Second-Line Systemic Therapy Following First-Line FOLFIRINOX or NALIRIFOX in Metastatic Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis.

PURPOSE: FOLFIRINOX and NALIRIFOX are now preferred first-line treatments for metastatic pancreatic ductal adenocarcinoma (mPDAC), yet optimal second-line therapy after frontline triplet chemotherapy remains unclear. Prior evidence largely addressed second-line treatment after gemcitabine-based first-line therapy, limiting relevance today. We conducted the first contemporary systematic review and meta-analysis of second-line therapy after frontline triplet chemotherapy.

METHODS

We searched MEDLINE, Embase, CINAHL, and PsycINFO through January 2026 for studies of second-line therapy after first-line FOLFIRINOX/NALIRIFOX in adults with advanced/metastatic PDAC. Two reviewers independently selected studies, extracted data, and assessed quality (ROBINS-I or RoB 2). Random-effects meta-analyses pooled median overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Registered in PROSPERO (CRD420251276176) per PRISMA 2020 guidelines.

RESULTS

Twenty-three studies (3888 patients) met inclusion criteria, mostly retrospective cohorts after first-line FOLFIRINOX. Pooled median OS from second-line initiation was 7.57 months (95% CI, 6.00-9.55); pooled median PFS was 3.18 months (95% CI, 2.74-3.68). Pooled ORR was 11.6%; pooled DCR was 47.8%. Combination gemcitabine-based regimens outperformed monotherapy, particularly with ECOG 0-1. The only randomized phase-III trial (GEMPAX) showed significantly improved PFS and ORR with gemcitabine plus paclitaxel versus gemcitabine alone, without significant OS benefit. ECOG performance status was the strongest outcome predictor.

CONCLUSION

This first contemporary synthesis of post-triplet second-line therapy in mPDAC shows meaningful benefit in carefully selected, fit patients. Gemcitabine-based combination therapy is a reasonable option for ECOG 0-1 patients, though treatment should remain individualized based on performance status, toxicity, and preference. These findings provide contemporary benchmarks for practice and future trials.