Glofitamab Demonstrates Durable Responses in Relapsed/Refractory B-Cell Lymphoma

Pipeline Report | <b>Pipeline Report: April 2021</b>

The novel T-cell–engaging bispecific antibody glofitamab demonstrated encouraging clinical activity, with frequent and durable complete remissions, and a manageable toxicity profile in patients with predominantly refractory, aggressive B-cell lymphoma.

The novel T-cell–engaging bispecific antibody glofitamab (RO7082859) demonstrated encouraging clinical activity, with frequent and durable complete remissions, and a manageable toxicity profile in patients with predominantly refractory, aggressive B-cell lymphoma, according to data from a phase 1 trial (NCT03075696) published in the Journal of Clinical Oncology.1

Among the 171 patients treated on the study, the agent elicited an overall response rate (ORR) of 53.8%, with 36.8% of patients achieving a complete response (CR). For patients who specifically received the recommended phase 2 dose of 2.5 mg given in cycle 1 day 1, 10 mg given on cycle 1 day 8, and 30 mg given on cycle 2 day 1, the ORR was 65.7%, with 57.1% of patients achieving a CR. Additionally, of the 63 patients who achieved a CR, 84.1% (n = 53) had an ongoing CR after 27.4 months of observation.

“The observation of rapidly achieved CRs lasting more than 18 months across a range of doses suggests that glofitamab is highly active in a difficult-to-treat patient group with few clinical treatment options,” lead study author Martin Hutchings, MD, PhD, a staff specialist in the Department of Hematology at the Finsen Centre, National Hospital, Copenhagen University Hospital in Denmark, and colleagues, wrote in the paper. “As a consequence, glofitamab is undergoing expanded evaluation in relapsed/refractory and untreated B-[cell lymphoma], alone and in combination with conventional chemotherapy and novel agents.”

Even with the emergence of CAR T-cell therapies in the B-cell lymphoma treatment paradigm, there is an unmet need for alternative therapies that offer the opportunity for off-the-shelf availability, high response rates, durable remissions, and a manageable safety profile.

Glofitamab is a novel T-cell–engaging, bispecific, full-length antibody. The product has a longer half-life vs non–Fc-bearing bispecific T-cell engagers, and a 2:1 configuration that enables bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells. In this first-in-human phase 1 trial, investigators sought to examine the activity of glofitamab monotherapy following single-dose obinutuzumab (Gazyva) pretreatment, as well as glofitamab with ongoing obinutuzumab.

To be eligible for enrollment, patients had to be at least 18 years of age and have confirmed, CD20-expressing B-cell lymphoma. Additionally, patients needed to have previously received 1 or more lymphoma treatments and have at least 1 measurable target lesion that was 1.5 cm or larger. Patients with central nervous system lymphoma, who had received another anticancer therapy within 4 weeks of study treatment, or who had received prior allogeneic stem cell transplantation within 100 days prior to study treatment were excluded.

Patients were pretreated with obinutuzumab 7 days prior to the first dose of glofitamab. Patients received 1,000 mg of obinutuzumab in an effort to deplete peripheral and tissue-based B cells and mitigate serious cytokine release syndrome (CRS).

In part 1 of the study, 3 patients were enrolled to single-patient cohorts and treated with glofitamab at doses of 0.005 mg, 0.015 mg, and 0.045 mg. Responses were not observed in any of these patients, and all 3 withdrew after disease progression.

In part 2, the dose-escalation portion of the study, a total of 171 patients were treated with glofitamab at a starting dose of 0.015 mg. Investigators began to observe significant clinical activity when the agent was given at a dose of 0.6 mg. As such, subsequent cohorts were expanded to provide additional information. At a cycle 1 day 1 dose of 25 mg, CRS was reported in all patients; this was determined to exceed the maximum tolerated day-1 dose (MTD).

Two step-up dosing cohorts were then evaluated. The dosing regimen comprised 2.5 mg on cycle 1 day 1, 10 mg on cycle 1 day 8, and 16 mg or 30 mg on cycle 2 day 1. Based on safety data and pharmacodynamic modeling, the recommended phase 2 dose was determined to be 2.5 mg on cycle 1 day 1, 10 mg on cycle 1 day 8, and 30 mg on cycle 2 day 1.

The primary end points of the study were safety and tolerability, pharmacokinetics, MTD, and dose-limiting toxicities, while secondary end points included ORR and CR, duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), pharmacodynamic biomarkers, and incidence of antidrug antibodies.

Patients enrolled on study had a median age of 64 years (range, 22-85), the majority were male (58.5%), and 51.2% had an ECOG performance status of 0. Moreover, 42.7% of patients (n = 73/171) had diffuse large B-cell lymphoma (DLBCL), 25.7% had follicular lymphoma grades 1 to 3A, 17.0% had DLBCL arising from follicular lymphoma, 5.8% had Richter’s transformation, and 1.8% had primary mediastinal B-cell lymphoma.

Additionally, patients had received a median of 3 prior lines of therapy (range, 1-13), with 24.0% previously undergoing transplant and 1.8% previously receiving CAR T-cell therapy. Most patients, or 90.6%, were refractory to prior therapy (n = 155/171) and 9.5% (n = 16) had relapsed. For patients who had received prior therapy, the median time since last therapy was a median of 2.4 months (range, 0.6-128.8).

Among the 127 patients with aggressive B-cell lymphoma, the ORR was 48.0% (n =61) with glofitamab and the CR rate was 33.1% (n = 42). Patients with DLBCL had an ORR of 41.1% (n = 30), with 28.8% (n = 21) achieving a CR. In patients with follicular lymphoma, the agent elicited an ORR of 55.2% and a CR rate of 34.5%.

Additionally, the median DOR of the agent in patients with aggressive NHL was 5.5 months (95% CI, 4.4–not evaluable), the median DOCR was not reached, and 72.8% of patients who achieved a CR still experienced a response at 12 months follow-up. Moreover, the median PFS was 2.9 months (95% CI, 2.1-3.9) with the agent.

In terms of safety, adverse effects (AEs) were observed in 98.2% of patients (n = 168), with 83.6% (n =143) experiencing at least 1 treatment emergent adverse effect associated with glofitamab.

The most common AE observed with the agent was CRS, which occurred in 50.3% of patients (n = 86). Grade 3 or higher AEs were observed in 56.7% of patients (n = 97), the most common of which included neutropenia (25.1%), thrombocytopenia (8.2%), and anemia (7.6%). Serious AEs were reported in 58.5% of patients, with 45.0% of effects determined to be related to glofitamab.

One patient who received the agent at 25 mg experienced a grade 5 effect of hypovolemic shock due to a gastrointestinal hemorrhage following recovery from CRS. Another patient who received the agent at 0.015 mg experienced grade 5 septic shock. However, both events were not determined to be associated with the study drug.

In total, 2.9% of patients discontinued treatment due to AEs. One patient did so because of acute myocardial infarction experienced at a dose of 0.22 mg, 1 did so because of grade 3 cytomegalovirus chorioretinitis at the 1-mg dose, 1 did so because of grade 4 neutropenia at the 2.5/10/30-mg dose, 1 did so because of grade 3 sepsis, and 1 did so because of grade 4 colitis, both at the 2.5/10/30-mg dose. One patient discontinued due to a fatal event of GI bleeding; the patient received the 25-mg dose of the agent.

“This novel T-cell–engaging bispecific antibody has shown high levels of single-agent activity in relapsed/refractory B-cell lymphoma,” the study authors concluded. “Glofitamab has demonstrated frequent, durable CRs and a manageable tolerability profile and allows off-the-shelf treatment for patients with refractory B-cell lymphoma in need of timely therapy.”

Reference

Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting cell–engaging bispecific antibody, induces durable complete remissions in relapsed or refractory B-cell Lymphoma: a phase I trial. J Clin Oncol. Published online March 19, 2021. doi:10.1200/JCO.20.03175