Background:Despite the groundbreaking introduction of rituximab for the treatment of diffuse large B cell lymphoma (DLBCL),approximately 30% of the patients ultimately experience refractory / relapse (R/R) disease and so far myriads attempts to improve survival outcomes have not yielded firm positive results. Glofitamab is a T-cell engaging bispecific antibody with a novel 2:1 configuration conferring bivalency for CD20 and monovalency for CD3 that is both effective and tolerable in patients with R/R B-cell lymphomas. On the otherhand, it is a well-known fact that the lenalidomide plus BTK inhibitor combination has a synthetic lethality against DLBCL. One of the major advantage of such combination is the absence of cytotoxic agents that may lead tounmanageable toxicities and dose limitations.

Aims:We planned to test the efficacy and safety of glofitamab in combination with lenalidomide and poseltinib.

Methods:This is an open-label single arm phase II study with intent to recruit 76 participants (ClinicalTrials.gov Identifier:NCT05335018). CD20 positive DLBCL (DLBCL NOS, HGBCL, trFL) patients older than 19 years of age with historyof exposure to anti-CD20 agents are deemed eligible for screening. Major exclusion criteria include (1) BCL6(-) andMYC(+) disease; (2) previous exposure to glofitamab; (3) 4 or more lines of prior therapies.The treatment schedules and durations are shown in Figure. To mitigate the risk of glofitamab associated cytokinerelease syndrome, obinutuzumab premedication and cycle 1 step-up dosing was implemented. From cycle 2, glofitama b 30mg is given on day 1 of each cycle. Lenalidomide 20mg is given daily from day 1-14 of each cycle.Poseltinib 40mg is given twice daily from day 1-21 of each cycle. Each cycle is 28 days. The primary endpoint is overall response rate. The secondary endpoints include duration of response, complete response rate, progression free survival, overall survival and treatment related adverse events.

Results:Herein, we report the initial safety and efficacy data of the first 6 patients in the safety cohort (Table). The mediantime from first diagnosis to study enrollment was 25 months, with median of 2 prior lines of therapy (range 1-3).There was 1 event of cytokine release syndrome grade 1, which resolved without sequalae. The most commonadverse event was skin rash (2 grade 2, 1 grade 1) which did not require study drug modifications. Neutropeniaoccurred in 2 patients, but no dose adjustment was necessary. One patient with a previous history of priorCOVID19 infection after TNB-486 (CD19/CD3 bispecific) clinical trial, despite receiving vaccination prior to thisstudy enrollment, experienced COVID19 reactivation after cycle 1. Glofitamab D8 and D15 doses were skipped,and both lenalidomide and posetinib were stopped for 14 days. The patient recovered and underwent full doses ofsubsequent therapies. After DSMB clearance, we are now enrolling patients in the expansion phase.For tumor response, all 6 patients achieved objective response per Lugano criteria at the end of cycle 2 (3 CR, 3PR). Based on the best overall response, there were 4 confirmed CR and the median duration of response 4 months (Table).Summary/Conclusion: Glofitamab, poseltinib and lenalidomide (GPL) is promising combination for the treatment of R/R DLBCL