Fixed-Duration Mosunetuzumab Demonstrates Preliminary Activity in BTK Inhibitor–Exposed R/R MCL

Pretreated R/R MCL | Image Credit:

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Treatment with fixed-duration mosunetuzumab-axgb (Lunsumio) as monotherapy showed clinical activity in heavily pretreated patients with relapsed/refractory mantle cell lymphoma (MCL) following prior BTK inhibitor exposure, according to findings from a phase 2 trial (NCT02500407) presented at the 2024 ASH Annual Meeting.1

Among all treated patients (N = 25), the overall response rate (ORR) with mosunetuzumab was 44.0% (95% CI, 24.4%-65.1%), including a complete response (CR) rate of 24.0% (95% CI, 9.4%-45.1%) and a partial response (PR) rate of 20.0% (95% CI, 6.8%-40.7%). The median duration of response (DOR) was 10.3 months (95% CI, 2.3-19.5), and the median duration of complete response (DOCR) was 18.0 months (95% CI, 10.3-22.3).

At a median follow-up of 54.5 months, the median overall survival (OS) was 7.3 months (95% CI, 3.6-25.9). The median progression-free survival (PFS) was 3.7 months (95% CI, 1.4-5.8).

“Fixed-duration mosunetuzumab demonstrated single-agent activity in a challenging-to-treat population of patients with refractory MCL, previously treated with a BTK inhibitor,” lead study author, Elizabeth Budde, MD, PhD, and colleagues stated in a poster presentation of the data. “Response rates were [also] generally consistent in high-risk subgroups.”

Budde is an associate professor in the Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, and the executive medical director of the Enterprise Immune Effector Cell Program at City of Hope in Duarte, California.

Phase 2 Study Design

To be eligible for enrollment in this phase 2 trial, patients must have relapsed or refractory MCL and have previously received at least 1 regimen containing a BTK inhibitor. Patients were also required to have histologically confirmed MCL and could not have received prior treatment with mosunetuzumab.

Patients enrolled in this phase II study received intravenous mosunetuzumab in 21-day cycles. A step-up dosing schedule was employed in cycle 1, with an initial dose of 1 mg on day 1, followed by 2 mg on day 8, and 60 mg on day 15. Patients then received 60 mg on day 1 of cycle 2 and 30 mg on day 1 of all subsequent cycles. Those who achieved a CR by cycle 8 completed treatment; those who achieved a PR or stable disease (SD) continued therapy for up to 17 cycles.

The study’s primary end points were safety and tolerability of mosunetuzumab, with a specific focus on cytokine release syndrome (CRS). Secondary end points included CR rate, ORR, DOCR, DOR, PFS, and OS.

Baseline Characteristics

At the data cutoff of May 13, 2024, 25 patients were enrolled onto the study. The median age was 70 years (range, 50-89), and most patients (92%) had Ann Arbor stage III/IV disease.

Of the 14 patients with available Ki-67 data,4% had a Ki-67 index of less than 30%, 8% had a Ki-67 index of more than 30% but less than 50%, and 44% had a Ki-67 index of more than 50%; Ki-67 status was unknown in 44% (n = 11) of patients. Additionally, the majority of patients (84%) had a Mantle Cell Lymphoma International Prognostic Index (MIPI) score greater than 6.

Bulky disease greater than 6 cm, 7 cm, and 10 cm was reported in 40%, 20%, and 12% of patients, respectively. Blastoid MCL was observed in 28% of patients, and 40% had classic MCL. Fifty-two percent of patients had bone marrow involvement.

Patients received a median of 5 cycles of mosunetuzumab (range, 1-17), with 3 patients completing more than 8 cycles. Regarding prior treatments, 32% of patients had undergone autologous stem cell transplantation. The median number of prior therapy lines was 3 (range, 2-6), with 80% of patients receiving 3 or more prior lines.

A total of 92% of patients were refractory to their last prior therapy, 96% were refractory to a previously administered BTK inhibitor, and 72% had received prior anti-CD20 therapy. Additionally, 64% of patients (n = 16) did not achieve a response with prior BTK inhibitor treatment.

Additional Subgroup and Safety Analyses

Among patients with Ki-67 status of 30% or greater (n = 13), the ORR was 46.2% (95% CI, 19.2%-74.9%), with CRs observed in 30.8% and PRs in 15.4% of patients. In the subgroup of patients with Ki-67 status of at least 50% (n = 11), the ORR was 54.5% (95% CI, 23.4%-83.3%), including CRs in 36.4% and PRs in 18.2%. For patients with blastoid MCL (n = 7), the ORR was 28.6% (95% CI, 3.7%-71.0%), with all responses classified as CRs. In patients with a MIPI score of 6 or higher (n = 21), the ORR was 42.9% (95% CI, 21.8%-66.0%), with CRs in 23.8% and PRs in 19.0% of patients.

Regarding safety, investigators noted that, “The safety profile in MCL was consistent with that demonstrated in the approved indication in [relapsed/refractory follicular lymphoma] and was characterized by predominantly low-grade CRS effects confined to cycle 1, all of which resolved.”

During the treatment period, all patients experienced at least 1 adverse effect (AE), with 88% of patients reporting treatment-related AEs (TRAEs). Grade 3 or higher AEs occurred in 76% of patients, 52% of which were TRAEs. No grade 5 AEs were reported.

Serious AEs, excluding fatal progressive disease, were observed in 56% of patients, 40% of which were TRAEs. Additionally, AEs led to dose interruptions, modifications, and study drug withdrawal in 40%, 4%, and 4% of patients, respectively. One patient discontinued treatment due to a subdural hematoma, which was deemed unrelated to mosunetuzumab.

The most frequently reported AEs included CRS (52%), fatigue (36%), and pyrexia (36%). Grade 3/4 AEs occurring in at least 10% of patients included neutropenia (28%), hypophosphatemia (20%), thrombocytopenia (16%), and anemia (12%). CRS was predominantly low grade, with 48% of patients experiencing grade 1/2 CRS; grade 3 CRS occurred in 4% of patients. No grade 4 or higher CRS effects were reported. The median duration of CRS was 3 days (range, 1-7). Among patients who experienced CRS events, 16% required tocilizumab, and 8% received corticosteroids.

Suspected immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 12% of patients, including grade 1 confusional state (n = 2) and grade 2 delirium (n = 1). Two of these cases occurred concurrently with CRS. All ICANS effects occurred in cycles 1 and 2, were low grade, and resolved without the need for corticosteroid intervention.

“Mosunetuzumab is an off-the-shelf treatment with a convenient dosing schedule and no mandatory hospitalization,” Budde and colleagues concluded. “Currently, mosunetuzumab is being investigated in combination with polatuzumab vedotin[-piiq [Polivy] for patients with relapsed/refractory MCL in a phase Ib/II trial (NCT03671018).”

Reference

Budde LE, Matasar M, Sehn LH, et al. Mosunetuzumab monotherapy demonstrates encouraging activity and a manageable safety profile in patients with heavily pre-treated relapsed or refractory mantle cell lymphoma. Blood. 2024;144(suppl 1): 1646. doi:10.1182/blood-2024-197902