Phase 1 study of MK-1045, a novel CD19xCD3 T-cell engager, in participants with relapsed or refractory diffuse large B-cell lymphoma

Abstract Introduction: A variety of treatments options are available for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after first-line chemoimmunotherapy, but a significant proportion of patients do not respond to currently available treatments. MK-1045 (CN201) is a humanized bispecific IgG4 CD19xCD3 T-cell engager that has demonstrated encouraging safety, tolerability, and preliminary efficacy in participants (pts) with R/R B-cell non-Hodgkin lymphomas (Xie et al. J Clin Oncol. 2024;42(16_suppl):7040; data cutoff: Dec 29, 2023). Here, we report updated safety and efficacy data from the cohort of pts with R/R DLBCL from this first-in-human, single-arm, phase 1 study (NCT06189391). Methods Eligible pts were aged ≥18 to ≤75 years, had R/R DLBCL per World Health Organization criteria, were refractory to treatment or relapsed after ≥2 prior lines of therapy, had ≥1 evaluable tumor lesion per Lugano 2014 criteria, and had an Eastern Cooperative Oncology Group performance status score of 0 or 1. Pts previously treated with CAR T-cell therapy were eligible following a 90-day washout period, contingent on continued expression of CD19 on tumor cells. This study used an i3+3 dose escalation design. Initial dose escalation was conducted in pts at fixed ascending doses with MK-1045 administered once per week, 3 weeks on/1 week off, in 28-day cycles. Later, a step-up dosing regimen was implemented with once-weekly dosing, including a priming dose on day 1 of cycle 1 followed by an intermediate dose on day 8, and the target dose administered on day 15 and weekly thereafter in 21-day treatment cycles. The primary end points were safety and identification of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of MK-1045. Secondary end points included objective response rate (ORR) and duration of response (DOR) per Lugano 2014 criteria by investigator review. The data cutoff date for this analysis was February 5, 2025. Results A total of 49 pts with DLBCL were enrolled and treated, including 10 at fixed doses from 0.075 mg to 0.6 mg and 39 at 13 step-up dose levels ranging from 0.6/1.2/1.2 mg (priming/intermediate/target dose) to 2/20/160 mg. Median age was 57 years with a median of 2 prior lines of therapy. Three pts (6%) had received prior CAR T-cell therapy. Median follow-up time from first dose to data cutoff was 34.6 months (range, 30.4-38.5) in the fixed-dose group and 13.1 months (range, 2.8-28.6) in the step-up dose group. No dose-limiting toxicities occurred, and the MTD has not been reached. Treatment-emergent adverse events (AEs) were observed in 47 pts (96%); grade 3 or 4 AEs occurred in 32 pts (65%). No grade 5 AEs occurred. Drug interruptions due to AEs occurred in 18 pts (37%), most frequently due to infections (n = 6 [12%]). Dose reduction due to an AE occurred in 1 pt (2.0%; neutrophil count decreased). Two pts (4%) discontinued treatment due to an AE (1 pt with COVID-19, 1 with pneumonia). The most frequent treatment-emergent AEs were neutrophil count decreased (n = 27 [55%]; grade 3 or 4, n = 11 [22%]), white blood cell count decreased (n = 25 [51%]; grade 3 or 4, n = 3 [6%]), and anemia (n = 24 [49%]; grade 3 or 4, n = 4 [8%]). Cytokine release syndrome (CRS) occurred in 8 pts (16.3%); all were grade 1 or 2. Neurotoxicity AEs occurred in 10 pts (20%); all were grade 1 and 2, and insomnia was the most frequent (n = 5 [10%]). No immune effector cell–associated neurotoxicity syndrome (ICANS) was reported. The ORR in the fixed-dose group was 0%. In the step-up dose group, the ORR was 46%, the CR rate was 28%, the median DOR was 6.7 months and the median duration of CR was not reached. In the 16 pts who received target doses of ≥60 mg, the ORR was 56% and the CR rate was 50%; median DOR was 6.7 months. Conclusion With 17 months of additional follow-up since the prior report, the results of this analysis have demonstrated that MK-1045 led to encouraging efficacy at target doses ≥60 mg with a manageable safety profile with low rates of CRS and no cases of ICANS in pts with R/R DLBCL. These findings are consistent with those of the earlier analysis of the broader cohort of pts with B-cell non-Hodgkin lymphoma.