6032 Background: Despite effective local treatment, up to 30% of patients with nasopharyngeal carcinoma (NPC) relapse and require systemic treatment. There are limited therapeutic options beyond cisplatin, gemcitabine and immunotherapy and the median survival of r/m disease is about 20 months. Capecitabine, a fluoropyrimidine, has shown some efficacy with a median time to progression of 4.9 months in heavily pretreated r/m NPC but there is a need for alternative treatments. FTD/TPI is an oral drug combination of trifluridine and tipiracil, a thymidine phosphorylase inhibitor preventing rapid degradation of trifluridine, thus increasing its exposure. It has shown activity in colorectal, gastric and breast cancers despite prior fluoropyrimidines. This study explores the efficacy and safety of FTD/TPI in r/m NPC, with or without prior exposure to fluoropyrimidines. Methods: In this single-arm phase II trial, patients were administered oral FTD/TPI twice daily at 35mg/m2 on days 1-5 and 8-12 of a 28-day cycle. The primary endpoint was disease control rate (DCR) at 12 weeks, with secondary endpoints including progression-free survival (PFS), overall response rate (ORR), safety, and tolerability. Results: A total of 33 patients were recruited. Median age was 56 years (range: 34-82), most were males (n=27, 82%), with median of 3 (range: 1-12) prior lines of treatment in the metastatic setting. Approximately half (48.5%) received prior fluoropyrimidines. DCR at 12 weeks was 63.6%, with an ORR of 18.2%. DCR was 68.8% and 58.8% in patients with and without prior fluoropyrimidine exposure respectively. Median PFS was 6.5 months (95% CI 2.8-10.2) and overall survival was 13.1 months (95% CI 7.1-19.2). FTD/TPI demonstrated a manageable safety profile, with most common treatment-related adverse events of neutropenia, anaemia, fatigue, nausea and anorexia. 60% of patients required dose modifications, most commonly due to neutropenia, that could be overcome by dose reduction or prolongation to 5-weekly cycles. 1 patient required discontinuation due to anaemia resulting in syncope. Conclusions: FTD/TPI is well tolerated, compares favorably to Capecitabine and showed promising anti-tumor activity with meaningful clinical benefit regardless of prior exposure to fluoropyrimidines. This oral chemotherapy offers an attractive choice for patients valuing quality of life, minimizing hospital visits and resource utilization such as chemotherapy infusions. Further investigations in randomized studies are warranted. Clinical trial information: NCT04627961 .