Dr Cohen on Frontline Chemotherapy Selection in Metastatic Pancreatic Cancer

“In 2026, we still do not have the perfect answer or biomarker for selecting a frontline [treatment] regimen, outside of homologous recombination deficiency or DNA damage response alterations... where we know that patients derive more benefit from a platinum-containing regimen.”

Deirdre J. Cohen, MD, MS, the director of the Gastrointestinal Oncology Program for the Mount Sinai Health System, an associate professor of medicine (Hematology and Medical Oncology), and the medical director of the Cancer Clinical Trials Office at The Tisch Cancer Institute, discussed factors informing therapeutic selection for patients with metastatic pancreatic cancer in the front line.

Until early 2024, the frontline standard of care was primarily limited to modified FOLFIRINOX (leucovorin, fluorouracil [5-FU], irinotecan, and oxaliplatin) and the doublet of gemcitabine plus nab-paclitaxel (Abraxane). This paradigm shifted in February 2024 with the FDA approval of NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-FU, and leucovorin) based on data from the phase 3 NAPOLI 3 trial (NCT04083235).

Established level 1 evidence shows NALIRIFOX has superior efficacy compared with gemcitabine plus nab-paclitaxel; however, because there is no level 1 evidence comparing NALIRIFOX with FOLFIRINOX, it remains unclear if one regimen is inherently superior to the other, Cohen noted.

In the absence of a “perfect answer” or universal biomarker, Cohen explained that treatment selection often relies on specific genetic alterations. Patients with homologous recombination deficiency or DNA damage response alterations—such as mutations in BRCA or PALB2—typically derive greater benefit from platinum-containing regimens. Beyond these markers, the clinical data must be weighed alongside patient preferences regarding logistics, delivery schedules, and potential toxicities, she stated.

Comorbidities and performance status are also critical factors in this decision-making process, Cohen added. For patients with a good performance status, Cohen generally leans toward prescribing FOLFIRINOX. Conversely, NALIRIFOX may be the preferred choice for patients where there is a significant concern regarding pre-existing peripheral neuropathy, she asserted. Ultimately, the choice between these intensive regimens requires a nuanced discussion between the oncologist and the patient to align the therapy with the individual's clinical needs, Cohen concluded.