Integrated NAL-IRI/5-FU/LV, benmelstobart, anlotinib with or without immunoradiotherapy for second-line metastatic pancreatic cancer: A phase II dual-cohort study.

Abstract

e16374 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is an immune cold tumor characterized by stromal and vascular barriers that limit the efficacy of immunotherapy alone. This study evaluated an integrated regimen combining cytotoxic chemotherapy (NAL-IRI/5-FU/LV), anti-angiogenesis (anlotinib), and PD-L1 inhibition (benmelstobart), with or without stereotactic body radiation therapy (SBRT) for second-line treatment of mPDAC (NCT06662006). Methods: This investigator initiated, prospective, open label, non-randomized phase II study enrolled patients (aged 18–75, ECOG PS ≤2) with confirmed mPDAC who progressed after first line therapy. All patients received liposomal irinotecan 50 mg/m² IV (D1,15), leucovorin 400 mg/m² IV (D1,15), 5-FU 2.4 g/m² 46 h infusion (D1,15) in 28 day cycles, plus benmelstobart 1200 mg IV Q3W and anlotinib 12 mg PO (D1–14) Q3W. Patients were assigned to one of two cohorts based on metastatic patterns: Cohort A ( > 5 dispersed metastases) received systemic therapy only; Cohort B (≤5 lesions and/or clustered metastases) received systemic therapy combined with SBRT (24 Gy in 3 fractions within 3–7 days). The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Results: From March 2024 to December 2025, 46 patients were enrolled (Cohort A: n = 26; Cohort B: n = 20). With a median follow up of 5.9 months, 36 patients had at least one efficacy evaluation: 23 in Cohort A and 13 in Cohort B. The overall ORR was 25.0% (95% CI: 10.9–39.1%), with rates of 17.4% (95% CI: 1.9–32.9%) in Cohort A and 38.5% (95% CI: 12.0–64.9%) in Cohort B. The overall DCR was 69.4% (95% CI, 54.4–84.5%) and differed significantly between cohorts, with a higher DCR in Cohort B than in Cohort A (92.3% [95% CI, 77.8–100%] vs. 56.5% [95% CI, 36.3–76.8%]; P = 0.031). The mPFS was 4.7 mo (95% CI: 3.9–5.4) overall, with 4.3 mo (95% CI: 3.3–5.4) in Cohort A and 7.1 mo (95% CI: 4.0–10.2) in Cohort B. Correspondingly, the overall 6-month PFS rate was 35.5% (95% CI: 18.6–52.3%), with rates of 27.3% (95% CI: 8.7–45.9%) and 55.6% (95% CI: 23.1–88.0%) in Cohorts A and B. OS data were immature at cutoff. Grade ≥3 treatment related adverse events occurred in 30.4% of patients (14/46), with grade 4 events in 4.3% (2/46). Toxicities were predominantly hematologic, and no unexpected safety signals emerged. Conclusions: The combination of NAL-IRI/5-FU/LV, benmelstobart, and anlotinib showed manageable toxicity and promising efficacy in second-line mPDAC. The addition of SBRT in patients with limited or clustered metastases significantly improved disease control and provided sustained PFS benefit. These results support a precision approach integrating SBRT for oligometastatic-like disease in mPDAC, warranting further randomized validation. Clinical trial information: NCT06662006 .