Lunsumio (mosunetuzumab-axgb)

Historically, B and T cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab or ofatumumab...In the treatment of cancer, chimeric antigen receptor (CAR) T cell therapy and T cell engagers (TCE) that recruit T cells to induce B cell cytotoxicity have delivered promising results for anti-CD19 CAR T cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab or epcoritamab. Limited evidence suggests that anti-CD19 CAR T cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T cell collaboration toward overcoming rituximab-resistant AID.

P1/2, N=187, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Nov 2027 --> Feb 2024

P2, N=396, Recruiting, SWOG Cancer Research Network | Trial primary completion date: Dec 2024 --> Dec 2025

P3, N=600, Not yet recruiting, National Cancer Institute (NCI)

P2, N=42, Recruiting, University of Washington | Trial completion date: Aug 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Dec 2025

P1/2, N=422, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Oct 2024 --> Jan 2024

P1/2, N=8, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed | N=118 --> 8 | Trial completion date: Dec 2023 --> Jul 2023 | Trial primary completion date: Dec 2023 --> Jul 2023

P3, N=790, Not yet recruiting, The Lymphoma Academic Research Organisation

P2, N=70, Recruiting, National Cancer Institute (NCI) | Initiation date: Jul 2024 --> Jan 2024

P1/2, N=836, Active, not recruiting, Genentech, Inc. | Trial completion date: Nov 2023 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2025

P1/2, N=40, Not yet recruiting, OHSU Knight Cancer Institute

P1, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: May 2025 --> Dec 2025 | Initiation date: Dec 2023 --> Sep 2024 | Trial primary completion date: May 2025 --> Dec 2025

P1/2, N=188, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P1, N=200, Recruiting, ADC Therapeutics S.A. | Phase classification: P1b --> P1

P1, N=137, Recruiting, Hoffmann-La Roche | N=56 --> 137 | Trial completion date: Jul 2027 --> Oct 2029 | Trial primary completion date: Feb 2026 --> May 2027

These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

This study expands knowledge about the occurrence of target antigen loss after anti-CD20 therapeutics to CD20-targeting bispecific antibodies and elucidates the underlying mechanisms for reduced CD20 expression at disease progression that may be generalizable to other anti-CD20 targeting agents. These results also establish the utility of readily-available IHC staining for CD20 as a tool to inform clinical decisions.

In subanalysis of CD20/CD3 products, pooled all-grade infections did not differ significantly between monotherapy epcoritimab (34% 95%CI: 21 - 47%) and glofitamab (39% 95%CI: 21 - 56%)...Mosunetuzumab was given with R-CHOP in a single study, but all-grade and severe infection rates were not reported...The higher rate of fatal viral and fungal infections highlights a potential need for increased clinical vigilance for infections classically associated with T-cell depletion. Although further data is needed, CD20-targeted BsAb may confer higher infection risk than CD19-directed products.

Eligible treatments included CAR T cell therapies (axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel), T cell engagers (mosunetuzumab, glofitamab, epcoritamab, odronextamab), phosphatidylinositol 3-kinase (PI3K) inhibitors (copanlisib, duvelisib, idelalisib), HSCT, yttrium-90 (90Y) ibritumomab tiuxetan, tazemetostat, and conventional therapies (immunochemotherapies, single- or multiagent chemo- or immunotherapies, and alkylating agents). This SLR demonstrated an evolving FL treatment landscape, with new agents such as CAR T cell therapies and T cell engagers exhibiting potential for improving effectiveness of treatment for patients in 3L+, 4L+, and 2L+ POD24 populations.

SC mosun therapy for newly diagnosed FL was associated with a unique peripheral blood immune profile, with early mobilization of pre-differentiated CD8+ T-cell effector cells and subsequent activation and expansion of newly primed CD8+ T-cells. Further immune phenotyping, including scRNA-seq and TCR clonal dynamics in the peripheral blood over time, as well as TCR clonality of distinct CD8+ and CD4+ T-cell populations are currently being analyzed on these and additional samples, and will be presented in detail.

By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on four post-mosunetuzumab follicular lymphoma relapses and discovered that in two of them downregulation of CD20 was accompanied by the V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.

P2, N=70, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Mar 2026 --> Oct 2026 | Initiation date: Oct 2023 --> Jul 2024 | Trial primary completion date: Mar 2026 --> Oct 2026

P1/2, N=187, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | Phase classification: P1 --> P1/2

P1/2, N=117, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P2, N=76, Recruiting, Memorial Sloan Kettering Cancer Center | N=53 --> 76

Conclusions Axi-cel is cost-effective versus mosun in r/r 3L+ FL at an ICER of $84,016/QALY gained, which is far lower than the commonly-cited US willingness-to-pay threshold of $150,000/QALY. This analysis demonstrates the value of using axi-cel, reflecting the aggregate benefits of a one-time therapy, reduction in need for subsequent treatment lines, and population segment experiencing effective cure.

Outcomes for R/R MCL pts with PD after the BTKi ibrutinib are very poor, demonstrated by a median overall survival of 2.9 months (Martin et al... Eligible pts had histologically confirmed R/R MCL and had received ≥2 prior regimens (including an anti-CD20 agent, BTKi, and anthracycline- or bendamustine-based therapy)...Ten pts (50%) experienced CRS events; 9 pts experienced Gr 1 events, and 1 pt experienced a Gr 2 event, which was managed with tocilizumab and low-flow oxygen... Fixed-duration Mosun SC in combination with Pola IV induced high CR rates in pts with R/R MCL who had previously received BTKi therapy, including those in high-risk subgroups and those who had received prior CAR T-cell therapy. CRs were observed early and persisted during the follow up period. M-Pola had a manageable safety profile, and all CRS events were low grade.

Premedication with dexamethasone (20mg) is mandatory in C1 and C2 and optional thereafter. Acetaminophen and diphenhydramine may also be given... Initial MorningSun data support that SC mosunetuzumab is active in patients with previously untreated, low-tumor burden FL. Safety data demonstrate a manageable safety profile that is consistent with that seen in patients with R/R B-cell NHLs and is supportive of outpatient administration.

Co-lead authors: Habib Hamidi and Patrick Kimes Background: Standard induction therapy cures ~60% of patients (pts) with DLBCL; however, most remaining non-responders die from lymphoma, highlighting a need for improved first-line treatments. Consistent with the Mosun mode of action, pts with high expression of TIMS and those with high levels of circulating T cells had improved PFS versus pts with low expression. In contrast, there was no association between immune cell signatures and PFS in pts treated with R-CHOP, suggesting that the different mode of action of rituximab versus Mosun may influence this. Future studies are warranted to confirm the potential clinical utility of immune cell signatures as biomarkers associated with CD20xCD3 bispecifics' activity.

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells... Baseline biomarker data reveal an important role for CD4 T cells in Mosun response and suggest that higher prevalence of CD4s may be a factor in the improved response to Mosun in indolent NHL. Our data specifically point to Tfh cells as potential drivers of response, although the mechanisms by which Tfh contributes to response, as well as the implications for other bispecifics, requires more exploration.

Prior to initiation of Mosun, many patients had circulating levels of other anti-CD20 drugs (e.g. rituximab (R) or obinutuzumab (G)) from prior treatment. Mosun PK was characterized using a two–compartment model with time dependent CL. R/G PK and CD20 binding kinetics were incorporated into the Mosun popPK model to calculate Mosun CD20 RO% over time. The use of two 60mg loading doses enables early achievement of Mosun steady-state target CD20 RO% range, especially benefitting those pts with high levels of precirculating R or G. Simulations with the popPK model supported labeling recommendations for restarting Mosun treatment after dose delays.

Of the 14 patients with CRS, six (42.9%) received tocilizumab, three (21.4%) received low-flow oxygen, one (7.1%) received a single pressor, and four (28.6%) received steroids; of the patients who received steroids, two (14.3%) received both tocilizumab and steroids. In patients with R/R RT, fixed-duration mosunetuzumab monotherapy demonstrates activity with durable responses and a manageable safety profile in a limited sample size of 20 patients. Treatment with mosunetuzumab warrants further study in this patient population with a high unmet medical need.

This fixed-duration, chemotherapy-free M+Len regimen offers a convenient means for outpatient SC administration, and has a manageable early safety profile with promising anti-lymphoma activity in pts with 1L FL requiring systemic therapy, based on the preliminary data. Advancing M+Len into the first-line setting offers potential benefits in chemotherapy-naïve pts. Safety, efficacy, biomarker, and pharmacokinetic data from the complete cohort (40 pts) will be presented.

Introduction: T cell bispecific antibodies (TCBs), such as blinatumomab, mosunetuzumab or glofitamab, redirect T cells toward cancer cells and rely on endogenous T cell activation and proliferation (Boissel et al., Nature 2023). In conclusion, our data demonstrates the impact of positive co-stimulation on TCB-mediated T cell function. Costimulatory bispecifics provide co-stimulation to T cells in cases of missing expression of costimulatory molecules on tumor cells as well as improving function of exhausted T cells. Clinical trials will be needed to assess the impact of combinatorial strategies to improve T-cell efficacy and to overcome resistance.

We observed higher peripheral blood lymphocytes after one cycle of mosunetuzumab in responding patients. Of interest, an increase in lymphocytes in responding patients had previously been described after blinatumomab (Klinger et al. Blood 2012).

Background: Mosunetuzumab (Mosun), approved for treatment of pts with R/R follicular lymphoma (FL) and ≥2 prior therapies, and glofitamab (Glofit), approved for treatment of pts with R/R diffuse large B-cell lymphoma, or large B-cell lymphoma arising from FL, and ≥2 prior therapies, are CD20xCD3 T-cell engaging bispecific antibodies that redirect T cells to eliminate B cells. qCP results and clinical experience in Mosun and Glofit studies support a TCZ dosing regimen of ≤2 IV doses of 8 mg/kg per CRS event administered q8h, not exceeding a total of 3 doses within a 6-week period. Further improvement in CRS management and symptom resolution with additional TCZ doses is unlikely given the predicted duration of s-IL6R occupancy and observed rapid decline in systemic inflammatory markers post dosing. This proposed TCZ dosing regimen reflects TCZ usage patterns in clinical trials evaluating Mosun and Glofit, and is included in their Summaries of Product Characteristics.

In this initial investigation of immune cell changes in patients who received mosunetuzumab without prior chemotherapy exposure, we observed B-cell depletion and a temporary decrease in CD8+ cytotoxic T-cells (implying their migration out of the bloodstream), aligning with mosunetuzumab's mechanism of action. Additional data from this trial will aid in understanding whether the persistent increase in PD1+CD8+ T-cells and expansion of Tregs are linked to a functionally exhausted phenotype and whether lenalidomide could potentially reverse it. Although our observation is limited by sample size, it can still provide insights into optimizing the administration schedules of BiAb therapy in future trials (e.g., intermittent vs.

At 100mg dose, there were 5 evaluable patients, with ORR 100% (5/5), CRR 80% (4/5) and PR (20%, 1/5; mosunetuzumab-refractory rrDLBCL patient)...All cases of CRS were grade 1 (8.5%, 4/47) or 2 (4.3%, 2/47), no grade 3 (Lee et al., ASTCT criteria), no interruptions of treatment, and no administration of Tocilizumab... GB261, a novel and highly differentiated CD20/CD3 bispecific antibody, is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated B-NHL patients, GB261 showed a highly advantageous safety/efficacy balance, consistent with the MOA. The safety profile is excellent especially for the CRS which is very mild, transient and less frequent compare with other CD20/CD3 bispecific antibodies.

Background: T cell engaging therapies including mosunetuzumab (mosun), a CD20/CD3 bispecific antibody, and two CAR-T cell products – axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are FDA approved for the treatment of third line and beyond relapsed/refractory (R/R) follicular lymphoma (FL). Our model indicates that mosun is more cost-effective compared to both axi-cel and tisa-cel at 1, 2, 5 and 10 years for treatment of R/R FL. Axi-cel showed improved QALY at 10 years due to improved long term PFS, however mosun remained cost effectiveness even at the 10 year horizon. Longer term follow up of patients treated with mosun as well as real world data of ORR, PFS and OS of patients treated with CAR-T after bispecific antibodies may impact future cost effectiveness and QALY comparisons.

P2, N=80, Recruiting, Oslo University Hospital | Not yet recruiting --> Recruiting | Initiation date: Jun 2023 --> Sep 2023

Here we show that treatment with mosunetuzumab in patients results in natural killer (NK) cell activation in the peripheral blood...Finally, we showed that TDB treatment enhanced the efficacy of Fc-driven killing to an orthogonal solid tumor target in vivo. These results provide rationale for novel antibody therapy combinations that take advantage of both adaptive and innate immune responses.