Mosunetuzumab

Mosunetuzumab is a full-length, humanised anti-CD20/CD3 immunoglobulin G1 (IgG1) antibody made in Chinese hamster ovary cells by recombinant DNA technology. One binding arm recognises CD20 on B cells and the other recognises CD3 on T cells, so it works as a T-cell-engaging bispecific antibody.

Mechanism of Action

• Conditional killing: B cells are killed only when mosunetuzumab is bound to CD20 on the B cell and to CD3 on a T cell at the same time.
• Immunologic synapse: engagement of both arms brings the target B cell and a cytotoxic T cell together in an immunologic synapse and activates the T cell. The T cell then releases perforin and granzymes through the synapse, which lyses the B cell.
• B-cell depletion: by the start of cycle 2, B cells (CD19 count below 5 cells/µL) were depleted in most patients (95.2% with the intravenous and 94.1% with the subcutaneous route), and depletion was maintained throughout treatment.
• Cytokine rise: starting treatment causes a transient increase in cytokine levels, which may inhibit CYP450 enzymes (see Drug Interactions).

Pharmacokinetics

• Dose proportionality: exposure rose approximately in proportion to dose over the range studied, 0.05 to 60 mg. Intravenous pharmacokinetics are described by a two-compartment model with time-dependent clearance.
• Absorption: after an intravenous infusion the serum concentration peaks at the end of the infusion (mean Cmax 17.9 µg/mL at the end of the cycle 2 day 1 dose) and then declines in two phases. After subcutaneous injection, absorption is slow and bioavailability is high (above 75% in clinical trials).
• Distribution: the central volume of distribution is 5.49 L. As an antibody, no protein-binding studies were done.
• Metabolism: not studied directly; like other protein therapeutics it is expected to be broken down into small peptides and amino acids by catabolic pathways.
• Elimination: mean clearance at steady state is 1.08 L/day and baseline clearance 0.584 L/day; the terminal half-life at steady state is 16.1 days.
• Special populations: age (19 to 96 years) had no clinically important effect on pharmacokinetics. On pharmacokinetic grounds no dose adjustment is considered necessary in mild to moderate renal impairment or in hepatic impairment, although severe renal impairment and hepatic impairment have not been studied.

• Follicular lymphoma: as monotherapy for adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.
• This indication applies to both the intravenous (infusion) and the subcutaneous (injection) formulation. They are not interchangeable.

• Hypersensitivity to mosunetuzumab or to any of the excipients (SmPC section 6.1).

The reactions below come from the pivotal trial GO29781 in 357 patients (218 given the recommended intravenous dose and 139 the recommended subcutaneous dose), who 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%) or other histologies (0.3%). The most common reactions (≥20%) were cytokine release syndrome, neutropenia, rash and upper respiratory tract infection. The most common serious reactions (≥2%) were cytokine release syndrome (17% by ASTCT grading), pneumonia (5%), pyrexia (3%), sepsis (3%) and upper respiratory tract infection (3%). Treatment was stopped permanently because of an adverse reaction in 5.8% of patients (21/357); in patients given the intravenous dose, cytokine release syndrome was the only reaction that led to discontinuation in more than one patient (2 patients, 0.9%).

Very common (≥1/10): upper respiratory tract infection, neutropenia, anaemia, thrombocytopenia, cytokine release syndrome, hypophosphataemia, hypokalaemia, headache, diarrhoea, nausea, rash, pruritus, dry skin, pyrexia, chills.

Common (≥1/100 to <1/10): urinary tract infection, pneumonia, lower respiratory tract infection, sepsis, tumour flare, febrile neutropenia, hypomagnesaemia, dizziness, immune effector cell-associated neurotoxicity syndrome (ICANS), skin exfoliation, increased alanine aminotransferase, increased aspartate aminotransferase.

Uncommon (≥1/1,000 to <1/100): haemophagocytic lymphohistiocytosis, tumour lysis syndrome.

Cytokine release syndrome, ICANS, serious and sometimes fatal infections, haemophagocytic lymphohistiocytosis (including fatal cases), tumour flare and tumour lysis syndrome are the most important serious reactions (see Special Instructions).

No interaction studies have been performed.

• CYP450 substrates with a narrow therapeutic index (for example warfarin, voriconazole, ciclosporin): the transient rise in cytokines when treatment starts may inhibit CYP450 enzymes, so a transient clinically relevant effect cannot be excluded. Consider therapeutic monitoring when starting Lunsumio and adjust the dose of the concomitant medicine as needed.
• Live and live-attenuated vaccines: should not be given at the same time as Lunsumio; studies have not been done in patients who recently received live vaccines.

Lunsumio must be given only under the supervision of a healthcare professional qualified in the use of anti-cancer therapies, in a setting with appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The patient should be well hydrated, and the trade name and batch number of the product given should be recorded.

There are two formulations, intravenous (IV) and subcutaneous (SC) fixed dose, and the product label must be checked so that the prescribed one is given. The IV formulation is for infusion only and the SC formulation for subcutaneous injection only.

Premedication

• IV infusion: all patients in cycles 1 and 2, and from cycle 3 only patients who had CRS of any grade with the previous dose. An intravenous corticosteroid (dexamethasone 20 mg preferred, or methylprednisolone 80 mg) is completed at least 1 hour before the infusion; an antihistamine (50–100 mg diphenhydramine hydrochloride or an equivalent oral or intravenous antihistamine) is given at least 30 minutes before; and an antipyretic (500–1,000 mg paracetamol) is also given.
• SC injection: all patients in cycle 1, and from cycle 2 only patients who had CRS of any grade with the previous dose. An intravenous or oral corticosteroid (dexamethasone 20 mg preferred, or methylprednisolone 80 mg) is given; an antihistamine (50–100 mg diphenhydramine hydrochloride or equivalent) and an antipyretic (500–1,000 mg paracetamol) are optional in cycle 1 and beyond.

Recommended Dose: Intravenous Infusion

Each cycle lasts 21 days.

• Cycle 1: day 1, 1 mg; day 8, 2 mg; day 15, 60 mg.
• Cycle 2: day 1, 60 mg.
• Cycle 3 and beyond: day 1, 30 mg.
• The cycle 1 infusions run over a minimum of 4 hours. If they were well tolerated, later infusions may run over 2 hours.
• The medicine is diluted under aseptic technique by a healthcare professional and given through a dedicated infusion line without an in-line filter (drip chamber filters may be used). It must never be given as an intravenous push or bolus.

Recommended Dose: Subcutaneous Injection

Each cycle lasts 21 days.

• Cycle 1: day 1, 5 mg; day 8, 45 mg; day 15, 45 mg.
• Cycle 2 and beyond: day 1, 45 mg.
• The injection goes into the tissue of the abdomen or thigh. The site is changed with each dose, and never into skin with tattoos, moles or scars, or skin that is red, bruised, tender, hard or not intact.

Duration of Treatment

• Both formulations are given for 8 cycles, unless the patient has unacceptable toxicity or disease progression.
• After a complete response, no treatment beyond 8 cycles is needed. After a partial response or stable disease at cycle 8, a further 9 cycles (17 in total) are given, unless there is unacceptable toxicity or disease progression.

Delayed or Missed Doses

For each formulation the SmPC (Table 3) states the action to take for every combination of last dose given and time since it. Shorter delays generally allow the next planned dose to be given; longer delays mean repeating earlier step-up doses, for example after a gap of more than 2 weeks following the first dose, or 6 weeks or more following any later dose. The exact intervals differ by dose and formulation, so the SmPC table should be followed, with premedication as it specifies.

Dose Modification for Toxicity

Patients with grade 3 or 4 reactions (for example serious infection, tumour flare or tumour lysis syndrome) should have treatment withheld until symptoms resolve.

Cytokine Release Syndrome: Management

CRS is identified from the clinical presentation and graded by the ASTCT criteria. Other causes of fever, hypoxia and hypotension, such as infection or sepsis, must be evaluated and treated. Premedication may mask fever, so the guidance applies whenever the presentation fits CRS. With the infusion, infusion-related reactions may be clinically indistinguishable from CRS and are managed in the same way. If CRS does not respond to management, other causes including haemophagocytic lymphohistiocytosis should be considered.

• Grade 1 (fever ≥38 °C). Infusion: if CRS occurs during the infusion, interrupt it and treat the symptoms, then restart at the same rate once they resolve (discontinue that infusion if they recur); if it occurs after the infusion, treat the symptoms. Injection: treat the symptoms. For both: if CRS lasts more than 48 hours despite symptomatic management, consider dexamethasone and/or tocilizumab. Before the next dose the symptoms must have resolved for at least 72 hours, with closer monitoring (infusion) or consideration of antihistamine and antipyretic premedication and close monitoring (injection).
• Grade 2 (fever ≥38 °C and/or hypotension not needing vasopressors and/or hypoxia needing low-flow oxygen, below 6 L/minute, by nasal cannula or blow-by). Infusion: interrupt and treat, then restart at 50% of the rate once symptoms resolve (discontinue that infusion if they recur). Injection: treat the symptoms. For both: if there is no improvement, consider dexamethasone and/or tocilizumab. Before the next dose the symptoms must have resolved for at least 72 hours, premedication should be maximised and monitoring more frequent; for the infusion, consider giving the next one at 50% of the rate.
• Grade 3 (fever ≥38 °C and/or hypotension needing a vasopressor, with or without vasopressin, and/or hypoxia needing high-flow oxygen, 6 L/minute or more, by nasal cannula, face mask, non-rebreather mask or Venturi mask). Treat the symptoms and give dexamethasone and tocilizumab (for the infusion, discontinue the current infusion if CRS occurs during it). If CRS is refractory to dexamethasone and tocilizumab, give alternative immunosuppressants and methylprednisolone 1,000 mg/day intravenously until clinical improvement. Before the next dose the symptoms must have resolved for at least 72 hours, premedication should be maximised, and the patient should be hospitalised for the next dose; the next infusion is given at 50% of the rate. For the injection, if CRS occurred after the 5 mg or 45 mg dose, the next dose should be 5 mg and the schedule resumed after recovery; if grade 3 CRS occurs with later doses, treatment is stopped permanently.
• Grade 4 (fever ≥38 °C and/or hypotension needing multiple vasopressors, excluding vasopressin, and/or hypoxia needing oxygen by positive pressure, such as CPAP, BiPAP or intubation and mechanical ventilation). Discontinue Lunsumio permanently, treat the symptoms and give dexamethasone and tocilizumab; if refractory, give alternative immunosuppressants and methylprednisolone 1,000 mg/day intravenously until clinical improvement.
• Doses used: dexamethasone 10 mg every 6 hours (or equivalent) until clinical improvement, intravenously as worded in the infusion SmPC and orally in the injection SmPC. In the pivotal study tocilizumab was given intravenously at 8 mg/kg (not more than 800 mg per infusion); if there is no improvement after the first dose, a second dose may follow at least 8 hours later (at most 2 doses per CRS event), and no more than 3 tocilizumab doses should be given in any 6 weeks of Lunsumio treatment.

ICANS: Management

ICANS is identified from the clinical presentation after other causes of neurological symptoms are ruled out, and is graded by the ASTCT criteria using the Immune Effector Cell-Associated Encephalopathy (ICE) assessment.

• Grade 1 (ICE score 7–9, or depressed consciousness but awakens spontaneously): withhold Lunsumio and monitor neurological symptoms until ICANS resolves (consider the type of toxicity before withholding); give supportive therapy and consider neurological consultation. Consider a single dose of dexamethasone 10 mg if no other corticosteroid is being taken, and non-sedating anti-seizure medicine (for example levetiracetam) for seizure prophylaxis.
• Grade 2 (ICE 3–6, or awakens to voice): as grade 1, but treat with dexamethasone 10 mg intravenously every 6 hours, if no other corticosteroid is being taken, until improvement to grade 1, then taper.
• Grade 3 (ICE 0–2, awakens only to tactile stimulus, any clinical seizure that resolves rapidly, or focal or local oedema on neuroimaging): withhold Lunsumio until ICANS resolves, give supportive therapy (which may include intensive care) and dexamethasone as for grade 2, and consider anti-seizure prophylaxis until resolution. Evaluate benefit and risk before restarting; consider permanent discontinuation if grade 3 ICANS recurs.
• Grade 4 (ICE 0, unarousable or needing vigorous or repeated stimuli, a life-threatening seizure longer than 5 minutes or repetitive seizures without return to baseline, deep focal motor weakness, or diffuse cerebral oedema): discontinue Lunsumio permanently, give supportive therapy and dexamethasone as above (or consider methylprednisolone 1,000 mg per day intravenously for 3 days) and anti-seizure prophylaxis until resolution.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years and older.
• Renal impairment: not studied in severe impairment; no adjustment considered necessary in mild to moderate impairment.
• Hepatic impairment: not studied; no adjustment considered necessary on pharmacokinetic grounds.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Traceability

To improve traceability of this biological medicine, the trade name and batch number of each dose given should be clearly recorded.

Cytokine Release Syndrome: Monitoring

CRS, including life-threatening reactions, has occurred. Signs and symptoms included pyrexia, chills, hypotension, tachycardia, hypoxia and headache. Events occurred mainly in cycle 1 and, with the infusion, were mostly linked to the day 1 and day 15 doses. Patients are premedicated according to the schedule for their formulation (see Administration and Dosage); for the infusion the SmPC specifies corticosteroids, antipyretics and antihistamines at least through cycle 2. They must be adequately hydrated and monitored for signs and symptoms of CRS, and counselled to seek immediate medical attention if these occur at any time. Physicians should start supportive care, tocilizumab and/or corticosteroids as indicated.

Serious Infections

Serious infections such as pneumonia, bacteraemia, sepsis, septic shock and opportunistic infections have occurred, some life-threatening or fatal, and febrile neutropenia has been seen after infusion. Cases of progressive multifocal leukoencephalopathy (PML) have been reported with CD20-directed antibodies, including CD3-CD20 bispecific antibodies. Lunsumio should not be given during an active infection, and caution applies to patients with recurring or chronic infections (for example chronic active Epstein-Barr virus), predisposing conditions or significant prior immunosuppressive treatment. Antibacterial, antiviral and/or antifungal prophylaxis should be given as appropriate, and patients monitored for infection before and after each dose. Febrile neutropenia is evaluated for infection and managed with antibiotics, fluids and supportive care according to local guidelines. Patients should be monitored for new or worsening neurological toxicity; if symptoms suggest PML, treatment is stopped and diagnostic and treatment measures started, including neurologist consultation.

ICANS

Serious and life-threatening ICANS has occurred. It can begin together with CRS, after CRS resolves or without CRS, and most cases were in cycle 1. Reported manifestations were confusional state, lethargy, encephalopathy, depressed level of consciousness and memory impairment. Patients are monitored after each dose and must seek immediate medical attention if symptoms appear at any time; they should take care when driving, cycling or using heavy or potentially dangerous machines, and avoid these if symptomatic. At the first signs, manage according to the ICANS guidance above.

Haemophagocytic Lymphohistiocytosis

HLH, including fatal cases, has been reported. It is a life-threatening syndrome with fever, hepatomegaly and cytopenias. HLH should be considered when CRS is atypical or prolonged; patients are monitored for its signs, and Lunsumio is interrupted and HLH treated if it is suspected.

Tumour Flare and Tumour Lysis Syndrome

• Tumour flare: new or worsening pleural effusions, local pain and swelling at lymphoma sites and tumour inflammation have been reported, probably from T-cell influx into the tumour. The risk of harm from mass effect is higher with bulky tumours close to the airways or a vital organ, so patients should be monitored for tumour flare at critical sites.
• Tumour lysis syndrome: patients need adequate hydration beforehand and prophylactic anti-hyperuricaemic therapy (for example allopurinol or rasburicase) as appropriate, with monitoring of signs, symptoms and blood chemistry, especially with high tumour burden, rapidly proliferating tumours or reduced renal function.

Immunisation and Patient Card

Live and live-attenuated vaccines should not be given at the same time as Lunsumio. The prescriber must discuss the risks with the patient, who receives a patient card describing the common signs and symptoms of CRS and ICANS and when to seek medical attention, and should carry it at all times.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 3 months after the last dose.
• Pregnancy: there are no human data and animal reproductive toxicity studies are insufficient. Lunsumio is not recommended in pregnancy, or in women of childbearing potential who do not use contraception.
• Breastfeeding: it is unknown whether mosunetuzumab or its metabolites pass into human milk; a risk to the infant cannot be excluded, so breast-feeding should be stopped during treatment.
• Fertility: no human data. In 26-week studies in cynomolgus monkeys at exposures similar to those in patients, no impairment of male or female reproductive organs was seen.

Polysorbate 20

The medicine contains polysorbate 20, which may cause allergic reactions: 0.6 mg per 1 mg vial and 18 mg per 30 mg vial (0.6 mg/mL) of the infusion concentrate, and 0.3 mg per 5 mg vial and 0.6 mg per 45 mg vial of the injection.

Effect on Driving

Lunsumio has a major influence on the ability to drive and use machines. Because of the potential for ICANS, patients are at risk of depressed consciousness and should take care when driving, cycling or using heavy or potentially dangerous machines, and avoid these if symptomatic.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. The cold chain should be maintained during transport and storage. For storage after dilution or after the solution has been drawn into a syringe, see Shelf Life.

• Unopened vial: 3 years.
• Diluted solution for infusion: chemical and physical in-use stability has been shown for 24 hours at 2–8 °C and for 24 hours at 9–30 °C. From a microbiological point of view it should be used immediately; otherwise in-use times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.
• Solution for injection in a syringe: it contains no antimicrobial preservative and should be injected immediately. If not, in-use times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless it was transferred under controlled and validated aseptic conditions; the capped syringe can then be kept at 2–8 °C for up to 28 days protected from light and/or at 9–30 °C for up to 24 hours in ambient light.

Prescription only (Rx); a medicinal product subject to restricted medical prescription (Annex II B), given under the supervision of a healthcare professional qualified in anti-cancer therapy. Lunsumio is administered in a hospital or clinic setting with medical support for CRS and ICANS, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.