In Heavily Pretreated Relapsed/Refractory Follicular Lymphoma, Mosunetuzumab Represents Effective Option

In heavily pretreated patients with relapsed or refractory follicular lymphoma, fixed-duration treatment with the bispecific antibody mosunetuzumab induced deep and durable responses with favorable tolerability, meeting the primary end point of the ongoing phase 1/2b GO29781 trial (NCT02500407).

Results, which were presented during a press briefing at the 2021 ASH Annual Meeting, showed that mosunetuzumab elicited a complete response (CR) rate of 60% (95% CI, 49%-70%) per independent review facility (IRF) assessment. The investigator-assessed CR rate with the agent was also 60% (95% CI, 49%-70%). Notably, the 60% CR rate is significantly greater than the historical control CR rate of 14% (P < .0001).

The objective response rate (ORR) achieved with the bispecific antibody was 80% (95% CI, 70%-88%) per IRF assessment; per investigator assessment, this rate was 78% (95% CI, 68%-86%). Moreover, the median duration of response (DOR) with the agent was 22.8 months (95% CI, 9.7–not evaluable [NE]). The median progression-free survival (PFS) was 17.9 months (range, 10.1–NE).

“[Mosunetuzumab is the] first T-cell–engaging bispecific antibody to demonstrate clinically meaningful outcomes for patients with relapsed or refractory follicular lymphoma in a pivotal phase 2 setting,” Elizabeth L. Budde, MD, PhD, lead study author and associate professor of the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, said in a presentation on the data.

Follicular lymphoma is characterized by recurrent relapses, and it is known that response rate and duration to conventional therapies tend to decrease with successive treatment lines. Moreover, POD24 and refractory disease have been linked with worse prognosis.

Mosunetuzumab, a CD20 x CD3 bispecific antibody, was designed to engage and redirect T cells to eradicate malignant B cells. In the phase 1 experience (NCT02500407), the agent was administered intravenously (IV) with cycle 1 step-up dosing for mitigation of effects like cytokine release syndrome (CRS) and produced promising activity with acceptable safety in patients with relapsed/refractory follicular lymphoma who received 2 or more prior therapies.

At the 2021 ASH Annual Meeting, Budde shared the first pivotal data from the single-arm, phase 2, expansion portion of the research. To be eligible for enrollment, patients needed to have follicular lymphoma, with grade 1 to 3a disease and an ECOG performance status of 0 or 1. They needed to have previously received 2 or more regimens, including at least 1 anti-CD20 antibody and at least 1 alkylating agent.

A total of 90 participants received IV mosunetuzumab every 3 weeks in 21-day cycles, utilizing a step-up dosing approach in cycle 1. In the first cycle, the agent was given at 1 mg on day 1, at 2 mg on day 8, and at 60 mg on day 15. In cycle 2, the agent was given at a dose of 60 mg on day 1. Mosunetuzumab was then administered at a dose of 30 mg on day 1 of cycle 3 and beyond. If a CR was achieved after cycle 8 of treatment, patients received fixed-duration treatment for 8 cycles. If a partial response or stable disease was achieved after cycle 8, patients received 17 cycles of treatment. There was no mandatory hospitalization for participants.

The primary end point of the trial is CR rate per IRF assessment; this was assessed in comparison with the historical CR rate of 14%. Key secondary end points of the trial include ORR, DOR, PFS, safety, and tolerability.

“Most patients had advanced disease, heavily pretreated disease, and characteristics commonly associated with poor prognosis,” Budde noted.

The median age of study participants was 60 years (range, 29-90) and 61.1% were male. Moreover, 58.9% of patients had an ECOG performance status of 0, and 41.1% had a status of 1. Regarding Ann Arbor disease stage, 23.3% of patients had stage I to II disease and 76.7% had stage III to IV disease.

Patients had received a median of 3 prior lines of therapy (range, 2-10). All patients previously received anti-CD20 therapy and an alkylator therapy. Other prior systemic therapies received included PI3K inhibitors (18.9%), immunomodulatory drugs (14.4%), and CAR T-cell therapy (3.3%). Moreover, 21.1% of patients previously underwent autologous stem cell transplant. Notably, 68.9% of patients were refractory to the last prior therapy they received.

Additionally, 78.9% of patients were refractory to a previous anti-CD20 therapy and 53.3% were double refractory to both an anti-CD20 therapy and an alkylator therapy. Approximately half, or 52.2%, of patients had POD24 disease.

Response rates achieved with mosunetuzumab in those with high-risk subgroups proved to be comparable to the overall population. The CR rate with the agent in patients who were younger than 65 years (n = 60) was 55% (95% CI, 42%-68%); in those aged 65 years and older (n = 30), the CR rate was 70% (95% CI, 51%-85%).

Among those who received 2 prior lines of therapies (n = 34), the CR rate was 74% (95% CI, 56%-87%). In those who received 3 or more prior therapies (n = 56), the CR rate with the bispecific antibody was 52% (95% CI, 38%-65%). In those who were relapsed or refractory to their last prior therapy (n = 62), the CR rate was 52% (95% CI, 39%-65%) vs 79% (95% CI, 59%-92%) in those who were not (n = 28). In those who were double refractory (n = 48), the CR rate was 50% (95% CI, 35%-65%) vs 71% (95% CI, 55%-84%) in those who were not.

Moreover, the CR rate achieved with mosunetuzumab was 57% (95% CI, 42%-72%) in those with POD24 disease (n = 47) vs 63% (95% CI, 47%-77%) in those who do not have POD24 disease (n = 43).

The median time to first response with the bispecific antibody was 1.4 months (range, 1.1-8.9), and the median time to first CR was 3.0 months (range, 1.1-18.9).

Regarding safety, all patients experienced adverse effects (AEs), 92.2% of which were related to the study drug. Seventy percent of patients experienced grade 3 or 4 AEs, 51.1% of which were mosunetuzumab related. Moreover, 46.7% of patients experienced serious AEs; 33.3% were related to the bispecific antibody. Two patients died, although neither toxicity was determined to be associated with the study agent.

Any-grade CRS was experienced by 44.4% of patients who received mosunetuzumab. CRS effects were predominantly grade 1 (25.6%) or grade 2 (16.7%). One patient experienced grade 3 CRS, and 1 patient reported grade 4 CRS. Notably, all these events resolved.

“AEs leading to discontinuation were uncommon,” Budde noted.

Four of the 90 patients experienced an AE that resulted in treatment discontinuation; 2 patients discontinued treatment because of an effect that was related to the study drug.

“Dr Budde and team found that most patients who responded to the treatment experienced no complications or cancer progression a year after treatment,” Laurie Sehn, MD, moderator of the Immune System 1, Cancer 0: Advances in Immunotherapy press briefing and clinical assistant professor at the University of British Columbia Cancer Centre for Lymphoid Cancer, said. “The results suggest that there is an opportunity to motivate the patient’s own immune systems to recognize lymphoma cells through a chemotherapy-free treatment.”

_Reference

_{Budde EL, Sehn LH, Matasar M, et al. Mosunetuzumab monotherapy is an effective and well-tolerated treatment option for patients with relapsed/refractory (R/R) follicular lymphoma (FL) who have received ≥2 prior lines of therapy: pivotal results from a phase I/II study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 127.}