PD-1 Antibody (Sintilimab) Plus Histone Deacetylase Inhibitor (Chidamide) for the Treatment of Refractory or Relapsed Extranodal Natural Killer/T Cell Lymphoma, Nasal Type (r/r ENKTL): Updates of the Phase Ib/II Scent Study
Authors: Yan Gao , Zhang Liling , Li Wenyu , Wei Xu , Feng Ru , Li Xue-Ping , Chen Yu , Wu Huijing , Wang Xiaoxiao , Bai Bing , Huang Huiqiang 
Published: December 2023

Background
Extranodal natural killer/T-cell lymphoma (ENKTL) is a highly aggressive of non-Hodgkin's lymphoma (NHL) closely related to Epstein-Barr virus (EBV), with a higher incidence in Asia than in Europe and North America. Patients with r/r ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-programmed death 1 (anti-PD-1) antibody monotherapy represented a favorable treatment for the patients with rr-ENKTL. ORIENT-4 trial demonstrated sintilimab(anti-PD-1antibody ) was effective and well tolerated in r/r ENKTL. The efficacy of chidamide monotherapy, an oral subtype-selective histone deacetylase inhibitor (HDACi) was reported on the patients with rr-ENKTL . Moreover, accumulating evidences have shown the synergism between epigenetic modulator and PD-1 antibody. In 2020 ASH meeting, we reported the preliminary results of sintilimab plus chidamide (SC) for treatment of r/r ENKTL orally. This report is an update of this trial with cumulative data of approximately 40 months.
Methods
This multicenter, single-arm, phase Ib/II clinical trial enrolled eligible patients with histologically confirmed r/r-ENKTL failing from asparaginase-based regimen. This study consisted of a Phase Ib (dose escalation) portion followed by a Phase II expansion portion. In the Phase Ib escalation portion, a standard “3+3” design was utilized to identify the maximum tolerated dose (MTD), dose limited toxicity (DLT) and recommended Phase II dosage (RP2D) of chidamide. Patients received oral escalating doses of chidamide (20, 25, 30 mg) twice a week and 200 mg of sintilimab intravenously every 3 weeks. In the phase II expansion portion, patients received six cycles of SC every 3 weeks. Patients with complete response (CR) or partial response (PR) received SC every 3 weeks for up to 1 year, until disease progression, intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIL 2017criteria. Key secondary endpoints included time to response (TTR), duration of response (DOR) and progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). This trial was registered at ClinicalTrials.gov (NCT 03820596).
Results
From March 2019 to May 2020, 41 patients were screened, and 37 eligible patients were enrolled. Overall, median age 48 years (range, 20-72), 26 (70.3%) patients with Stage IV, 20 (54.1%) patients with PINK-E score ≥ 3 points, 16 (43.2%) patients received ≥ 2 lines of prior systemic therapy. RP2D of chidamide was 30 mg twice a week. Of 36 response evaluable patients, 21 patients (58.3%) achieved an objective response including 16 (44.4%) patients with CR. The median time to initial response was 6.0 weeks (range, 5.0 to12.4). Cut-off data was July 28, 2023. The median cycles of SC were 6 (range, 2 to 44). Median follow-up time of whole cohort was 38.3 (range, 0.9 to 51.5; Interquartile range [IQR] range 8.5 to 46.3) months, 3-year OS rate was 56% (95% CI: 0.44-0.75, Figure 1 A), median PFS was 23.4 months (Figure 1 B). Twenty-one patients still alive, median follow-up time for this group was 44.9 (IQR 43.2 to 49.3) months. Estimated 4-year PFS rate was 76% (95% CI: 0.51-0.89, Figure 1 C). Median follow-up time of 21 responded(CR+PR) patients was 43.4 (IQR 34.3 to 47.6) months, estimated 4-year DOR was 68% (95% CI: 0.45-0.83, Figure 1 D). Twenty-six (26, 70.3%) patients reported treatment-related AEs (TRAEs). There were no new safety signals were identified after August 2020. The most frequently observed (≥10%) TRAEs were neutropenia (21,56.8%), thrombocytopenia (17, 45.9%), transaminase increased (11, 29.7%), nausea (9, 24.3%). The most frequent Grade (G) ≥3 TRAEs were neutropenia (6, 16.2%) and thrombocytopenia (4, 10.8%). Immune-related AEs were reported in 16 (43.2%) patients including a G4 exfoliative dermatitis, and the most common irAEs were G1 hypothyroidism and rash. TEAEs that led to permanent treatment discontinuation occurred in only one (2.7%) patient. No death was related to the study drug.
Conclusion
Sintilimab combined with Chidamide showed long-lasting therapeutic effects with manageable toxicity in patients with r/r-ENKTL. Epigenetic modulator can synergize with anti-PD-1 antibody to enhance antitumor activity to r/r-ENKTL.