Glofitamab effective in patients with relapsed/refractory diffuse large B-cell lymphoma and ≥2 prior therapies

Patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) who received at least two prior therapies have a poor prognosis. Fixed-duration glofitamab induces durable complete remissions and has favourable safety in patients with R/R DLBCL and ≥2 prior therapies, including those with prior exposure to CAR-Ts. Glofitamab is a promising new therapy for patients with heavily pre-treated and/or highly refractory DLBCL.

Patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) who received at least two prior therapies have a poor prognosis. CAR-T cell therapy is an option for patients with R/R DLBCL but its use may be restricted by logistical challenges. Glofitamab is a T-cell engaging bispecific antibody (Ab) with a novel 2:1 configuration that confers bivalency for CD20 (B cells) and monovalency for CD3 (T cells). As such, glofitamab offers an off-the-shelf and fixed duration treatment option. In a phase I/II trial (NCT03075696), encouraging efficacy and manageable safety with glofitamab monotherapy was observed in patients with R/R B-cell non-Hodgkin lymphoma. At EHA 2022, Prof. Dickinson shared the pivotal phase II expansion results with glofitamab in R/R DLBCL and at least two prior therapies.

Study design

All patients had DLBCL (DLBCL not otherwise specified [NOS], high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, or transformed follicular lymphoma) and had received ≥2 prior regimens, including an anti-(a) CD20 Ab and an anthracycline. Intravenous (IV) obinutuzumab pre-treatment (1,000 mg) was given 7 days before the first glofitamab dose. IV glofitamab was then given as step-up doses on Day (D) 1 (2.5 mg) and D8 (10 mg) of cycle 1 and at the target dose (30 mg) on D1 of cycle 2–12 (21-day cycles). Glofitamab was given for a maximum of twelve cycles (approximately 9 months). The primary endpoint was complete response (CR) rate assessed by Independent Review Committee (IRC) using Lugano 2014 criteria. Cytokine release syndrome (CRS) was assessed using ASTCT criteria.

Results

In total, 154 patients had received ≥1 dose of study treatment. This was a heavily pre-treated, highly refractory population with a median age of 66 years and Ann Arbor stage III–IV disease in 75.3% of patients. Median number of prior therapies was 3 (2–7), 59.7% had ≥3 prior therapies and 33.1% had received prior CAR T-cells (CAR-Ts). Most patients were refractory to a prior anti CD20 Ab-containing regimen (83.1%) and to their most recent regimen (85.7%). Many were refractory to their initial therapy (58.4%) and to prior CAR-Ts (29.9%).

After a median follow-up of 12.6 months, overall response and CR rates by IRC were 51.6% and 39.4%, respectively. At the time of the primary analysis, the primary endpoint was met in the primary efficacy population (N= 108). In that population, the CR rate by IRC was 35.2%, which is significantly greater (p< 0.0001) than the 20% historical control CR rate. CR rates were consistent across important subgroups, including patients with and without prior CAR-Ts (35% vs. 42%). Although 58% of the population had refractory lymphoma, there was a signal that patients with relapsed disease had a higher complete remission rate (70% vs. 34%). Responses were achieved early, with a median time to first CR of 42 days. The majority of CRs (49/61; 80.3%) were ongoing at data cut. An estimated 77.6% of complete responders and 63.6% of responders remained in response at 12 months, which is striking since patients are completely off therapy at nine months. The median duration of response and duration of complete response was 18.4 months and not estimable, respectively. Furthermore, there was a clinically significant freedom from progression at 12 months (37.1%) and long-term overall survival (median OS 11.5 months).

Glofitamab was well tolerated, with a favourable safety profile. The median relative dose intensity was 100% (range 94-100) and only 3.2% discontinued glofitamab due to treatment-related adverse events (AEs). CRS occurred in 63% of patients, was primarily associated with the initial doses, and was mostly grade 1 (47.4%) or 2 (11.7%). The median time of CRS onset is very predictable and occurs at a median of 13.6 hours after infusion. The incidence of CRS was lower with mandatory dexamethasone. There were 8 deaths reported, of which 5 were related to COVID-19. In this heavily pre-treated population, 14.9% of patients experienced grade ≥3 infections. Neurologic AEs occurred in 38.3% of patients but were only of grade ≥3 in 3.2% of patients.

Conclusion

With a CR rate of 39.4% in heavily pre-treated, highly refractory patients with DLBCL, the primary efficacy endpoint was met. There was a consistent CR rate in patients with prior CAR-T treatment, and a higher CR rate in relapsed vs. refractory patients. CRs were achieved early and were durable after the fixed treatment duration. Glofitamab was well tolerated, with low rates of treatment discontinuations. As such, glofitamab is the first T-cell-engaging bispecific monoclonal antibody to demonstrate clinically meaningful outcomes for patients with R/R DLBCL in a pivotal phase II setting.

Reference

Dickinson M, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥2 prior therapies: pivotal phase II expansion results. Presented at EHA 2022; Abstract S220.