Glofitamab Produces Durable Remissions in R/R Mantle Cell Lymphoma

Updated findings from an ongoing phase 1/2 trial (NCT03075696) demonstrated that fixed-duration glofitamab-gxbm (Columvi) monotherapy induced durable responses in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), including those with clinically and histologically defined high-risk features.

Findings presented at the 2024 ASH Annual Meeting showed that at a median follow-up of 24.2 months (range, 0-50), evaluable patients (n = 60) achieved an overall response rate (ORR) of 82% and a complete response (CR) rate of 77%. The median time to first response was 42 days (range, 29-164), and the median duration of CR (DOCR) was 46.5 months (95% CI, 14.4-not estimable [NE]). The 12-month event-free rate among complete responders was 73.3% (95% CI, 60.3%-86.2%). The median progression-free survival (PFS) was 18.0 months (95% CI, 11.3-NE) and the median overall survival (OS) was NE (95% CI, 21.6-NE).

“Notably, most patients who were in CR at end of treatment were progression free and alive 18 months after the end of treatment,” lead study author Tycel Phillips, MD, and colleagues wrote in a poster presentation of the data. “Most responders rapidly achieved undetectable minimal residual disease [MRD], which was sustained after the end of treatment.”

Phillips serves as an associate professor in the Division of Lymphoma of the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California.

Study Design

The phase 1/2 study included patients with relapsed/refractory MCL who received at least 1 prior line of therapy.

Enrolled patients received pretreatment with a single dose of obinutuzumab (Gazyva) at either 1000 mg or 2000 mg on day 1 of cycle 1. Glofitamab was administered in a step-up dosing schedule during cycle 1 at 2.5 mg on day 8 and 10 mg on day 15. The target dose of 16 mg or 30 mg was given on day 1 of cycle 2, and patients received the agent once every 3 weeks at the target dose through cycle 12. Two patients received glofitamab at the 16-mg target dose, and the remainder received the agent at 30 mg.

Tumor responses were assessed using Lugano 2014 criteria, and MRD analyses were performed on genomic DNA isolated from circulating tumor cells or plasma using the clonoSEQ assay.

The primary objective of the study was to evaluate the efficacy of fixed-duration glofitamab monotherapy, including response rates and durability of remission. Secondary end points included safety, MRD negativity rates, and outcomes in high-risk subgroups.

Baseline Patient Characteristics

As of the data cutoff of May 17, 2024, 61 patients had been enrolled, and 60 received at least 1 dose of study treatment. All 61 enrolled patients were included in the intention-to-treat (ITT) population, 60 patients comprised the safety population, and a subset of 46 patients formed the biomarker-evaluable population (BEP).

The median age of patients in the safety population was 72 years (range, 41-86). The majority were male (73.3%), and most patients (86.7%) had Ann Arbor stage III/IV MCL. The median number of prior lines of therapy was 2 (range, 1-5); 46.7% of patients received at least 3 prior lines of therapy. Notably, 55.0% of patients had prior exposure to BTK inhibitors. Additionally, 83.3% of patients had disease refractory to any prior therapy, and 73.3% were refractory to their most recent line of treatment. Furthermore, 51.7% of patients were refractory specifically to BTK inhibitors.

Among the 46 patients in the BEP cohort, 53.0% had at least 1 high-risk histological feature, which included blastoid morphology (11.9%), a Ki-67 expression of over 50% (41.3%), and a p53 expression of over 50% (19.6%).

Subgroup Analyses Findings

A subgroup analysis of the ITT population revealed consistent CR rates irrespective of age, number of prior lines of therapy, exposure to a prior BTK inhibitor, and refractory disease status. CR rates were 76% in patients under 70 years of age and 78% in those 70 years of age or older. Patients who received 1 prior line of therapy achieved a CR rate of 80% compared with 78% for 2 prior lines and 75% for 3 or more prior lines. Among patients refractory to their last therapy, the CR rate was 76% vs 81% for those who were not refractory to their last therapy. Patients previously treated with a BTK inhibitor had a CR rate of 71% vs 85% for those naive to a BTK inhibitor.

In the BEP, patients with at least 1 high-risk histological feature had a CR rate of 65% compared with 93% for those without these features. Patients with blastoid morphology experienced a CR rate of 60%; patients with Ki-67 expression of more than 50% and those with a p53 expression of more than 50% had CR rates of 67% each.

Notably, the median DOCR was shorter in patients with at least 1 high-risk feature at 14.4 months (95% CI, 10.0-NE) compared with 46.5 months (95% CI, NE-NE) for those without any high-risk features.

An analysis of MRD kinetics demonstrated that 14 out of 15 patients (93.3%) with evaluable samples achieved undetectable MRD at cycle 3, and most patients who attained undetectable MRD maintained molecular remission after the end of treatment.

Safety findings demonstrated that all patients experienced at least 1 any-grade adverse effect (AE). Serious AEs occurred in 78.3% of patients, and grade 3 to 5 AEs were reported in 80.0% of the population. Grade 5 AEs occurred in 15.0% of patients.

Any-grade cytokine release syndrome (CRS) was observed in 70.0% of patients,; the rate of grade 3/4 CRS was 11.7%. Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 11.7% of patients (n = 7), although all ICANS events were grade 1 (6.7%) or grade 2 (5.0%). All cases of ICANS were nonserious and resolved.

AEs leading to the discontinuation of glofitamab occurred in 8.3% of patients, including 1.7% who discontinued due to AEs attributed to glofitamab.

Reference

Phillips TJ, Marek Trněný, Carlo-Stella C, et al. Glofitamab induces high response rates and durable remissions in patients with heavily pretreated relapsed/refractory mantle cell lymphoma, including those with a poor prognosis: subgroup results from a phase I/II study. Blood. 2024;144(suppl 1):1631. doi:10.1182/blood-2024-200018