A PHASE II TRIAL OF PEMBROLIZUMAB CONCURRENT WITH RADIOTHERAPY FOR FRAIL PATIENTS WITH NEWLY DIAGNOSED EARLY-STAGE NATURAL KILLER/T-CELL LYMPHOMA (IELSG50)

H. Zhong, C. Chen, S. Cheng, G. Cai, P. Sun, P. Liu Z. Li, and W. Zhao equally contributing authors.

Introduction: Natural killer/T-cell lymphoma (NKTCL) is highly aggressive and characterized by Epstein-Barr virus (EBV) infection and overexpression of immune checkpoints. The therapeutic options were limited for patients unsuitable for chemotherapy. Immune checkpoint inhibitors have been shown effective in refractory and relapsed NKTCL. This study aims to investigate the efficacy and safety of programmed death 1 (PD-1) antibody pembrolizumab concurrent with radiotherapy as a first-line treatment in newly diagnosed early-stage frail NKTCL patients.

Methods: This is a multicenter phase II study. Eligible patients met the following criteria: (1) age ≥ 18 years; (2) newly diagnosed NKTCL with Ann Arbor stage I-II disease; (3) presence of at least one risk factor (age > 60 years, elevated serum lactate dehydrogenase, Ann Arbor stage II or primary tumor invasion); (4) unsuitable for systemic chemotherapy. All patients received induction treatment with pembrolizumab (200 mg intravenously on day 1 in each 21-day cycle for 6 cycles) concurrently with radiotherapy (a total dose of 50–54 Gy). The patients achieved complete remission (CR), partial remission (PR), or stable disease (SD) have been given pembrolizumab 200 mg every 21 days as a maintenance up to 2 years. The primary endpoint was 2-year progression-free survival (PFS) rate. The main secondary endpoints included CR rate (CRR), overall response rate (ORR), adverse events and plasma EBV DNA change.

Results: From August 2020 to January 2025, a total of 30 patients with median age of 62 (20–74) years were enrolled in Shanghai Ruijin Hospital and Guangzhou Sun Yat Sen University Cancer Center. All patients were intermediate (60%, n = 18) and high (40%, n = 12) risk according to nomogram-revised risk index. Until February 2025, 62.5% CRR (95% CI: 40.6%–81.2%) and 91.7% ORR (95% CI: 73.0%–99.0%) have been achieved in twenty-four evaluable patients after induction treatment. With median follow-up time of 10.2 months (not yet mature for the analysis of the primary endpoint), the best CRR and ORR were 83.3% (95% CI: 62.6%–95.3%) and 91.7% (95% CI: 73.0%%–99.0%), respectively (Figure). The responses improved with the increase of cycles. The most common adverse events were lymphocytopenia, leukopenia, oral mucositis, radiodermatitis and dry mouth. Grade 3/4 adverse events were low, including lymphocytopenia (16.6%) and oral mucositis (13.3%). The treatment was well-tolerated. Among patients who were EBV DNA positive before treatment, 70% achieved EBV DNA negativity following induction therapy.

Conclusion: Pembrolizumab concurrent with radiotherapy was effective and safe in newly diagnosed early-stage frail NKTCL patients, even in those with intermediate or high risk. Immune checkpoint inhibitors could be applied as first-line alternative therapeutic approach in early-stage NKTCL.

Research funding declaration: The research was funded by MSD.

Keywords: non-Hodgkin; combination therapies

Potential sources of conflict of interest:

E. Zucca

Consultant or advisory role: AbbVie, BeiGene, BMS, Curis, Eli/Lilly, Incyte, Ipsen, Merck, Roche, Sobi

Honoraria: Medical educational event Abbvie

Educational grants: AstraZeneca, BeiGene, Janssen, and Gilead

Other remuneration: research support (Institution) from AstraZeneca, Beigene, Celgene/BMS, Incyte, Janssen, and Roche