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Mosunetuzumab, a Dual-Targeted Antibody, Shows Complete Remissions in Relapsed/Refractory NHL After CAR T-Cell Therapy

JHOP - February 2020 Vol 10, No 1 - ASH Highlights, CAR T-Cell Therapy, Lymphoma
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Mosunetuzumab is an investigational bispecific T-cell engager (BiTE) agent dually targeting 2 proteins on the surface of lymphoma cells—CD3 (on the surface of T-cells) and CD20 (on the surface of B-cells).

New data presented at ASH 2019 show that mosunetuzumab holds promise as a durable and safe treatment for patients with treatment-refractory non-Hodgkin lymphoma (NHL), including those whose disease progressed after receiving chimeric antigen receptor (CAR) T-cell therapy. In a phase 1/1b clinical trial, the novel BiTE mosunetuzumab achieved durable responses in patients with refractory NHL, including complete remissions in 22.2% of patients who had previously received CAR T-cell therapy.

Lead investigator Stephen J. Schuster, MD, Director, Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, discussed the results.

“CAR-T was the first therapy in about 20 years to make a dent in the treatment of B-cell lymphoma in patients who fail other treatments. About one-third of patients treated with CAR-T have sustained remissions after 5 years, but we need treatments for the other two-thirds who fail. Nothing thus far has been reliable, and the vast majority of patients die within months,” said Dr Schuster.

“Unlike CAR T-cell therapy, mosunetuzumab is an off-the-shelf immunotherapy product that can be given to patients without having to genetically modify their T-cells,” Dr Schuster added.

Dr Schuster envisions mosunetuz­umab as a bridge to CAR T-cell therapy or a rescue therapy for patients who do not respond to CAR T-cell therapy. Mosune­tuzumab is a humanized antibody that binds to CD20 on the surface of malignant B-cells and to CD3 on ­cytotoxic T-cells.

“In binding to the T-cells, it’s [mosunetuzumab] capable of inducing T-cell activation, and, when engaged with a B-cell, it will cause a death of the target cell and eliminate those cells,” Dr Schuster explained.

Study Details

Dr Schuster reported efficacy results for 191 evaluable patients who received treatment with mosune­tuzumab monotherapy during the ongoing phase 1/1b dose-escalation GO29781 study in patients with relapsed or refractory B-cell NHL who had received several lines of therapy.

He focused on the patients in Group B who received mosunetuzumab intravenously, with stepped-up dosing on days 1, 8, and 15 of cycle 1, and then as a fixed dose on day 1 of each subsequent 21-day cycle (maximum, 17 cycles).

Among the 124 patients with aggressive NHL, 46 (37.1%) patients had objective response, including 24 (19.4%) who had a complete remission, according to pooled data from participants who received mosune­tuzumab at doses ranging from 2.8 mg to 40.5 mg. After a median follow-up of 6 months, 17 patients remain in complete remission.

In the 67 patients with indolent NHL, the objective response rate was 62.7% (N = 42), including 29 (43.3%) who had complete remission; the dosing in these cohorts ranged from 2.8 mg to 13.5 mg. A total of 24 patients remain in complete remission up to 26 months after initial treatment.

In addition, mosunetuzumab resulted in responses in patients who had previously received CAR T-cell therapy. Among 18 evaluable patients in this cohort, 7 (38.9%) had an objective response, including 4 (22.2%) with complete remission. The investigators also observed an expansion of lymphocytes, including residual CAR T-cells in 2 of 8 patients, and complete remissions with and without CAR T-cell expansions.

In an interview, Dr Schuster pointed out that these were very sick patients, “who progressed after third-line therapy and would have a dire prognosis. We desperately need solutions for patients who fail CAR-T,” he emphasized.

The evaluable safety population included 270 patients—66.7% of patients with aggressive NHL, mainly diffuse large B-cell lymphoma, and 31.5% with follicular lymphoma and other types of indolent NHL. The patients received a median of 3 previous systemic therapies (range, 1-14). In addition, 28.5% of patients had received autologous stem-cell transplantation, and 71.9% had disease refractory to the last previous therapy.

Of 30 patients who had received CAR T-cell therapy, 22 (73.3%) had refractory disease, with a median of 5 previous systemic treatments.

Mosunetuzumab Safety

Mosunetuzumab had a tolerable safety profile, with mostly low-grade cytokine release syndrome (28% of all grades) and neurologic adverse events (43.7% of all grades), including headache, insomnia, and dizziness.

Overall, 3 (1.1%) cases of grade 3 cytokine release syndrome were reported in the total population (N = 218) and 1 (3.3%) in the previous CAR cohort. The incidence of grade 3 neurologic adverse events was 3.7% in the broad population and 10.0% in the CAR group.

“The safety with regard to cytokine release syndrome and neurological adverse events is almost identical, whether the patients have had prior CAR T-cell therapy or not,” Dr Schuster noted. “What’s interesting is that these events are much more frequent during CAR T-cell therapy.”

Ongoing studies are evaluating mosunetuzumab as monotherapy and in combination with checkpoint inhibitors, in patients with different types of NHL.

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