Despite advances in systemic therapy, metastatic pancreatic cancer (mPC) remains one of the most lethal malignancies. Current frontline regimens, including FOLFIRINOX and gemcitabine plus nab-paclitaxel, provide limited long-term benefit, and there is no established standard of care for patients whose disease progresses after multiple lines of chemotherapy. To address this unmet need, we conducted a prospective phase II study to assess the therapeutic potential of combining TAS-102 (trifluridine/tipiracil) with the multi-target tyrosine kinase inhibitor surufatinib in patients with heavily pretreated mPC. Patients with mPC who had experienced disease progression following at least two prior systemic treatment regimens were enrolled. Participants received oral TAS-102 at 35 mg/m² twice daily on days 1–5 and 8–12, along with continuous daily surufatinib at 250 mg, in repeating 28-day cycles. Radiographic evaluations were performed at 8-week intervals. Treatment was maintained until objective disease progression, unacceptable adverse effects, clinical decision to discontinue, or patient withdrawal. Clinical outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related toxicity. Between January 2023 and June 2024, 22 patients were enrolled, of whom 20 were evaluable for efficacy. The median PFS achieved with the combination therapy was 2.35 months (95% CI, 1.91–3.94), while the median OS was 6.34 months (95% CI, 3.81–10.09). Tumor shrinkage meeting criteria for partial response was observed in four patients, yielding an ORR of 20%, and disease stabilization or response was achieved in 30% of patients overall. All participants experienced at least one treatment-emergent adverse event, with hematologic toxicities predominating. The most frequently reported events included anemia, neutropenia, leukocytopenia, and lymphocytopenia. Severe (grade ≥3) adverse events occurred in half of the cohort, most commonly neutropenia. Exploratory subgroup analyses indicated reduced clinical benefit in patients with liver metastases or dissemination to more than two organ sites. Proteomic profiling identified elevated expression of OCIAD2 as a marker of poor clinical outcome, a result that was independently corroborated using data from the CPTAC and RuiJin cohorts. In this prospective study, the combination of TAS-102 and surufatinib exhibited measurable antitumor activity and an acceptable safety profile in patients with metastatic pancreatic cancer who had exhausted standard treatment options. The identification of clinical and proteomic correlates of outcome suggests potential avenues for patient selection and personalized therapy, which warrant confirmation in larger studies. This trial was registered at ClinicalTrials.gov (NCT05481463).
