Combination of Mitoxantrone Hydrochloride Liposome with Tislelizumab in Patients with Relapsed or Refractory NK/T Cell Lymphoma: A Phase Ib/Ⅱ Study

Background: Natural killer/T-cell lymphoma (NKTCL) is a rare and highly aggressive subtype of non-Hodgkin lymphoma (NHL) strongly associated with Epstein-Barr virus (EBV) infection and characterized by extranodal involvement. Survival outcome in patients with relapsed or refractory (r/r) extranodal NKTCL remains poor. In patients who relapsed after initial non-anthracycline-based treatment, the median overall survival is only 6 months. Mitoxantrone hydrochloride liposome (Lipo-MIT) is a nano-drug that has been approved as the first treatment option for relapsed/refractory (r/r) PTCL, and has shown certain efficacy and safety in a pivotal phase Ⅱ study. Tislelizumab is a humanized immunoglobulin G4 variant monoclonal antibody against PD-1. This study aims to investigate the safety and efficacy of combining Lipo-MIT with tislelizumab in patients (pts) with r/r extranodal NKTCL.

Methods: Pts with r/r extranodal NKTCL were recruited in this ongoing, prospective, multicenter, open-label phase Ib/Ⅱ study (NCT05464433). Phase Ib was 3+3 dose escalation design with two dose levels of Lipo-MIT (16 mg/m² and 20 mg/m², d1) plus tislelizumab 200 mg (d1, Q4W) induction therapy for up to 6 cycles, then tislelizumab 200 mg (Q3W) to continue maintenance therapy until disease progression, discontinuation, withdrawal or one year of therapy (including induction therapy period). Phase II was a dose expansion at the recommended phase II dose (RP2D). The primary endpoints were safety and tolerability, and determination of the maximum tolerated dose (or RP2D) of Lipo-MIT in phase Ib, and the overall response rate (ORR) of phase II. Secondary endpoints were complete response (CR) rate, ORR, disease control rate (DCR) and safety of phase Ib, and CR rate, DCR, progression-free survival (PFS), overall survival (OS) and safety of phase II.

Results: As of the data cut-off on July 10, 2024, a total of 30 eligible pts were enrolled (phase Ib, n=6 and phase II, n=24). The median age was 45 (range 22-71) years, with 53.3% being male. Among the pts, 66.7% had advanced stage III or IV (Ann Arbor) and 53.3% had nasal type NKTCL. No dose-limiting toxicities (DLT) were observed at 16 mg/m² and 20 mg/m² in the phase Ib study. The RP2D was determined to be Lipo-MIT 20 mg/m² plus tislelizumab 200 mg. The CR rate, ORR and DCR in phase Ib were 66.7% (4/6, 95% CI 27.1%-93.7%), 100.0% (6/6, 95% CI 60.7%-100.0%) and 100.0% (6/6, 95% CI 60.7%-100.0%), respectively. In the ongoing phase II study, the CR rate, ORR and DCR among the 21 pts evaluated were 42.9% (9/21, 95% CI 21.8%-66.0%), 71.4% (15/21, 95% CI 47.8%-88.7%) and 81.0% (17/21, 95% CI 58.1%-94.6%), respectively. Overall,combining data from phase Ib and phase II, the CR rate was 48.1 (14/27, 95% CI 28.7%-68.1%) and the ORR was 77.8% (21/27, 95% CI 57.7%-91.4%). Among the 14 pts who had not used PD-1 before, CR rate was 57.1% and ORR reached 85.7%. The median PFS and OS will be reported with longer follow-up. Treatment-related adverse events (TRAEs) of any grade were observed in all 30 pts, with 56.7% of pts experiencing grade 3/4. Common grade 3/4 TRAEs included leucopenia (40.0%), decreased lymphocyte count (40.0%), neutropenia (26.7%) and increased alanine aminotransferase (6.7%). Notably, no cardiac events occurred during the study.

Conclusions: Lipo-MIT in combination with tislelizumab demonstrated an encouraging efficacy in r/r extranodal NKTCL pts with a manageable safety profile.