Mosunetuzumab

Live and/or live-attenuated vaccines should not be given concurrently with mosunetuzumab. Studies have not been conducted in patients who recently received live vaccines.

A transient clinically relevant effect on CYP450 substrates with a narrow therapeutic index (e.g. warfarin, voriconazole, cyclosporine, etc) cannot be excluded, since initiation of mosunetuzumab treatment causes a transient increase in cytokine levels which may cause inhibition of CYP450 enzymes. On initiation of mosunetuzumab therapy in patients being treated with CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered. The dose of the concomitant medicinal product should be adjusted as needed.

Mosunetuzumab has not been studied in patients with severe renal impairment.

Mosunetuzumab should not be administered in the presence of active infections. Caution should be exercised when considering the use of mosunetuzumab in patients with a history of recurring or chronic infections (e.g., chronic, active Epstein-Barr Virus), with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Patients should be administered prophylactic antibacterial, antiviral and/or antifungal medicinal products, as appropriate. Patients should be monitored for signs and symptoms of infection, before and after mosunetuzumab administration, and treated appropriately. In the event of febrile neutropenia, patients should be evaluated for infection and managed with antibiotics, fluids and other supportive care, according to local guidelines.

There are no data from the use of mosunetuzumab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Mosunetuzumab is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether mosunetuzumab/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with mosunetuzumab therapy.

Women of childbearing potential/Contraception

Women of childbearing potential should use effective contraception while receiving mosunetuzumab and for at least 3 months after the last infusion of mosunetuzumab.

Fertility

No human data on fertility are available. No impairments were observed in male or female reproductive organs in the 26-week toxicity studies with cynomolgus monkeys at exposures (AUC) similar to exposure (AUC) in patients receiving the recommended dose.

Mosunetuzumab has a major influence on the ability to drive and use machines. Due to the potential for ICANS, patients receiving mosunetuzumab are at risk of depressed level of consciousness. Due to the potential for ICANS, patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling or using heavy or potentially dangerous machines.

Summary of safety profile

The adverse reactions described in this section were identified from the pivotal clinical trial GO29781 in patients treated at the recommended intravenous dose (n=218) and the recommended subcutaneous dose (n=139). Patients had follicular lymphoma (51.8%), diffuse large B-cell lymphoma (26.9%), transformed follicular lymphoma (9.8%) mantle cell lymphoma (7.3%), Richter's transformation (3.9%), and other histologies (0.3%). The median number of cycles of mosunetuzumab intravenously received was 8 (range 1-17), 37% of patients received 8 cycles, and 15% received more than 8 cycles up to 17 cycles.

Patients who received the recommended intravenous dose (n=218) and subcutaneous (n=139) dose are pooled (n=357) for this safety population. In this pooled safety population, the most common adverse reactions (≥20%) observed were cytokine release syndrome, neutropenia, rash and upper respiratory tract infection. The most common serious adverse reactions (≥2%) observed included cytokine release syndrome (CRS) (17% by ASTCT grading system), pyrexia (3%), sepsis (3%), upper respiratory tract infection (3%) and pneumonia (5%). Permanent discontinuation of mosunetuzumab due to an adverse reaction occurred in 5.8% (21/357) of patients. In patients who received the recommended intravenous dose (n=218), CRS was the only adverse reaction that led to discontinuation in more than one patient (2 patients [0.9%]).

Tabulated list of adverse reactions

The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions occurring in patients treated with mosunetuzumab:

¹ Upper respiratory tract infection includes upper respiratory tract infection, viral upper respiratory tract infection, nasopharyngitis, sinusitis, rhinovirus infection, sinusitis bacterial, viral sinusitis, respiratory tract infection, COVID-19 and respiratory tract infection viral
² Urinary tract infection (UTI) includes UTI, Escherichia UTI, pyelonephritis acute
³ Pneumonia includes pneumonia and COVID-19 pneumonia
⁴ Lower respiratory tract infection includes lower respiratory tract infection and bronchitis
⁵ Sepsis includes sepsis, septic shock, bacteraemia, Candida sepsis
⁶ Tumour flare includes tumour flare, pleural effusion, tumour inflammation and flank pain
⁷ Neutropenia includes neutropenia and neutrophil count decreased
⁸ Thrombocytopenia includes thrombocytopenia and platelet count decreased
⁹ Haemophagocytic lymphohistocytosis (HLH) includes HLH
¹⁰ By American Society for Transplantation and Cellular Therapy
¹¹ Hypophosphatemia includes hypophosphatemia and blood phosphorus decreased
¹² Hypokalemia includes hypokalemia and blood potassium decreased
¹³ Hypomagnesemia includes hypomagnesemia and blood magnesium decrease
¹⁴ Headache includes headache, migraine and head discomfort
¹⁵ Dizziness includes dizziness and vertigo
¹⁶ Consistent with the medical concept of ICANS according to American Society for Transplantation and Cellular Therapy and includes confusional state, ICANS, lethargy, encephalopathy, depressed level of consciousness, and memory impairment
¹⁷ The frequency calculation is based on additional clinical studies
¹⁸ Rash includes rash, rash erythematous, exfoliative rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, erythema, palmar erythema, dermatitis, dermatitis acneiform, dermatitis contact, palmar-planta erythrodysaesthesia and rash morbiliform
¹⁹ Grade 5 AEs only occurred for ADR terms HLH, pneumonia, sepsis and URTI (i.e., COVID-19) in mosunetuzumab subcutaneous injection (1 each) and for ADR terms Pneumonia and Sepsis in mosunetuzumab intravenous infusion (1 each)

Description of selected adverse reactions

Cytokine release syndrome (CRS)

In patients treated with mosunetuzumab intravenous infusion, CRS (ASTCT grading system) of any grade occurred in 39% (86/218) of patients, with grade 2 occurring in 14%, grade 3 occurring in 2.3%, and grade 4 occurring in 0.5% of patients treated with mosunetuzumab. The one patient with the grade 4 event was a patient with FL in the leukemic phase who also experienced concurrent TLS.

CRS of any grade occurred in 15% of patients after the Cycle 1, Day 1 dose; 5% after the Cycle 1, Day 8 dose; 33% after the Cycle 1, Day 15 dose, 5% occurred in patients after the Cycle 2 and 1% in Cycles 3 and beyond. The median time to CRS onset from the start of administration in Cycle 1 Day 1 was 5 hours (range: 1-73 hours), Cycle 1 Day 8 was 28 hours (range: 5-81 hours), Cycle 1 Day 15 was 25 hours (range: 0.1-391 hours), and Cycle 2 Day 1 was 46 hours (range: 12-82 hours). CRS resolved in all patients, and the median duration of CRS events was 3 days (range 1-29 days).

Of the 86 patients that experienced CRS, the most common signs and symptoms of CRS included pyrexia (98%), chills (36%), hypotension (35%), tachycardia (24%), hypoxia (22%) and headache (16%).

Tocilizumab and/or corticosteroids were used to manage a CRS event in 16% of patients: 6% received tocilizumab alone, 6% received corticosteroids alone, and 4% received both tocilizumab and corticosteroids. Among the 10% of patients who received tocilizumab (with or without a corticosteroid), 86% received only one dose of tocilizumab, with no more than two doses of tocilizumab administered for a single CRS event. In patients experiencing Grade 2 CRS, 48% of patients were treated with symptomatic management without corticosteroids or tocilizumab, 18% received tocilizumab alone, 21% received corticosteroids alone, and 12% received both corticosteroids and tocilizumab. Patients with grade 3 or grade 4 CRS received tocilizumab, corticosteroids, vasopressors and/or oxygen supplementation. Three percent of patients experienced hypotension and/or hypoxia without fever following mosunetuzumab administration; 2% of patients received tocilizumab and/or corticosteroids in the absence of fever.

Hospitalisations due to CRS occurred in 21% of patients and the median duration of hospitalisation was 5 days (range 0-30 days).

Neutropenia

In patients treated with mosunetuzumab intravenous infusion or subcutaneous injection, neutropenia of any grade occurred in 26.1% (93/357) of patients, including 22.7% Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased events was 50 days (range: 1-280 days), with median duration of 8 days (range: 1-487 days). Of the 93 patients who had neutropenia/neutrophil count decreased events 68% (63/93) received treatment G-CSF to treat the events.

Serious infections

In patients treated with mosunetuzumab intravenous infusion or subcutaneous injection, serious infections of any grade occurred in 17% (60/357) of patients. Five (1.4%) of patients experienced serious infections concurrently with grade 3-4 neutropenia. The median time to onset of first serious infection was 92 days (range: 1-408 days), with median duration of 15.5 days (range: 2-174 days). Grade 5 events occurred in 2.5% (9/357) of patients, which included COVID-19 pneumonia, COVID-19, pneumonia, septic shock and sepsis.

Immune Effector Cell-Associated Neurotoxicity Syndrome

Across a broader clinical trial population, Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurred in 2.1% (20/949) of patients, 19 patients had Grade 1-2 events and 1 patient had Grade 3 event. The majority of events occurred during the first cycle of treatment. The majority of cases resolved. The median time to onset from initial dose was 17 days (range: 1 to 48 days). The median duration was 3 days (range: 1-20 days). Immune Effector Cell-Associated Encephalopathy (ICE) scoring was not systematically performed across the referenced trial population.

Tumour flare

In patients treated with mosunetuzumab intravenous infusion or subcutaneous injection, tumour flare (including pleural effusion and tumour inflammation) occurred in 3.1% (11/357) of patients, which included 1.4% grade 2 and 1.4% grade 3 events. The median time to onset was 13 days (range 2-84 days), and median duration was 36 days (range 15-105 days).

Tumour Lysis Syndrome (TLS)

In patients treated with mosunetuzumab intravenous infusion or subcutaneous injection, TLS occurred in 0.6% (2/357) of patients, concurrent with CRS. One patient with follicular lymphoma was in the leukemic phase who experienced Grade 4 TLS. TLS onset was on days 2 and 24, and resolved within 3 and 6 days, respectively.