December 8, 2020 - Fixed-duration treatment with mosunetuzumab elicited high, durable, and consistent responses across numerous subgroups of patients with follicular lymphoma.
Fixed-duration treatment with mosunetuzumab elicited high, durable, and consistent responses across numerous subgroups of patients with follicular lymphoma, according to updated findings from a phase 1 trial presented during the 2020 ASH Annual Meeting & Exposition.
Results showed that in the overall study population of patients with follicular lymphoma (n = 62), the objective response rate (ORR) was 67.7%, with a 51.6% complete response (CR) rate and a 16.1% partial response (PR) rate.
The ORR was significantly higher in patients who were refractory to a PI3K inhibitor (n = 13), at 92.3%; this included an 84.6% CR rate and a 7.7% PR rate. In patients who previously received CAR T-cell therapy (n = 4), the ORR was 100%, with a CR rate of 50.0% and a PR rate of 50%.
Mosunetuzumab also showed an acceptable safety profile with low grade 2 cytokine release syndrome (CRS)—and no grade 3 events—in patients with previously treated disease.
“Fixed duration of mosunetuzumab induces high and consistent response rates across multiple high-risk follicular lymphoma subsets, with durable responses,” lead study author Sarit Assouline, MD, physician in the Division of Hematology, Sir Mortimer B. Davis-Jewish General Hospital, senior Investigator, Lady Davis Institute for Medical Research, and associate professor in the Department of Oncology, McGill University in Canada. “Assessment of higher dose levels is ongoing to maximize efficacy.”
Despite available therapies, follicular lymphoma remains an incurable disease, and those who have received 2 or more prior therapies generally have a poor prognosis. Patients with high-risk disease experience progression within 2 years after the initiation of frontline therapy (POD24) and are double refractory—refractory to both a prior anti-CD20 antibody and an alkylating agent.
Mosunetuzumab is a full-length, fully humanized immunoglobulin G1 CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. The findings presented at the 2020 ASH Annual Meeting & Exposition include updated data from 62 patients with relapsed/refractory follicular lymphoma who were treated with mosunetuzumab after 2 or more prior systemic treatments.
In the ongoing phase 1/1b trial, mosunetuzumab was given intravenously (IV) at a step-up dosing schedule of 0.4/1.0/2.8 mg to 1/2/13.5 mg during cycle 1 on days 1, 8, and 15. Premedication with 20 mg of IV dexamethasone or 80 mg of IV methylprednisolone was required in cycles 1 and 2 and was optional in cycle 3 and beyond.
Patients who achieved a CR by cycle 8 discontinued treatment. However, for patients who achieved a partial response (PR) or stable disease (SD), treatment could continue for up to 17 cycles until disease progression or unacceptable toxicity. Retreatment was also allowed for patients with a CR who relapsed.
To be eligible for enrollment, patients had to be at least 18 years old, have grades 1 to 3A relapsed/refractory follicular lymphoma and were expected to express CD20, must have received 2 or more prior systemic treatments, and must have had an ECOG performance status of 0 or 1.
The primary end points of the trial were safety and tolerability, establishing the recommended phase 2 dose, identifying the maximum-tolerated dose, dose-limiting toxicities, and best objective response.
High and consistent CR rates were observed in high-risk populations. Additional data showed that the ORR was 65.2% in those who were refractory to their last prior therapy (n = 46); in these patients, the CR rate was 47.8% and the PR rate was 17.4%. The ORR was 71.1% in patients who were double refractory (n = 38) with a 50.0% CR rate and a 21.1% PR rate. Finally, in those with POD24 (n = 29), the ORR was 75.9%; this was comprised of a CR rate of 55.2% and a PR rate of 20.7%.
Moreover, mosunetuzumab elicited antitumor activity in patients with relapsed/refractory across dose levels with an ORR of 67.7% and a CR rate of 51.6%.
The median follow-up after patients’ first response was 18.4 months (range, 2-34), and the median DOR was 20.4 months (95% CI, 9.4-22.7). In patients achieving CR, the median DOR was 21.0 months (95% CI, 16.0-22.7). In patients who were retreated with mosunetuzumab, 2 patients had a CR and 2 had a PR.
Results also showed that mosunetuzumab also induces pharmacodynamic changes in T-cell margination and activation. Pharmacodynamic changes due to mosunetuzumab activity were observed in multiple cycles but were not associated with response.
In the patients who were evaluable for safety (n = 62), treatment-related AEs (TRAEs) occurred in 72.6% and treatment-related serious AEs were in 14.5% of patients. TRAEs that were grade 3 or higher occurred in 35.5% of patients and 1 death occurred that was due to pneumonia. Four patients (6.5%) had TRAEs that led to treatment discontinuation. The most common grade 3 or higher mosunetuzumab-related AE was hypophosphatemia.
Grade 3/4 neutropenia occurred in 22.6% of patients, and 15.1% were found to be related to treatment. The median time to any-grade neutropenia onset was 106.5 days, with a median duration of 13 days; serious neutropenia occurred in 1 patient. Out of 23 events of any-grade neutropenia, 91.3% (n = 21) resolved by the data cutoff; 20 events resolved with growth-colony stimulating factor.
Grade 3/4 hypophosphatemia occurred in 21.0% (n = 13) of patients and was found to be related to treatment in all cases. Most events occurred during cycle 1, and all events resolved by the data cutoff date; no events were considered serious. Anemia occurred in 4 patients (6.5%), 1 of which was found to be related to treatment. No events were serious, and all events had resolved by the data cutoff date.
Serious infections occurred in 19.5% of patients (n = 12); the most frequent grade 3/4 serious ones were pneumonia (4.8%) and influenza (3.2%).
All CRS events (17.7%) were grade 1/2 and occurred during cycle 1 step-up dosing; serious CRS events were reported in 6.5% (n = 4) of patients. All CRS events resolved without tocilizumab (Actemra), admission to the intensive care unit, or vasopressors.
Investigators are currently assessing mosunetuzumab at higher dose levels in an effort to maximize efficacy, and ongoing studies are examining immune cell subsets and correlation with response.
Assouline S, Kim WS, Sehn LH, et al. Mosunetuzumab shows promising efficacy in patients with multiply relapsed follicular lymphoma: updated clinical experience from a phase I dose-escalation trial. Presented at: 2020 ASH Annual Meeting & Exposition; December 4-8, 2020; Virtual. Abstract 702.