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.
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 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.