FOLFIRINOX Significantly Improves PFS Over Gemcitabine in Locally Advanced Pancreatic Carcinoma

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Fluorouracil plus oxaliplatin and irinotecan (FOLFIRINOX) significantly improved progression-free survival (PFS) over gemcitabine alone and had favorable tolerability in patients with locally advanced pancreatic cancer (LAPC), according to data from the phase 3 PRODIGE 29-UCGI 26 (NEOPAN) trial (NCT02539537) published in the Journal of Clinical Oncology.1

At a median follow-up of 59.6 months (IQR, 42.3-not reached), the median PFS was 9.7 months (95% CI, 7.0-11.7) with FOLFIRINOX (n = 85) vs 7.7 months (95% CI, 6.2-9.2) with gemcitabine (n = 86; HR, 0.66; 95% CI, 0.46-0.95; stratified log-rank P = .02). The 12-month PFS rate in the FOLFIRINOX arm was 36.5; at 24 and 36 months, these respective rates were 5.9% and 3.5%; the 12-, 24-, and 36-month PFS rates in the gemcitabine-alone arm were 17.4%, 3.5%, and 1.2%, respectively.

No significant difference in overall survival (OS) was observed between the treatment arms. The median OS with FOLFIRINOX was 15.7 months (95% CI, 11.9-20.4) vs 15.4 months (95% CI, 11.7-18.6) with gemcitabine (HR, 1.00; 95% CI, 0.69-1.44; stratified log-rank P = .99). With FOLFIRINOX, the 12-, 24-, and 36-month OS rates were 61.2%, 27.1%, and 11.8%, respectively; with gemcitabine, these respective rates were 60.5%, 26.1%, and 12.3%.

FOLFIRINOX elicited a higher objective response rate (ORR) than that of gemcitabine alone, at 42.4% (95% CI, 31.7%-53.6%) and 15.1% (95% CI, 8.3%-24.5%), respectively.

“The fact that this study showed a significant difference in primary end point and the [ORR] suggests that FOLFIRINOX should be considered as a standard of care for LAPC in fit patients,” Michel Ducreux, MD, PhD, of Gustave Roussy Cancer Center, Tumor Cells Dynamics, INSERM U1279, Universite ́ Paris-Saclay, in Villejuif, France, wrote in the paper. “The absence of a clear difference in OS suggests that an initial advantage provided by a more intensive treatment may be made up secondarily, making it possible to consider a milder treatment such as gemcitabine monotherapy in patients whose general condition is initially more impaired and who may subsequently receive FOLFIRINOX if they become metastatic.”

Previewing PRODIGE 29-UCGI 26 (NEOPAN): Eligibility, Treatment, End Points

The multicenter, randomized, phase 3 study enrolled patients with cytologically or histologically confirmed LAPC who did not have prior exposure to chemotherapy. Patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, and acceptable bone marrow, liver, renal, and cardiac function. Those with symptomatic cerebral metastases, active infection, a history of another cancer treated during the 5 preceding years except cutaneous basal dermatologic cancer or in situ cervix cancer, or severe chronic diarrhea were excluded.

Within 1 week of enrollment, participants were randomized 1:1 to receive FOLFIRINOX or gemcitabine alone. Those in the gemcitabine arm received the agent at a dose of 1,000 mg/m2 of body surface area once weekly for 7 weeks, followed by a 1-week rest, then once weekly for 3 weeks in subsequent 4-week cycles. Those in the FOLFIRINOX arm received oxaliplatin at a dose of 85 mg/m2, immediately followed by leucovorin at 400 mg/m2 plus irinotecan at 180 mg/m2. This treatment was followed by a continuous infusion of FU at 2400 mg/m2 over a 46-hour period once every 2 weeks.

Stratification factors included center, tumor localization (head vs body or tail of the pancreas), ECOG performance status (0 vs 1), and age (≤60 years vs >60 years).

The trial’s primary efficacy end point was PFS, and secondary end points included OS, safety, and quality of life (QOL).

“Demographic and baseline disease characteristics of the patients were similar in the two treatment groups,” the study authors wrote.

After receipt of treatment, 4 patients in the gemcitabine-alone arm and 5 in the FOLFIRINOX arm underwent surgery; 4.7% (95% CI, 1.3%-11.0%) and 5.9% (95% CI, 1.9%-13.0%) of patients in the respective arms experienced a pathologist-confirmed R0 resection of their tumor. Stereotactic radiotherapy was given to 5% and 6% of those in the gemcitabine and FOLFIRINOX arms, respectively; chemotherapy was given to 19% and 27% of patients, respectively. Maintenance chemotherapy was given to 17% and 21% of patients, respectively. Second-line chemotherapy was given to 64% of those in the gemcitabine arm and 77% of those in the FOLFIRINOX arm.

Safety Spotlight

In the FOLFIRINOX arm, the most common adverse effects (AEs) were thrombocytopenia (grade 1, 55%; grade 2, 10%; grade 3/4, 6%), anemia (51%; 21%; 5%), diarrhea (43%; 19%; 18%), nausea (27%; 35%; 12%), fatigue (26%; 35%; 18%), vomiting (20%; 21%; 12%), neutropenia (12%; 21%; 13%), fever (10%; 5%; 2%), and febrile neutropenia (1%; 1%; 2%).

Seven patients in the gemcitabine-alone arm died from causes related to treatment vs 1 in the FOLFIRINOX arm. AEs led to treatment discontinuation for 8% and 7% of patients, respectively.

Top Takeaway

“FOLFIRINOX significantly increased the PFS of patients with LAPC compared with the group treated with gemcitabine alone. PFS, the main end point of this study, was achieved with a clinically relevant difference of 2 months between the medians,” the study authors wrote. “However, there was no difference in OS, probably due to a large crossover, as patients treated in a locally advanced setting could receive FOLFIRINOX in the event of local and/or systemic progression.”

Associate editor of JCO, Eileen M. O’Reilly, MD, FASCO, added: “The results of the NEOPAN randomized phase 3 trial endorse the superiority of FOLFIRINOX over gemcitabine in LAPC, and these data are in line with outcomes in other disease settings. Next steps are moving beyond cytotoxic therapy including the integration of KRAS targeted therapy and late-stage trials are underway.”

Disclosures: Dr Ducreux disclosed employment with Sandoz. He received honoraria from Bayer, TERUMO, Pierre Fabre, and Roche/Genentech. He serves in a consulting or advisory role for Roche, Merck Serono, Servier, Amgen, Novartis, Ipsen, Lilly, Pierre Fabre, HalioDx, Daiichi Sankyo/Astra Zeneca, AstraZeneca, Basilea, Bayer, GlaxoSmithKline, MSD, Rafael Pharmaceuticals, Sotio, Zymeworks, Astellas Pharma, Abcely, Scandion Oncology, and AbbVie (Inst). He is on the Speakers’ Bureau for Roche, Merck KGaA, Bayer, Servier, Amgen, Pierre Fabre, AstraZeneca, HalioDx, GlaxoSmithKline, Lilly, and MSD. Research funding was received from Roche (Inst) and Keocyt (Inst). Travel, accomodations, and expenses were provided by Roche, Merck Serono, Bayer, Pierre Fabre, and Servier.

Reference

Ducreux M, Desgrippes R, Rinaldi Y, et al. PRODIGE 29-UCGI 26 (NEOPAN): a phase III randomized trial comparing chemotherapy with FOLFIRINOX or gemcitabine in locally advanced pancreatic carcinoma. J Clin Oncol. Published online May 16, 2025. doi:10.1200/JCO-24-02210