Spectrum: Phase II Study of Tislelizumab Plus Pemetrexed in Patients with Relapsed or Refractory (R/R) Primary Diffuse Large B-Cell Lymphoma (DLBCL) of the Central Nervous System (CNS): The Korean Cancer Study Group LY22-07
Authors: Kim Tae Min , Kim Jung Sun , Lee Gyeong-Won , Lee Myung-Won , Youk Jeonghwan , Lee Hyun Jung , Lim Sung-Nam , Kim Soyeon , Jeon Yoon Kyung , Park Chul-Kee , Heo Dae Seog 
Published: December 2024

Introduction:
Primary DLBCL of the CNS is a rare extranodal lymphoma that originates within the CNS without evidence of systemic involvement. Although high-dose methotrexate (HD-MTX)-based regimen is recommended as induction therapy, 25% of patients (pts) experienced relapse after initial response (Ferreri et al. Ann Oncol 2024). Salvage therapies for R/R primary DLBCL of the CNS showed marginal benefits. Pemetrexed had objective response rate (ORR) of 55% in R/R primary CNS lymphoma (Raizer et al. Cancer 2012) and synergized with anti-PD-(L)1 therapy against in vivo xenografts (Schaer et al. Clin Cancer Res 2019). Therefore, the SPECTRUM trial was launched to evaluate efficacy and safety of tislelizumab plus pemetrexed in pts with R/R primary DLBCL of the CNS (NCT05253118).
Methods:
SPECTRUM is a phase 2, multicenter, open-label study in South Korea. Pts with histologically confirmed primary DLBCL of the CNS, ≥1 prior chemotherapy including HD-MTX-based regimen, available next-generation sequencing data, and adequate organ function were eligible. Tislelizumab at 200 mg fixed dose and pemetrexed at a dose of 500 mg/m2 were given intravenously every three weeks until disease progression, unacceptable toxicity or withdrawal of informed consent. The primary endpoint was the investigators-assessed ORR using IPCG response criteria. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), overall survival (OS), and adverse events. Exploratory analyses were performed to investigate baseline CSF and serial plasma genotyping of MYD88 L265P mutation using droplet digital PCR (ddPCR) and genetic subtypes based on the LymphGen probabilistic classification (Wright et al. Cancer Cell 2020).
Results:
As of June 14, 2024, 24 pts were evaluable for efficacy and safety. The median age was 60 years (range, 41-86), 14 (58.3%) had male, 21 (87.5%) received prior rituximab-based regimen and 4 (16.7%) failed to autologous stem cell transplantation. After the median follow-up of 4.4 months, pts received median 4 cycles of tislelizumab plus pemetrexed (range, 1-33). The ORR was 70.8% with complete response (CR) rate of 41.7%. The median DoR was 6.18 months (95% CI, 0.72-not reached [NR]). Median PFS and OS were 7.43 months (95% CI, 2.04-NR) and NR (95% CI, 8.02-NR), respectively. Treatment-emergent adverse events (TEAEs) occurred in 28 (33.7%) and 5 (6.0%) among total 83 AEs in all grades and grade ≥3, respectively and the most common TEAEs were skin rash (14.5%) and fatigue (3.6%). TEAEs at grade 5 was reported in one and 5 pts discontinued tislelizumab (1 pt) or pemetrexed (5 pts) due to treatment-related AEs. The incidence of immune-related AEs was low including skin rash (3.6%) and dry mouth (1.2%).
Based on the LymphGen classification, 18/21 (85.7%) pts were classified as MCD subtype and 14/21 (66.7%) pts had MYD88 L265P mutation. Baseline CSF MYD88 L265P mutation was detected in 13/14 (92.9%) pts and cell-free DNA (cfDNA) MYD88 L265P mutation in baseline plasma was detected in 2/14 (14.3%) pts. MYD88 L265P mutation was detectable in baseline cfDNA in SNU-23 pt with extra-CNS relapse and MCD subtype harboring MYD88 L265P mutation and PIM1-CD274 fusion. Plasma MYD88 L265P mutation at Weeks 6 and 12 was undetectable in SNU-23 pt who achieved metabolic CR by PET/CT scan.
Conclusion:
The SPECTRUM trial met its primary endpoint and tislelizumab plus pemetrexed demonstrated an encouraging efficacy with manageable safety profiles in pts with R/R primary DLBCL of the CNS after failure to prior HD-MTX-based regimen. Updated efficacy, safety, and biomarker data will be presented in all 28 pts.