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

Abstract Introduction: Anti-CD20–based therapies are the standard-of-care first-line treatment for advanced follicular lymphoma (FL), but most patients eventually relapse or experience disease progression. There is no agreed-upon approach to second-line treatment; various options depend on prior therapies received and patient and disease characteristics. MK-1045 (CN201) is a humanized bispecific IgG4 CD19xCD3 T-cell engager that has shown encouraging safety, tolerability, and preliminary efficacy in participants (pts) with relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (Xie et al. J Clin Oncol. 2024;42(16_suppl):7040; data cutoff: December 29, 2023). Here we report updated safety and efficacy data from the cohort of pts with R/R FL from this first-in-human, single-arm, phase 1 study (NCT06189391). Methods: Eligible pts were aged ≥18 to ≤75 years, had R/R grade I to III FL per WHO criteria, were treatment refractory or had relapsed after ≥1 prior line of therapy, had ≥1 evaluable tumor lesion per Lugano 2014 criteria, and had an ECOG performance status score of 0 or 1. Pts who had received prior CAR T-cell therapy were eligible following a 90-day washout period, provided they continued to express CD19 on tumor cells. Dose escalation followed an i3+3 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 a intermediate dose on day 8; the target dose was 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 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 41 pts with FL were enrolled and treated, including 6 at fixed doses from 0.0025 mg to 0.075 mg and 35 at 13 step-up dose levels ranging from 0.6/1.2/1.2 mg (priming/intermediate/target dose) to 2/20/160 mg. The median age was 50 years, and median prior lines of therapy was 2. Three pts (7%) had received prior CAR T-cell therapy. Median time from first dose to data cutoff was 43.9 months (range, 39.5-46.3) in the fixed-dose group and 12.5 months (range, 6.0-28.8) in the step-up dose group. No dose-limiting toxicities occurred, and the MTD has not been reached. Treatment-emergent adverse events (AEs) occurred in 41 pts (100%); 28 pts (68%) experienced grade 3 or 4 events. No grade 5 AEs were observed. Drug interruptions due to AEs occurred in 21 pts (51%), most commonly due to infections (n = 15 [37%]). Dose reductions due to AEs occurred in 2 pts (6%; 1 pt due to dizziness, headache, pyrexia and rash; 1 pt due to neutrophil count decreased). One pt (3%) discontinued treatment due to an AE (interstitial lung disease). The most frequent AEs were neutrophil count decreased (n = 21 [51%], grade 3 or 4, n = 15 [37%]), white blood cell decreased (n = 20 [49%]; grade 3 or 4, n = 8 [20%]), anemia (n = 17 [41%]; grade 3 or 4, n = 2 [5%]), and lymphocyte count decreased (n = 16 [39%]; grade 3 or 4, n = 15 [37%]). Cytokine release syndrome (CRS) occurred in 7 pts (17%); all were grade 1 or 2. Neurotoxicity AEs occurred in 8 pts (19.5%); all were grade 1 and 2, and the most frequent was headache (n = 4 [9.8%]). No immune effector cell–associated neurotoxicity syndrome (ICANS) was reported. Six pts in the fixed dose group and 33 pts in the step-up dose group had sufficient follow up for an efficacy assessment. The ORR in the fixed-dose group was 0%. In the step-up dose group, the ORR was 76%, the complete response (CR) rate was 64% and the median DOR and median duration of CR were not reached. Among 29 pts who received target doses of >5 mg, the ORR was 86% and the CR rate was 72%; the median DOR and duration of CR were not reached. Conclusion: With 17 months of additional follow-up since the prior report, the results of this analysis have shown that MK-1045 led to high CR rates at target doses ≥5 mg and a manageable safety profile with low rates of CRS and no cases of ICANS in pts with R/R FL. These findings are consistent with those of the earlier analysis of the broader cohort of pts with B-cell non-Hodgkin lymphoma.