Novel highly effective and low-toxicity combination therapy for localized extranodal natural-killer/T-cell lymphoma (ENKTL) remains a clinically unmet need. This phase II trial (NCT03936452) investigated the efficacy and safety of sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy as first-line treatment in patients with newly-diagnosed stage I-II ENKTL. The patients received sintilimab 200 mg plus pegaspargase 2500 U/m2 on day 1 and anlotinib 12 mg once daily on days 1-14 for three 21-day cycles, followed by intensity-modulated radiotherapy and another three cycles of systemic therapy. The primary endpoint was the complete response rate (CRR) after six treatment cycles. The secondary endpoints included progression-free survival (PFS), overall survival (OS), CRR after two cycles, overall response rate (ORR) after six cycles, duration of response (DOR), and safety. Between May 2019 and July 2021, 58 patients were enrolled. The CRR was 55.1% (27/49) after two cycles and 87.8% (43/49) after six cycles. The ORR was 87.8% (43/49; 95% CI, 75.2-95.4) after six cycles. After a median follow-up of 22.5 months (95% CI, 20.4-24.6), the median PFS, OS, and DOR were not reached. The 2-year PFS, OS, and DOR rates were 87.6% (95% CI, 78.8-97.4), 97.9% (95% CI, 94.0-100), and 91.1% (95% CI, 83.2-99.8), respectively. Grade 3-4 treatment-related adverse events occurred in 41.4% (24/58) of patients, with the most common being hypertension (15.5%), hypertriglyceridemia (8.6%), oral mucositis (6.9%), and anemia (5.2%). No treatment-related deaths occurred. First-line sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy demonstrated promising efficacy in treatment-naïve early-stage ENKTL patients with a favorable safety profile.
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