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e18029 Background: Patients with recurrent or metastatic nasopharyngeal cancer (R/M NPC) who failed platinum-based chemotherapy have poor prognoses. We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor (TGF)-βRII receptor fused to a human IgG1 antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated R/M NPC. Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Methods: Eligible patients had histologically confirmed NPC that had recurred at distant sites and were not amenable to curative treatment. All patients received at least one prior line of platinum-based chemotherapy for recurrent disease. Patients were treated with bintrafusp alfa (1200mg every 2 weeks) until disease progression. The sample size was estimated to assume a 40% objective response rate (ORR) to bintrafusp alfa compared with 20% for checkpoint inhibitors. Modified Simon two-stage optimal design was used (power, 80%; a = 0.05; P0 = 0.20; P1 = 0.40; n1 = 18; n = 33 with an additional five patients to allow for ineligibility or other reasons). The primary endpoint was ORR and secondary endpoints included survival and toxicity. Expression of PD-L1 in archived tumors, plasma clearance of Epstein-Barr virus (EBV) DNA, plasma clearance of TGF-β, and exosomal PD-L1 were assessed for a potential correlation with ORR. (NCT 04396886). Results: Out of 43 patients screened, 38 patients were enrolled. After a median follow-up of 14.9 months (range: 1.6-23.3 months), the confirmed ORR was 23.7% (95% CI: 12.4-38.8%) (complete response, n = 1; partial response, n = 8). The median treatment duration was 1.8 months (range: 0.5-14.3 months). 8 patients (21.1%) and 2 patients (5.3%) received bintrafusp alfa for > 6 months and > 12 months respectively. The 1-year overall survival (OS) rate was 57.5% (95% CI, 40.2% to 71.5%) and 1-year progression-free survival rate was 23% (95% CI, 10.1% to 39.4%). ORR was higher in patients with a decreasing trend in EBV-DNA at week 4 (40% vs. 6.3%, p = 0.02), whereas high exosomal PD-L1 levels at week 4 were predictive of worse ORR (5.3% vs. 41.7%, p = 0.012). There were no associations between clinical outcome and tissue PD-L1 expression (p = 0.952) or plasma TGF-β clearance (p = 0.28). 16 patients (42.4%) experienced ≥ grade 3 treatment-related adverse events, most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). Conclusions: Bintrafusp alfa has promising activity in heavily pretreated R/M NPC and a favorable 1-year OS rate, though the observed activity was not as high as the study initially aimed. The biomarker results warrant validation in larger cohorts. Clinical trial information: NCT04396886.