Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Pharmacotherapeutic group: Antineoplastic agents; Other monoclonal antibodies and antibody drug conjugates
ATC code: L01FX25
Mosunetuzumab is an anti-CD20/CD3 T-cell engaging bispecific antibody targeting CD20-expressing B-cells. It is a conditional agonist; targeted B-cell killing is observed only upon simultaneous binding to CD20 on B-cells and CD3 on T-cells. Engagement of both arms of mosunetuzumab results in the formation of an immunologic synapse between a target B-cell and a cytotoxic T cell leading to T-cell activation. Subsequent directed release of perforin and granzymes from T-cell activation through the immunologic synapsis induce B-cell lysis leading to cell death.
Lunsumio subcutaneous injection caused B-cell depletion (defined as CD19 B-cell counts <5 cells/uL) after the initial cycle of administration (by Cycle 2 Day 1) by both intravenous and subcutaneous administration routes in a majority of patients (95.2% and 94.1% respectively) and depletion was maintained throughout the duration of treatment.
An open-label, multicenter, multi-cohort study (GO29781) was conducted to evaluate Lunsumio SC in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. In the follicular lymphoma (FL) subcutaneous cohort (n=94), patients with relapsed or refractory FL (grade 1-3A) were required to have received at least two prior systemic therapies, including an anti-CD20 monoclonal antibody and an alkylating agent.
The study excluded patients with active autoimmune disease, active infections (i.e. chronic active EBV, acute or chronic hepatitis C, hepatitis B, HIV), progressive multifocal leukoencephalopathy, a history of CNS lymphoma, a history of macrophage activation syndrome/haemophagocytic lymphohistiocytosis, prior allogeneic stem cell transplant, or prior organ transplantation.
Patients received Lunsumio subcutaneously in a 21-day Cycle as follows:
The median number of cycles was 8, 63% received 8 cycles, and 14.9% received more than 8 cycles up to 17 cycles.
The median age was 65 years (range 35 to 84 years) with 50% being > age 65, and 12.8% being ≥ age 75. Fifty-six percent were male, 85% were white, 11% were Asian, 2% were Black, 100% had an ECOG performance status of 0 or 1 and 25% of patients had bulky disease (at least one lesion >6 cm). The median number of prior therapies was 3 (range: 2-9), with 47% receiving 2 prior therapies, 19% receiving 3 prior therapies and 34% receiving more than 3 prior therapies.
All patients received prior anti-CD20 and alkylator therapies, 20% received autologous stem cell transplant, 12% received PI3K inhibitors, 16% received prior rituximab plus lenalidomide therapy, and 4% received CAR-T therapies. Sixty-seven percent of patients were refractory to prior anti-CD20 monoclonal antibody therapy and 46% were refractory to both anti-CD20 monoclonal antibody and alkylator therapy. Sixty-three percent of patients were refractory to the last prior therapy and 44% had progression of disease within 24 months of first systemic therapy.
The primary objective in this cohort was to demonstrate pharmacokinetic non-inferiority (PKNI) of Lunsumio subcutaneous injection compared to Lunsumio intravenous infusion based on the exposure endpoints of AUC0-84days, and Ctrough(Cycle 3). The efficacy results are summarised in Table 7.
Table 7. Summary of efficacy in patients with relapsed/refractory FL:
| Efficacy parameter | Lunsumio subcutaneous injection N=94 |
| Median observation time 20.7 months (range 1–34 months) | |
| Complete response (CR), n (%), (95% CI) | 55 (58.5) (47.9, 68.6) |
| Objective response rate (ORR), n (%) (95% CI) | 70 (74.5) (64.4, 82.9) |
| Partial response (PR) n (%) (95% CI) | 15 (16.0) (9.2, 25.0) |
| Duration of response (DOR)1 | N=70 |
| Patients with event, n (%) | 26 (37.1) |
| Median, months (95% CI) | 22.4 (16.8, 22.8) |
| K-M event-free proportion, | |
| 12 months (95% CI) | 69.9 (58.5, 81.4) |
| 18 months (95% CI) | 59.6 (45.8, 73.3) |
| Duration of complete response (DOCR)2 | N=55 |
| Patients with event, n (%) | 19 (34.5) |
| Median, months (95% CI) | 20.8 (18.8, NR) |
| K-M event-free proportion, | |
| 12 months (95% CI) | 72.4 (59.9, 84.8) |
| 18 months (95% CI) | 65.6 (51.0, 80.2) |
CI=confidence interval; K-M=Kaplan-Meier; NR=not reached.
Clinical Cut-off: 01 February 2024
1 DOR is defined as the time from the initial occurrence of a documented PR or CR until the patient experiences an event (documented disease progression or death due to any cause, whichever occurs first).
2 DOCR is defined as the time from the initial occurrence of a documented CR until the patient experiences an event (documented disease progression or death due to any cause, whichever occurs first).
The median follow-up for DOR was 16.0 months. Additional exploratory efficacy outcomes included the median time to first response (2.8 months, range: 1-16) and the median time to first complete response (2.9 months, range: 1-14).
The immunogenicity of mosunetuzumab was evaluated using an enzyme-linked immunosorbent assay (ELISA). No patients tested positive for anti-mosunetuzumab antibodies in 216 ADA-evaluable patients who received Lunsumio single-agent subcutaneous treatments in Groups D and F of Study GO27981. Based on the available information, the clinical relevance of anti-mosunetuzumab antibodies could not be assessed.
The European Medicines Agency has deferred the obligation to submit results of studies with Lunsumio in one or more subsets of the paediatric population in treatment of mature B-cell neoplasms (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The Lunsumio subcutaneous monotherapy dosing regimen of 5/45/45 mg was found to be pharmokinetically non-inferior to the Lunsumio intravenous infusion 1/2/60/30 mg monotherapy dosing regimen in relapsed or refractory follicular lymphoma patients with ≥2 prior therapies. The subcutaneous intravenous geometric mean ratio (90% CI) was 1.39 (1.20-1.61) for CtroughCYC3_OBS and 1.06 (0.92-1.21) for AUC0-84.
Similar to Lunsumio intravenous infusion, Lunsumio subcutaneous injection pharmacokinetic exposure increased in an approximately dose-proportional manner over the dose ranges studied. As compared to the intravenous route, the subcutaneous route maintained a high relative bioavailability, and had a slower absorption resulting in a lower Cmax, and delayed Tmax.
After the first cycle (i.e. 21 days) of the dosing with mosunetuzumab, the serum concentration reaches the Cmax before the start of Cycle 2 Day 1 of the mosunetuzumab subcutaneous dosing regimen with an average maximum concentration of 3.81 μg/mL and %CV of 53.9%. Pharmacokinetic exposures are summarized in Table 8.
Table 8. Exposure parameters of mosunetuzumab subcutaneous injection:
| Model-predicted AUC (day·μg/mL)1 | Model-predicted Cmax (μg/mL)1 | Model-predicted Ctrough (μg/mL)1 | |
| Cycle 1 (0-21 days) | 36.7 (57.0) | 3.81 (53.9) | 3.45 (54.1) |
| Cycle 2 (21-42 days) | 82.3 (50.9) | 5.16 (50.3) | 2.52 (55.7) |
| Steady-state2 | 72.8 (34.5) | 4.40 (36.7) | 2.41 (34.2) |
1 Values are geometric mean with geometric CV%
2 Steady-state values are approximated at Cycle 4 (63–84 days)
Lunsumio is administered subcutaneously. Tmax was reached around 4 to 7 days. Relative bioavailability (F) of the subcutaneous injection regimen relative to the intravenous infusion regimen at steady state was 0.898 (95% CI: 0.828–0.975).
The population estimate of central volume of distribution for mosunetuzumab was 5.49 L with intravenous infusion and subcutaneous injection of Lunsumio. Because mosunetuzumab is an antibody, protein binding studies were not conducted.
The metabolic pathway of mosunetuzumab has not been directly studied. Like other protein therapeutics, mosunetuzumab is expected to be degraded into small peptides and amino acids via catabolic pathways.
Based on a population pharmacokinetic analysis, when administered intravenously, the estimated mean CLss and baseline clearance (CLbase) were 1.08 L/day and 0.584 L/day, respectively. The terminal half-life for mosunetuzumab subcutaneous was 16.8 days at steady state based on population pharmacokinetic PK model estimates.
Age did not have an effect on the pharmacokinetics of mosunetuzumab based on a population pharmacokinetic analysis with patients aged 18-88 years (n=228). No effect age related effect on subcutaneous absorption of mosunetuzumab was observed for patients in this age groups.
Like other therapeutic proteins, bodyweight was positively associated with mosunetuzumab estimated clearance and volume of distribution. However, based on exposure-response analysis and clinical exposure margins, considering the exposures in patients at either "low" (<50 kg) or "high" (≥112 kg) weight, no dose adjustment is required due to patient bodyweight.
Based upon population pharmacokinetic analysis, steady-state clearance of mosunetuzumab is marginally lower in females (~13%) compared to males. No dose adjustment is required due to gender, based on exposure-response analysis.
Race (Asian vs. non-Asian) was not identified as a covariate influencing mosunetuzumab pharmacokinetics.
No dedicated studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of mosunetuzumab. The renal elimination of intact mosunetuzumab, an IgG monoclonal antibody, is expected to be low and of minor importance.
The population pharmacokinetic PK analysis of mosunetuzumab subcutaneous administration showed that creatinine clearance (CrCl) does not affect pharmacokinetics of mosunetuzumab. Pharmacokinetics of mosunetuzumab in patients with mild (CrCl 60 to 89 mL/min, n=92) or moderate (CrCl 30 to 59 mL/min, n=41) renal impairment were similar to those in patients with normal renal function (CrCl ≥90 mL/min, n=88). Pharmacokinetic data in patients with severe renal impairment (CrCl 15 to 29 mL/min) is limited (n=1), therefore no dose recommendations can be made. Lunsumio subcutaneous injection was not studied in patients with end-stage renal disease and/or who are on dialysis.
No specific studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of mosunetuzumab. IgGs are mainly eliminated via intracellular catabolism and hepatic impairment is not expected to influence clearance of mosunetuzumab.
The population PK analysis of mosunetuzumab showed that hepatic impairment does not affect pharmacokinetics of mosunetuzumab. Pharmacokinetics of mosunetuzumab in patients with mild hepatic impairment (total bilirubin > ULN to 1× x ULN or AST > ULN, n=35) were similar to those in patients with normal hepatic function (n=191). The number of patients with moderate (total bilirubin >1.5–3 x ULN, any AST, n=1) or severe (total bilirubin >3-10 x ULN, any AST, n=2) hepatic impairment is limited.
No studies have been conducted to investigate the pharmacokinetics of mosunetuzumab in the paediatric population (<18 years old).
Key nonclinical findings with mosunetuzumab identified in single- and repeat-dose toxicity studies up to 26-weeks in duration included transient post-dose CRS primarily limited to the first dose, vascular/perivascular inflammatory cell infiltrates that were primarily in the CNS and infrequently in other organs that were likely secondary to cytokine release and immune cell activation, and increased susceptibility to infection following chronic dosing due to sustained B-cell depletion.
All of the findings were considered pharmacologically-mediated effects and reversible. Across studies there was a single incidence of convulsion in one animal at Cmax and AUC exposures (time-averaged over 7 days) of 3.3- and 1.8-fold higher, respectively, than those in patients receiving Lunsumio at the recommended dose and schedule in Study GO29781.
An assessment of the male and female reproductive organs was included in a 26-week chronic toxicity study in sexually mature cynomolgus monkeys administered by intravenous infusion. Mosunetuzumab had no effect on either male or female reproductive organs at exposures (AUC) similar to exposure (AUC) in patients receiving the recommended dose.
No developmental toxicity studies in animals have been conducted with mosunetuzumab. Based on low placental transfer of antibodies during the first trimester, the mechanism of action and available data of mosunetuzumab, and the data on the anti-CD20 antibody class, the risk for teratogenicity is low. Studies with mosunetuzumab in non-pregnant animals have demonstrated that prolonged B-cell depletion can lead to increased risk of opportunistic infection, which may cause foetal loss. Transient CRS associated with Lunsumio administration may also be harmful to pregnancy.
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