Evidence of Benefit of Mosunetuzumab in Relapsed/Refractory NHL Following CAR-T Cell Therapy

The following article features coverage from the American Society of Hematology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

According to results of a study reported in a plenary session at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, FL, nearly one-quarter of patients with non-Hodgkin lymphoma (NHL) who had received prior chimeric antigen receptor T-cell (CAR-T) therapy achieved a complete remission (CR) following administration of mosunetuzumab, a bispecfic antibody that binds both CD3 on T cells and CD20 on B cells.¹

Therapeutic options for patients with heavily pretreated B-cell malignancies are limited, particularly for those patients who have previously received CAR-T cell therapy, and the prognosis for these patients is poor.

Single-agent, off-the-shelf mosunetuzumab, an immunoglobulin –G₁ bispecific antibody that induces crosslinks between the CD3 component of the T-cell receptor, and CD20, a surface antigen on B cells, has previously been reported to show antitumor activity and good tolerability according to results of an ongoing, open-label, phase 1/1b schedule-optimizing, dose-escalation and expansion study (ClinicalTrials.gov Identifier: NCT02500407) of mosunetuzumab in patients with relapsed/refractory NHL receiving late-line therapy.^2,3

This interim analysis included 270 adult patients with relapsed/refractory NHL in the dose-escalation cohort of the study, including 85 patients with indolent NHL (ie, mostly follicular lymphoma) and 180 patients with aggressive NHL (ie, mostly those with either diffuse large B-cell lymphoma [DLBCL] or follicular lymphoma). These patients were heavily pretreated with a median of 3 prior systemic therapies.

Treatment with mosunetuzumab involved cycle 1 “step-up” dosing with increasing amounts of the antibody delivered on days 1, 8, and 15 of the first cycle, followed by administration of a fixed dose every 3 weeks. Patients achieving a CR discontinued treatment after 8 cycles, while a maximum of 17 cycles of mosunetuzumab was administered to those with a best response of partial response or stable disease.

In the overall group of 67 patients with indolent NHL who were evaluable for efficacy, the ORR was 62.7% and the CR rate was 43.3%, whereas in the corresponding group of 124 patients with aggressive NHL, the respective rates were 37.1% and 19.4%.

Also notable was the durability of the CRs to mosunetuzumab — 82.8% of patients with indolent NHL and 70.8% of patients with aggressive NHL who achieved a CR maintained this CR at a median follow-up period of up to 26 and 16 months off treatment, respectively.

A patient subgroup of particular interest was comprised of those who had previously received CAR-T therapy. Eighteen of the 30 patients in this subgroup were eligible for the efficacy analysis, which showed an overall response rate (ORR) of 38.9% and a CR rate of 22.2%. Notably, approximately three-quarters of these patients were refractory to CAR-T therapy.

Four patients who experienced disease relapse following a CR were retreated with mosunetuzumab. Within this small subgroup, 1 and 2 patients achieved a CR and a PR, respectively. Interestingly, the former patient received additional treatment with mosunetuzumab following disease progression at 16 months off treatment, and subsequently experienced at CR after cycle 2 of mosunetuzumab retreatment that was ongoing at a follow-up of 13 months.

Regarding the safety of mosunetuzumab in the overall study population, grade 3/4 neutropenia occurred in 21.8% of patients, and a single grade 5 event of pneumonia occurred in a nonneutropenic patient.

Cytokine release syndrome (CRS) occurred at a frequency 28.9%, although most of these events were classified as grade 1/2, with grade 3 CRS in 1.1% of patients, and most CRS events occurring during cycle 1 of treatment. Tocilizumab was administered to only 8 patients with CRS (3%).

“With early step-up fractionated dosing, there has been no apparent increase in CRS frequency with dose escalation,” commented Stephen Schuster, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, who presented the results of this study.

While none of the 4 patients undergoing retreatment with mosunetuzumab experienced CRS, 26.7% (grade 3: 3.3%) of the 30 patients treated with mosunetuzumab following disease relapse after CAR-T therapy experienced this adverse event, similar to findings for the overall population

Neurological adverse events, such as headache, insomnia, and dizziness, occurred at a frequency of 44%; while most were classified as either grade 1/2, grade 3 events were reported in 3.7% of patients. Potential immune effector cell-associated neurotoxicity syndrome (ICANS)-like neurological adverse events, manifesting as transient grade 1 or 2 confusion and/or lethargy, were identified in 3 patients. 

Dose optimization of mosunetuzumab is ongoing in this study.

Disclosures: Nine of the study authors reported financial relationships with Genentech, Inc., the sponsor of the presented clinical trial, and with Hoffmann-La Roche, Ltd., of which Genentech, Inc. is a subsidiary.  For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of ASH’s annual meeting by visiting the conference page.

References

1. Schuster SJ, Bartlett  NL, Assouline S, et al.Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell (CAR-T) therapies and is active in treatment through multiple lines. Presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 6.
2. Bartlett NL, Sehn LH, Assouline SE, et al. Managing cytokine release syndrome (CRS) and neurotoxicity with step-up dosing of mosunetuzumab in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. J Clin Oncol. 2019;37(15_suppl):Abstract 7518.
3. 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 . Blood. 2018;132(suppl_1):Abstract 399.