPD deficiency: A regulatory history of FDA labeling
  Evan Bryson, PharmD, BCOP, U.S. Food and Drug Administration, Silver Spring, Maryland

Session 2: CURRENT LANDSCAPE—CLINICAL CONSIDERATIONS AND EVIDENCE

Moderator: Jennifer Gao, MD, U.S. Food and Drug Administration

• When should a tumor biomarker be applied in the clinic?
  Daniel Hayes, MD, FACP, FASCO, The University of Michigan, Ann Arbor, Michigan
• Clinical utility of pre-treatment for DPYD testing
  Daniel Hertz, PharmD, PhD, The University of Michigan College of Pharmacy, Ann Arbor, Michigan
• Guidelines and diagnostics: Details matter
  Alan Venook, MD, FASCO, The University of California, San Francisco, California

Session 3: FUTURE DIRECTION—WHERE DO WE GO FROM HERE?

Moderator: William Pierce, PharmD, MPH, BCPS, U.S. Food and Drug Administration, Silver Spring, Maryland

• Current State of DPYD genotype testing at Mayo Clinic
  Christina Wu, MB, BCh, MD, Mayo Clinic, Phoenix, Arizona