Pegylated granulocyte colony-stimulating factor primary prophylaxis versus no prophylaxis in patients with unresectable pancreatic cancer treated with modified-FOLFIRINOX: a randomized, open-label, multicenter, phase 2 trial.

Background: FOLFIRINOX treatment for pancreatic cancer often causes severe neutropenia, leading to dose reductions and potentially fatal outcomes. Despite this, high-level evidence supporting pegylated granulocyte colony-stimulating factor (peg-GCSF) as the primary prophylaxis is lacking. This study aimed to determine whether primary prophylaxis of peg-GCSF can prevent severe neutropenia in patients with pancreatic cancer treated with modified-(m)FOLFIRINOX. Methods: This was an investigator-initiated, open-label, multi-institutional, randomized phase 2 trial in patients aged ≥19 years with treatment-naïve locally advanced or metastatic pancreatic cancer. Patients received oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, and fluorouracil 2400 mg/m2 via continuous infusion, every other week. After 1:1 randomization, peg-GCSF (pegteograstim 6 mg, GC Biopharma Corp.) was subcutaneously administered on day 4 for the initial eight cycles for the primary prophylaxis group, whereas no G-CSF was given to the control group. Crossover to administering peg-GCSF was permitted if patients in the control group developed grade 3-4 neutropenia during the initial eight cycles. Co-primary endpoints were grade 3-4 neutropenia or febrile neutropenia within the first eight cycles. Secondary endpoints included survival, relative dose intensity, patient-reported quality of life (QOL), and bone pain. This trial is registered with the CRIS (KCT0006536) and ClinicalTrials.gov (NCT06353581). Findings: Seventy-seven patients were enrolled from February 2022 to January 2024, with 38 in the peg-GCSF primary prophylaxis group and 39 in the control group. The primary endpoints were achieved, with significantly lower grade 3-4 neutropenia in the peg-GCSF group (2.6% vs. 38.5%, P = 0.0001) compared to the control group, and febrile neutropenia occurring only in controls (12.8%). With a median follow-up duration of 19.7 months, survival outcomes favored peg-GCSF, although not statistically significant. The adjusted mean change of global health status or QOL scores were significantly higher for the peg-GCSF primary prophylaxis group than for the control group (P = 0.0264), without an increase in reported bone pain. Survival, QOL, and bone pain were secondary endpoints. Interpretation: Peg-GCSF primary prophylaxis significantly reduced grade 3-4 neutropenia and febrile neutropenia in patients with locally advanced or metastatic pancreatic cancer treated with mFOLFIRINOX. Peg-GCSF primary prophylaxis also provided a numerical survival benefit with better patient-reported QOL. This study provides a rationale for peg-GCSF primary prophylaxis in patients with pancreatic cancer treated with mFOLFIRINOX. Funding: GC Biopharma Corp.; Severance Hospital Research Fund for Clinical Excellence; National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT).