Sintilimab/Chidamide Combo Shows Activity in Early-Stage ENKTL

Most toxicities emerged from treatment with pegaspargase, gemcitabine, and oxaliplatin, and 2 patients died from disease progression.

The addition of sintilimab (Tyvyt) and chidamide to pegaspargase, gemcitabine, and oxaliplatin (P-GemOx), demonstrated encouraging efficacy in patients with treatment-naïve, early stage extranodal natural killer/T-cell lymphoma (ENKTL), according preliminary results from the phase 2 SCENT-2 trial (NCT04994210) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

After treatment of sintilimab/chidamide in part A of the study, patients (n = 47) achieved an objective response rate (ORR) of 80.8%, of which 63.8% achieved complete response (CR); the partial response (PR), stable disease (SD), and progressive disease (PD) rates were 17.0%, 14.9%, and 4.3%, respectively. Following treatment with P-GemOx in part B, the ORR was 95.7% with 93.6% achieving CR. The respective PR, SD, PD, and not evaluable (NE) rates were 2.1%, 0%, 0%, and 4.3%. After patients were treated with involved-field radiotherapy in part C, the ORR was 95.7%, which were all CRs; the remaining 4.3% were NE.

“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,” 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, said in a presentation at the meeting.

Background and SCENT-2 Trial Design

The prospective, phase 1/2 SCENT trial (NCT03820596) demonstrated the preliminary efficacy of sintilimab/chidamide in the relapsed/refractory setting, where the combination generated favorable progression-free survival (PFS) in patients with relapsed/refractory ENKTL.² The median PFS among patients in the as-treated population was 23.2 months (95% CI, 22.2-53.0); the 36-month PFS was 38.8% (95% CI, 24.2-55.2%).

Sintilimab is an anti–PD-1 antibody, and chidamide is an oral subtype-selective histone deacetylase inhibitor.¹

The phase 2 SCENT-2 study evaluated sintilimab/chidamide followed by P-GemOx in patients with histopathologically confirmed untreated, early-stage ENKTL who were 18 to 80 years of age with at least 1 evaluable or measurable lesion per Lugano 2016 Lymphoma criteria. Patients on the study were also required to have adequate organ and bone marrow function and an ECOG performance status of 0 to 2. Patients were not permitted to be on the study if they had invasive natural killer cell leukemia, hemophagocytic syndrome, central nervous system involvement, or required systemic glucocorticoid therapy or other immunosuppressive therapy for a given condition within 14 days prior to treatment.

In part A of the study, all patients (n = 47) were treated with intravenous sintilimab at 200 mg once every 3 weeks plus oral chidamide at 30 mg twice a week. In part B, patients who achieved CR or PR after receiving sintilimab/chidamide were treated with 2 cycles of P-GemOx, which 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. Those who had SD or PD after sintilimab/chidamide were treated with 4 cycles of P-GemOx at the same dosing levels as patients who achieved CR/PR. Part C of the study treated patients with involved field radiotherapy of at least 50 Gy and at least 25 Df 1 month after part B. Additionally, follow-up comprised a safety visit, survival follow-up, and radiology follow-up.

The primary end point was CR rate in parts A and B; secondary end points included CR rate of part A, duration of CR (DOCR), PFS, overall survival, safety, and exploration of biomarkers for predicting response.

Baseline Patient Characteristics

With a data interval between November 2022 and April 2025, the median age was 43 years (range, 18-80), of which 17.0% were 60 years of age and older, and the majority were male (76.6%). ECOG performance statuses included 0 (55.3%) and 1 (44.7%). Additionally, more than half of patients did not have B-cell symptoms (55.3%). Ann Arbor stages included I (55.3%) and II (44.7%). Serum lactate dehydrogenase levels included normal (66.7%) and elevated (33.3%). Notably, most patients had low PINK-E scores (89.4%) and detectable serum EBV-DNA levels (87.2%).

Additional Efficacy and Safety Data

At a median follow-up of 17.0 months (95% CI, 0.8-29.4), the 1-year PFS rate was 95.7% (95% CI, 83.9%-98.9%), and the 1-year OS rate was 95.3% (95% CI, 82.2%-98.8%). Of note, 1 patient who achieved a CR died due to an intracranial hemorrhage from an accidental fall. Furthermore, the 1-year DFS rate was 97.8% (95% CI, 85.3%-99.7%), and the 1-year DOCR rate was 97.8% (95% CI, 85.3%-99.7%).

Regarding plasma EBV-DNA clearance after sintilimab/chidamide and P-GemOx, 73.3% of patients who achieved CR following sintilimab/chidamide had undetectable plasma EBV-DNA. Moreover, this rate was 90.9% in patients who achieved CR after receiving P-GemOx.

In the total population, adverse effects included leukopenia (all grade, 66.0%; grade 3/4, 14.9%), agranulocytosis (78.7%; 46.8%), anemia (51.1%; 4.2%), thrombocytopenia (46.8%; 10.6%), lymphopenia (72.3%; 34.0%), increased transaminase levels (44.7%; 6.3%), increased amylase/lipase levels (17.0%; 2.1%), increased FT3/4 levels (10.6%; 2.1%), increased creatine levels (12.7%; 2.1%), nausea/vomiting (all grade, 42.6%), fever (19.1%), asthenia (29.8%), rash (6.3%), and peripheral nerve numbness (6.3%). Notably, most toxicities emerged from P-GemOx, and 2 patients died from disease progression.

Disclosures: No disclosures were presented for Huang.

References

1. Huang H, Gao Y, Li X, et al. Sintilimab (anti-PD-1 antibody) combined with chidamide (an oral subtype-selective HDACi) followed by P-GemOx regimen in patients with treatment-naive extranodal natural killer/T cell lymphoma (TN-ENKTL): a multicenter, open-label, single-arm, phase II study (SCENT-2 trial). J Clin Oncol. 2025;43(suppl 16):7006. doi: 10.1200/JCO.2025.43.16_suppl.7006
2. Gao Y, He H, Li X, et al. Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study. Signal Transduct Target Ther. 2024;9(1):121. Published 2024 May 17. doi:10.1038/s41392-024-01825-0