Background: Stage IVA NPC had the worst prognosis despite the current standard of neoadjuvant chemotherapy and concurrent chemoradiation (CRT). There is no safety and efficacy data combining immune checkpoint inhibitor (ICI) and CRT in NPC. Methods: We conducted an open label, single arm, multi-site, phase 2 clinical trial in AJCC 8th Edition Stage IVA (T4 and/or N3, M0) WHO type 2/3 Epstein Barr virus (EBV) +ve NPC (Clinical trial register NCT03734809). The experimental treatment consisted of neoadjuvant pembrolizumab (200 mg D1), gemcitabine (1000 mg/m2 D1+8) and cisplatin (80 mg/m2 D1) q3w x2 followed by concurrent pembrolizumab (200 mg x3 week 1, 4 and 7) and cisplatin (40 mg/m2 weekly x7) during intensity-modulated radiation (IMRT), and maintenance pembrolizumab 200 mg q3w x12 from 4 weeks post-RT. By Fleming one-stage design (type I error 0.05, power 0.80, 10% drop out), planned sample size is 46. Primary endpoint is 2-year (yr) progression free survival (PFS). Secondary endpoints include safety and tolerability. Plasma EBV DNA (pEBV DNA) was monitored. Results: Accrual was completed with 46 subjects recruited at two study sites from May 2019 to June 2022 in Hong Kong (n=31) and Singapore (n=15). This protocol specified analysis included 37 subjects with >12 months post-treatment follow up (median 26.8 months, 95% CI 21.3-32.9). Patient demographics: mean age 52 (range 27 - 84); M:F 31:6; ECOG 0=23, 1=14; stages: T4N1-2 (16), T1-3N3 (18), T4N3 (3). Overall compliance rate: neoadjuvant cisplatin 98.6%, gemcitabine 97.7%, concurrent cisplatin 73.7%, pembrolizumab 100% (neoadjuvant), 77.5% (concurrent), 77% (maintenance), IMRT 99.7% (69.96 Gy). Treatment related adverse events (≥ grade 3, >10%): dysphagia (32.4%), mucositis (29.7%), neutropenia (29.7%), radiation dermatitis (24.3%), anemia (18.9%), hyponatremia (13.5%), thrombocytopenia (10.8%). No ≥ grade 4 mucositis/dermatitis. The 2-yr PFS was 69.6% (95% CI 53.8 - 88.5%). At the end of neoadjuvant, CRT and maintenance phases, molecular remission (pEBV DNA = 0) was achieved in 24.3%, 70.3% and 70.3% of patients respectively, which strongly correlated with PFS (p=0.0253, 0.0007 and <0.0001 respectively, Table). Conclusions: Pembrolizumab incorporated into neoadjuvant, CRT and maintenance protocol is safe with promising results. This strategy of combining ICI with neoadjuvant chemotherapy and CRT is being tested in several ongoing phase 3 trials in advanced NPC. Clinical trial information: NCT03734809.