Mosunetuzumab Shows Promise for Non-Hodgkin Lymphoma

Elizabeth Lihua Budde, MD, PhD

The CD3 and CD20 bispecific antibody mosunetuzumab demonstrated promising complete remission (CR) rates with tolerable toxicity for patients with relapsed/refractory B-cell indolent and aggressive non-Hodgkin lymphoma (NHL), according to findings from a phase I/Ib open-label study presented at the 2018 ASH Annual Meeting.

In patients with relapsed/refractory follicular lymphoma, the objective response rate (ORR) was 69.2% across doses of mosunetuzumab. The CR rate in this group was 38.5%. In patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or transformed follicular lymphoma, the ORR was 34% and the CR rate was 19.1% across dose levels.

"Mosunetuzumab induces durable CRs in late-line relapsed/refractory indolent and aggressive NHL, and pharmacodynamic activation of peripheral T-cells confirms the mechanism of action," said lead investigator Elizabeth Lihua Budde, MD, PhD, an assistant professor at City of Hope. "Clinical activity was observed with intermittent dosing and limited treatment duration."

The study included two groups of patients. In group A, mosunetuzumab was administered at a fixed dose on day 1 of a 21-day cycle at doses ranging from 0.05 mg to 2.8 mg. In group B, step up dosing was utilized during the first cycle on days 1, 8, and 15 followed by a fixed dose on the first day of each 21-day cycle thereafter. Doses in this group started at 0.4, 1.0, and 2.8 mg and were escalated to 1.0, 2.0, and 20.0 mg by the end of the first cycle.

The study enrolled 75 patients with DLBCL or transformed follicular lymphoma and 38 patients with follicular lymphoma. Across both groups (N = 131), the median age of patients was 63 years (range, 19-85). Patients had a median number of 3 prior systemic regimens, and 26% had received a prior stem cell transplant. Overall, 67.9% were refractory to prior therapy and all patients had received a prior anti-CD20 agent, with 67.9% refractory to this treatment. A subsection of patients (6.1%) had received prior CAR T-cell therapy.

The first response in the trial was observed in group A at doses ≥1.2 mg. Complete responses were observed across all histologies, and the median duration of CR had not yet been reached. The median follow-up for CR in those with DLBCL and transformed follicular lymphoma was 298 days (range, 46-816). In the follicular lymphoma arm, the follow-up for CR was 330 days.

More than half of patients discontinued from initial treatment (54.2%), primarily due to progressive disease (60/71). Treatment-related adverse events (AEs) were experienced by 72.7% of patients in group A and by 59.2% for those in group B. Treatment-related grade ≥3 AEs were experienced by 21.2% of patients in group A and by 27.6% in group B.

"Mosunetuzumab has a favorable safety profile," said Budde. "Cycle 1 step-up dosing appears to mitigate toxicity, and a maximum tolerated dose was not reached."

Most treatment-related AEs were transient and reversible, she noted. Overall, 19% of events resolved within 24 hours, and the median duration for an event was 4 days (range, 1-144 days). The median time to onset for all AEs was 18 days and there was no evidence of cumulative or chronic toxicity. The most common treatment-related AEs were cytokine release syndrome (CRS), neutropenia, fatigue, hypophosphatemia, anemia, nausea, pyrexia, diarrhea, and headache.

"There was a low rate of treatment discontinuation due to AEs, and no grade 3 CRS," said Budde. "There was a low frequency of grade 3 neurotoxicity related to mosunetuzumab."

By Lee criteria, grade 1 and 2 CRS occurred in 22.9% of patients, with no grade 3 or 4 events. Neurologic AEs of grade 1 or 3 in severity were experienced by 46.6% of patients, and 2.3% had a grade ≥3 event. Overall, 20.6% of the neurologic events were deemed to be treatment-related. Grade 1 and 2 neutropenia occurred in 19.1% of patients, and febrile neutropenia occurred in 3.1% of patients.

"Febrile neutropenia did occur but it was responsive to G-CSF. Ninety percent of events resolved and there was no concurrent grade greater than 3 infections reported," Budde said.

Ongoing research is looking to optimize the dose and schedule for monotherapy with mosunetuzumab. Moreover, trials are under way to look at the agent in combination with chemotherapy, the PD-L1 inhibitor atezolizumab (NCT02500407), and the investigational anti-CD79b antibody-drug conjugate polatuzumab vedotin (NCT03677141, NCT03671018).

Budde LE, Sehn LH, Assouline S, et al. Mosunetuzumab, a Full-Length Bispecific CD20/CD3 Antibody, Displays Clinical Activity in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (NHL): Interim Safety and Efficacy Results from a Phase 1 Study. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017. Abstract 399.

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