The combination of sintilimab (Tyvyt) and chidamide followed by pegaspargase, gemcitabine, and oxaliplatin (P-GemOx) demonstrated encouraging efficacy in patients with treatment-naïve, early-stage extranodal natural killer/T-cell lymphoma (ENKTL), according to preliminary results from the phase 2 SCENT-2 trial presented at the 2025 American Society of Clinical Oncology Annual Meeting.
The study enrolled 47 patients with histopathologically confirmed untreated, early-stage ENKTL who received treatment in a sequential three-part protocol. After treatment with sintilimab/chidamide in part A, patients achieved an objective response rate (ORR) of 80.8%, with 63.8% achieving complete response (CR). Following P-GemOx treatment in part B, the ORR increased to 95.7% with 93.6% achieving CR.
"Sintilimab/chidamide with P-GemOx might be a promising novel chemotherapy-reduced combination therapy with manageable toxicities for this population, and [it] may be an effective induction regimen for treatment-naive [patients with] ENKTCL," said lead study author Huiqiang Huang, MD, PhD, professor and deputy director of the Medical Oncology Department at Sun Yat-sen University Cancer Center in Guangzhou, China.
Trial Design and Treatment Protocol
The phase 2 SCENT-2 study evaluated a sequential treatment approach in patients aged 18 to 80 years with at least one evaluable or measurable lesion per Lugano 2016 Lymphoma criteria. Patients were required to have adequate organ and bone marrow function and an ECOG performance status of 0 to 2.
In part A, all 47 patients received intravenous sintilimab at 200 mg once every 3 weeks plus oral chidamide at 30 mg twice a week. Sintilimab is an anti-PD-1 antibody, while chidamide is an oral subtype-selective histone deacetylase inhibitor.
Part B treatment was tailored based on response to the initial combination. Patients who achieved CR or partial response (PR) after sintilimab/chidamide received 2 cycles of P-GemOx, while those with stable disease or progressive disease received 4 cycles. The P-GemOx regimen comprised pegaspargase at 2000 U/m² on day 1, gemcitabine at 1000 mg/m² on days 1 and 8, and oxaliplatin at 130 mg/m² on day 1.
Part C involved involved-field radiotherapy of at least 50 Gy administered one month after part B completion.
Patient Population and Baseline Characteristics
The study population had a median age of 43 years (range 18-80), with 17.0% of patients aged 60 years or older and 76.6% being male. Most patients had ECOG performance status 0 (55.3%) or 1 (44.7%), and 55.3% did not have B-cell symptoms. Ann Arbor stages were evenly distributed between stage I (55.3%) and stage II (44.7%).
Notably, most patients had low PINK-E scores (89.4%) and detectable serum EBV-DNA levels (87.2%). Serum lactate dehydrogenase levels were normal in 66.7% of patients and elevated in 33.3%.
Survival Outcomes and Biomarker Analysis
At a median follow-up of 17.0 months (95% CI, 0.8-29.4), the treatment demonstrated excellent survival outcomes. The 1-year progression-free survival rate was 95.7% (95% CI, 83.9%-98.9%), and the 1-year overall survival rate was 95.3% (95% CI, 82.2%-98.8%). The 1-year disease-free survival rate was 97.8% (95% CI, 85.3%-99.7%), and the 1-year duration of complete response rate was 97.8% (95% CI, 85.3%-99.7%).
One patient who achieved CR died due to an intracranial hemorrhage from an accidental fall, and two patients died from disease progression.
Plasma EBV-DNA clearance served as an important biomarker, with 73.3% of patients who achieved CR following sintilimab/chidamide having undetectable plasma EBV-DNA. This rate increased to 90.9% in patients who achieved CR after receiving P-GemOx.
Safety Profile
The treatment combination demonstrated a manageable safety profile, with most toxicities attributed to the P-GemOx component. Common adverse effects included agranulocytosis (all grade 78.7%; grade 3/4 46.8%), lymphopenia (72.3%; 34.0%), leukopenia (66.0%; 14.9%), anemia (51.1%; 4.2%), and thrombocytopenia (46.8%; 10.6%).
Non-hematologic toxicities included increased transaminase levels (44.7%; 6.3%), nausea/vomiting (42.6%), asthenia (29.8%), fever (19.1%), increased amylase/lipase levels (17.0%; 2.1%), increased creatine levels (12.7%; 2.1%), increased FT3/4 levels (10.6%; 2.1%), rash (6.3%), and peripheral nerve numbness (6.3%).
Clinical Context
The SCENT-2 trial builds upon the earlier phase 1/2 SCENT trial, which demonstrated preliminary efficacy of sintilimab/chidamide in the relapsed/refractory ENKTL setting. In that study, the combination generated a median progression-free survival of 23.2 months (95% CI, 22.2-53.0) with a 36-month PFS of 38.8% (95% CI, 24.2-55.2%) in the as-treated population.
The current results suggest that this immunotherapy-based approach may offer a chemotherapy-reduced treatment option for patients with early-stage ENKTL, potentially improving outcomes while maintaining manageable toxicity profiles in this rare but aggressive lymphoma subtype.
