Efficacy and Safety of Glofitamab Combined with Tislelizumab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Preliminary Results
Authors: Zhou De , Yu Wenjuan , Huang Xin , Wei Juying , Mao Liping , Ye Xingnong , Ghoushi Ehsan , Zheng Xiaolong , Hu Xuelian , Jin Jie , Xie Wanzhuo , Tong Hongyan 
Published: December 2024

Background
The prognosis for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor, and bispecific antibodies have emerged as a novel promising strategy. Glofitamab is a CD20×CD3 bispecific antibody which engages and redirects T cells to eliminate B cells. The complete remission (CR) rate of glofitamab monotherapy is 39% in R/R DLBCL patients (Dickinson MJ et al. N Engl J Med 2022). However, patients with R/R DLBCL may have insufficient T cells or impaired function, then glofitamab may not work so well in these patients. Immune checkpoint inhibitors are believed to relieve the exhaustive state of T cells, and when combined with chimeric antigen receptor (CAR) T-cell therapy, it can prolong the duration of remission (DOR) and has a good safety profile (Hirayama AV et al. Blood Adv 2024; Xiangke Xin et al. Cell Oncol 2024). Based on these studies, we conducted a study of glofitamab combined with tislelizumab in R/R DLBCL to assess the efficacy and safety. Here we present the characteristics of 10 enrolled patients and preliminary results.
Methods
Patients aged 18 years or older diagnosed with DLBCL were enrolled. All the patients had disease that had relapsed after, or was refractory to, at least two previous lines of therapy. The protocol was as follows: twenty-one days was a cycle. In the first cycle, obinutuzumab (1000mg) was given on day 1, glofitamab was administered on day 8 (2.5mg) and day 15 (10mg). During the first cycle, if no grade 2 or higher cytokine release syndrome (CRS) occurred, subsequent cycles included glofitamab (30mg on day 1) and tislelizumab (200mg on day 8). Whole body 18F-FDG PET/CT scan or contrast-enhanced CT scan (magnetic resonance imaging for the patient with central nervous system relapse, patient 9) was scheduled every 3 cycles, ultrasound and physical examination were performed every cycle. Patients with disease progression (PD) were withdrawn for salvage therapies, while those with stable disease (SD) or partial remission (PR) continued up to 12 cycles, unless unacceptable toxicity occurred. Patients achieving CR after 6 cycles would enter the follow-up phase. Treatment response was assessed by 2014 Lugano response criteria. Adverse events and CRS were graded by CTCAE 5.0 and ASTCT respectively. The primary endpoint is safety, the secondary endpoints are CR rate, overall response rate (ORR), DOR, progression-free survival (PFS), and overall survival (OS).
Results
Ten patients were enrolled from February 20, 2024 to June 11, 2024 in the First Affiliated Hospital, Zhejiang University School of Medicine. Six patients were female and 4 patients were male, with a median age of 68.5 years (range 25-80). The median previous lines of therapy was 3.5, and all were previously treated with rituximab, 90% with an anthracycline-containing regimen, and 60% with polatuzumab vedotin. All the patients are refractory to last-line therapy. As of 2024-07-20, the median follow-up was 3.4 months. All 10 patients were evaluated for safety, and 1 patient developed grade 2 CRS, five patients developed grade 1 CRS, and no immune effector cell-associated neurotoxicity syndrome or grade 3-4 CRS were observed. Grade 3 to 4 adverse events occurred in 5 patients, including 1 patient with grade 4 neutrophil count decrease combined with grade 3 platelet count decrease, two patients with grade 3 neutrophil count decrease combined with grade 3 platelet count decrease, one patient with grade 3 neutrophil count decrease, and 1 patient with grade 3 alanine aminotransferase increase and aspartate aminotransferase increase. Eight patients could be evaluated for efficacy, the ORR was 62.5% (5/8), of which 4 (50.0%) patients achieved CR, and 3 (37.5%) patients developed PD. At present, patients had received a median of 3 treatment cycles. The OS rate is 80%, while the PFS rate is 60%. Currently, six patients are continuing to receive treatment with a combination of glofitamab and tislelizumab.
Conclusions
In this study, glofitamab combined with tislelizumab showed a favorable safety profile and an acceptable response rate in RR DLBCL patients. Considering this combination therapy has the potential to improve the efficacy and prolong the DOR on the basis of glofitamab monotherapy, we plan to initiate a phase 2, single-arm prospective study to further evaluate its efficacy and safety. Ongoing treatment and follow-up of these 10 patients will also be further updated.