LUNSUMIO 30mg perfusive solution concentrate medication leaflet

Each vial contains 1 mg of mosunetuzumab in 1 mL at a concentration of 1 mg/mL.

Each vial contains 30 mg of mosunetuzumab in 30 mL at a concentration of 1 mg/mL.

Mosunetuzumab is a full-length, humanized anti-CD20/CD3 immunoglobulin (Ig)G1 isotype that isproduced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear, colourless liquid, pH 5.8 and osmolality of 240-356 mOsm/kg.

Lunsumio as monotherapy is indicated for the treatment of adult patients with relapsed or refractoryfollicular lymphoma (FL) who have received at least two prior systemic therapies.

Lunsumio must only be administered under the supervision of a healthcare professional qualified inthe use of anti-cancer therapies, in a setting with appropriate medical support to manage severereactions such as cytokine release syndrome (CRS) and Immune Effector Cell-Associated

Neurotoxicity Syndrome (ICANS) (see below and section 4.4).

Lunsumio should be administered to well-hydrated patients.

Table 1 provides details on recommended premedication for CRS and infusion related reactions.

Table 1 Premedication to be administered to patients prior to Lunsumio infusion

Patients requiring Premedication Administrationpremedication

Intravenous corticosteroids: Complete at least 1 hourdexamethasone 20 mg or prior to Lunsumio infusion

Cycles 1 and 2: all patients methylprednisolone 80 mg

Anti-histamine: 50-100 mg At least 30 minutes prior to

Cycles 3 and beyond: patients diphenhydramine hydrochloride or Lunsumio infusionwho experienced any grade CRS equivalent oral or intravenouswith previous dose anti-histamine

Anti-pyretic: 500-1000 mgparacetamol

The recommended dose of Lunsumio for each 21 day-cycle is detailed in Table 2.

Table 2 Dose of Lunsumio for patients with relapsed or refractory follicular lymphoma

Day of treatment Dose of Lunsumio Rate of infusion

Cycle 1 Day 1 1 mg Infusions of Lunsumio in Cycle 1 should be

Day 8 2 mg administered over a minimum of 4 hours.

Day 15 60 mg

Cycle 2 Day 1 60 mg If the infusions were well-tolerated in

Cycles 3 and Day 1 30 mg Cycle 1, subsequent infusions of Lunsumiobeyond may be administered over 2 hours.

Lunsumio should be administered for 8 cycles, unless a patient experiences unacceptable toxicity ordisease progression.

For patients who achieve a complete response, no further treatment beyond 8 cycles is required. Forpatients who achieve a partial response or have stable disease in response to treatment with Lunsumioafter 8 cycles, an additional 9 cycles of treatment (17 cycles total) should be administered, unless apatient experiences unacceptable toxicity or disease progression.

If any dose in cycle 1 is delayed for > 7 days, the previous tolerated dose should be repeated prior toresuming the planned treatment schedule.

If a dose interruption occurs between Cycles 1 and 2 that results in a treatment-free intervalof ≥ 6 weeks, Lunsumio should be administered at 1 mg on Day 1, 2 mg on Day 8, then resume theplanned Cycle 2 treatment of 60 mg on Day 15.

If a dose interruption occurs that results in a treatment-free interval of ≥ 6 weeks between any Cyclesin Cycle 3 onwards, Lunsumio should be administered at 1 mg on Day 1, 2 mg on Day 8, then resumethe planned treatment schedule of 30 mg on Day 15.

Patients who experience grade 3 or 4 reactions (e.g. serious infection, tumour flare, tumour lysissyndrome) should have treatment temporarily withheld until symptoms are resolved (see section 4.4).

Cytokine Release Syndrome

CRS should be identified based on clinical presentation (see section 4.4). Patients should be evaluatedand treated for, other causes of fever, hypoxia, and hypotension, such as infections/sepsis. Infusionrelated reactions (IRR) may be clinically indistinguishable from manifestations of CRS. If CRS or IRRis suspected, patients should be managed according to the recommendations in Table 3.

Table 3 CRS grading1 and management

CRS grade CRS management2 Next scheduled infusion of

Lunsumio

Grade 1 If CRS occurs during infusion: The symptoms should be

* The infusion should be interrupted and resolved for at least 72 hours

Fever ≥ 38ºC symptoms treated prior to next infusion

* The infusion should be re-started at thesame rate once the symptoms resolve The patient should be

* If symptoms recur with monitored more frequentlyre-administration, the current infusionshould be discontinued

If CRS occurs post-infusion:

* The symptoms should be treated

If CRS lasts > 48 hours after symptomaticmanagement:

* Dexamethasone3 and/or tocilizumab4,5should be considered

Grade 2 If CRS occurs during infusion: The symptoms should be

Fever ≥ 38ºC * The infusion should be interrupted and resolved for at least 72 hoursand/or hypotension symptoms treated prior to next infusionnot requiring * The infusion should be re-started at 50% Premedication should bevasopressors the rate once the symptoms resolve maximized as appropriate7and/or hypoxia * If symptoms recur with re-requiring administration, the current infusion Consideration should below-flow oxygen6 should be discontinued given to administration of theby nasal cannula next infusion 50% rate, withor blow-by more frequent monitoring of

If CRS occurs post-infusion: the patient

* The symptoms should be treated

If no improvement occurs after symptomaticmanagement:

* Dexamethasone3 and/or tocilizumab4,5should be considered

Grade 3 If CRS occurs during infusion: The symptoms should be

Fever ≥ 38ºC * The current infusion should be resolved for at least 72 hoursand/or hypotension discontinued prior to next infusionrequiring a * The symptoms should be treated Patients should bevasopressor * Dexamethasone3 and tocilizumab4, 5 hospitalized for the next(with or without should be administered infusionvasopressin)and/or Premedication should behypoxia requiring If CRS occurs post-infusion: maximized as appropriate7high * The symptoms should be treatedflow oxygen8 by The next infusion should benasal cannula, face * Dexamethasone3 and tocilizumab4, 5 administered at a 50% ratemask, should be administerednon-rebreathermask, or Venturi If CRS is refractory to dexamethasone andmask tocilizumab:

* Alternative immunosuppressants9 andmethylprednisolone 1 000 mg/dayintravenously should be administereduntil clinical improvement

Grade 4 If CRS occurs during or post-infusion:

Fever ≥ 38ºC * Treatment with Lunsumio should be permanently discontinuedand/or hypotension * The symptoms should be treatedrequiring multiple * Dexamethasone3 and tocilizumab4, 5 should be administeredvasopressors(excludingvasopressin) If CRS is refractory to dexamethasone and tocilizumab:and/or * Alternative immunosuppressants9 and methylprednisolone 1 000 mg/dayhypoxia requiring intravenously should be administered until clinical improvementoxygen by positivepressure(e.g., CPAP,

BiPAP,intubation andmechanicalventilation)1 ASTCT = American Society for Transplant and Cellular Therapy. Premedication may mask fever,therefore if clinical presentation is consistent with CRS, please follow these management guidelines.2 If CRS is refractory to management, consider other causes including hemophagocyticlymphohistiocytosis3 Dexamethasone should be administered at 10 mg intravenously every 6 hours (or equivalent)until clinical improvement4 In study GO29781, tocilizumab was administered intravenously at a dose of 8 mg/kg (not to exceed800 mg per infusion), as needed for CRS management5 If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, a seconddose of intravenous tocilizumab 8 mg/kg may be administered at least 8 hours apart (maximum 2doses per CRS event). Within each time period of 6 weeks of Lunsumio treatment, the total amountof tocilizumab doses should not exceed 3 doses6 Low-flow oxygen is defined as oxygen delivered at < 6 L/minute.7 Refer to Table 1 for additional information8 High-flow oxygen is defined as oxygen delivered at ≥ 6 L/minute9 Riegler L et al. (2019)

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) grading and management

ICANS should be identified based on clinical presentation (see Section 4.4). Rule out other causes ofneurologic symptoms. If ICANS is suspected, it should be managed according to the recommendationsin Table 4.

Table 4 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Gradea Actions

Grade 1 Withhold Lunsumio and monitor neurologic toxicitysymptoms until ICANS resolves.c,d

ICEb 7-9 or depressed level ofconsciousness but awakens spontaneously Provide supportive therapy and consider neurologicconsultation and evaluation.

Consider a single dose of dexamethasone 10mg, ifnot taking other corticosteroids.

Consider non-sedating, anti-seizure medicinalproducts (e.g., levetiracetam) for seizureprophylaxis.

Grade 2 Withhold Lunsumio and monitor neurologic toxicitysymptoms until ICANS resolves.c,d

ICEb 3-6 or depressed level ofconsciousness but awakens to voice Provide supportive therapy and consider neurologicconsultation and evaluation.

Treat with dexamethasone 10 mg intravenouslyevery 6 hours, if not taking other corticosteroids,until improvement to Grade 1, then taper.

Consider non-sedating, anti-seizure medicinalproducts (e.g., levetiracetam) for seizureprophylaxis.

Grade 3 Withhold Lunsumio and monitor neurologic toxicitysymptoms until ICANS resolves.d,e

ICEb 0-2 or depressed level ofconsciousness but awakens to tactile Provide supportive therapy, which may includestimulus or any clinical seizure that intensive care, and consider neurologic consultationresolves rapidly or focal/local oedema on and evaluation.neuroimaging

Treat with dexamethasone 10 mg intravenouslyevery 6 hours, if not taking other corticosteroids,until improvement to Grade 1, then taper.

Consider non-sedating anti-seizure medication forseizure prophylaxis until resolution of ICANS. Useanti-seizure medication for seizure management asneeded.

For recurrent grade 3 ICANS, consider permanentlydiscontinuing Lunsumio.

Grade 4 Permanently discontinue Lunsumio.

ICEb is 0 or patient is unarousable or Provide supportive therapy, which may includerequires vigorous or repetitive tactile intensive care, and consider neurologic consultationstimuli, or life-threatening prolonged and evaluation.seizure (>5 min) or repetitive seizureswithout return to baseline or deep focal Treat with dexamethasone 10 mg intravenouslymotor weakness or diffuse cerebral oedema every 6 hours, if not taking other corticosteroids,on neuroimaging until improvement to Grade 1, then taper.

Alternatively, consider administration ofmethylprednisolone 1 000 mg per day intravenouslyfor 3 days, if symptoms improve, then manage asabove.

Consider non-sedating anti-seizure medication forseizure prophylaxis until resolution of ICANS. Useanti-seizure medication for seizure management asneeded.

a American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria.b If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE)

Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers”or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standardsentence = 1 point; and Attention (count backwards from 100 by ten = 1 point). If patient isunarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

c Consider the type of neurologic toxicity before deciding to withhold Lunsumio.d See Delayed or missed dose for guidance on restarting Lunsumio after dose delay.e Evaluate benefit/risk before restarting Lunsumio.

No dose adjustment of Lunsumio is required in patients ≥ 65 years of age (see section 5.2).

Lunsumio has not been studied in patients with severe renal impairment. Dose adjustments are notconsidered necessary in patients with mild to moderate renal impairment based on pharmacokinetics(see section 5.2).

Lunsumio has not been studied in patients with hepatic impairment. Dose adjustments are notconsidered necessary based on pharmacokinetics (see section 5.2).

The safety and efficacy of Lunsumio in children below 18 years of age have not yet been established.

Lunsumio is for intravenous use only.

Lunsumio must be diluted using aseptic technique under the supervision of a healthcare professional.

It should be administered as an intravenous infusion through a dedicated infusion line. Do not use anin-line filter to administer Lunsumio. Drip chamber filters can be used to administer Lunsumio.

The first cycle of Lunsumio should be administered over a minimum of 4 hours as intravenousinfusion. If the infusions are well-tolerated in cycle 1, the subsequent cycles may be administered overa 2-hours infusion.

Lunsumio must not be administered as intravenous push or bolus.

For instructions on dilution of the medicinal product before administration, see section 6.6

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve traceability of biological medicinal products, the trade name and the batch numberof the administered product should be clearly recorded.

CRS, including life-threatening reactions, have occurred in patients receiving Lunsumio (seesection 4.8). Signs and symptoms included pyrexia, chills, hypotension, tachycardia, hypoxia, andheadache. Infusion related reactions may be clinically indistinguishable from manifestations of CRS.

CRS events occurred predominantly in cycle 1 and were mainly associated with Day 1 and Day 15dose administrations.

Patients should be premedicated with corticosteroids, antipyretics and antihistamines at least throughcycle 2. Patients must receive adequate hydration prior to the administration of Lunsumio. Patientsshould be monitored for signs or symptoms of CRS. Patients should be counselled to seek immediatemedical attention should signs or symptoms of CRS occur at any time. Physicians should institutetreatment with supportive care, tocilizumab and/or corticosteroids as indicated. (see section 4.2).

Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, have been reported in patientsreceiving Lunsumio. HLH is a life-threatening syndrome characterized by fever, hepatomegaly andcytopenias. HLH should be considered when the presentation of CRS is atypical or prolonged. Patientsshould be monitored for clinical signs and symptoms of HLH (see Section 4.2). For suspected HLH,

Lunsumio must be interrupted and treatment for HLH initiated.

Serious infections such as pneumonia, bacteraemia, and sepsis or septic shock have occurred inpatients receiving Lunsumio, some of which were life-threatening or fatal events (see section 4.8).

Febrile neutropenia was observed in patients after receiving Lunsumio infusion.

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

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS have occurred in patients receiving Lunsumio, including serious and life threatening reactions.

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of

CRS. Manifestations of ICANS reported in clinical trials included confusional state, lethargy,encephalopathy, depressed level of consciousness, and memory impairment. The majority of casesoccurred during Cycle 1.

Patients should be monitored for signs and symptoms of ICANS following Lunsumio administration.

Patients must be counselled to seek immediate medical attention should signs or symptoms occur atany time (see Patient card below).

Patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling orusing heavy or potentially dangerous machines (see section 4.7).

At the first signs or symptoms of ICANS, manage according to the ICANS guidance provided in Table4. Treatment with Lunsumio should be withheld or discontinued permanently as recommended.

Tumour flare has been reported in patients treated with Lunsumio (see section 4.8). Manifestationsincluded new or worsening pleural effusions, localised pain and swelling at the sites of lymphomalesions and tumour inflammation. Consistent with the mechanism of action of Lunsumio, tumour flareis likely due to the influx of T-cells into tumour sites following Lunsumio administration.

There are no specific risk factors for tumour flare that have been identified, however, there is aheightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patientswith bulky tumours located in close proximity to airways and/or a vital organ. Patients treated with

Lunsumio should be monitored and evaluated for tumour flare at critical anatomical sites.

TLS has been reported in patients receiving Lunsumio (see section 4.8). Patients must have adequatehydration prior to the administration of Lunsumio. Patients should be administered prophylactic anti-hyperuricemic therapy (e.g allopurinol, rasburicase), as appropriate. Patients should be monitored forsigns or symptoms of TLS, especially patients with high tumour burden or rapidly proliferativetumours, and patients with reduced renal function. Patients should be monitored for blood chemistriesand abnormalities should be managed promptly.

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

The prescriber must discuss the risks of Lunsumio therapy with the patient. The patient should beprovided with the patient card and instructed to carry it at all times. The patient card describes thecommon signs and symptoms of CRS and ICANS, including instructions on when a patient shouldseek medical attention.

No interaction studies have been performed.

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 Lunsumio treatmentcauses a transient increase in cytokine levels which may cause inhibition of CYP450 enzymes. Oninitiation of Lunsumio therapy in patients being treated with CYP450 substrates with a narrowtherapeutic index, therapeutic monitoring should be considered. The dose of the concomitantmedicinal product should be adjusted as needed.

Women of childbearing potential should use effective contraception while receiving Lunsumio and forat least 3 months after the last infusion of Lunsumio.

There are no data from the use of Lunsumio in pregnant women. Animal studies are insufficient withrespect to reproductive toxicity (see section 5.3). Lunsumio is not recommended during pregnancy andin women of childbearing potential not using contraception.

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

Lunsumio therapy.

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

Lunsumio has major influence on the ability to drive and use machines.. Due to the potential for

ICANS, patients receiving Lunsumio are at risk of depressed level of consciousness (see section 4.4).

Due to the potential for ICANS, patients should be advised to exercise caution while (or avoid ifsymptomatic) driving, cycling or using heavy or potentially dangerous machines.

The adverse reactions (ARs) described in this section were identified from the pivotal clinical trial

GO29781 in patients treated at the recommended dose (n=218). Patients had follicular lymphoma(41.3%), diffuse large B-cell lymphoma/transformed follicular lymphoma (40.4%) mantle celllymphoma (11.5%), Richter’s transformation (6.4%), and other histologies (0.5%). The mediannumber of cycles of Lunsumio received was 8 (range 1 -17), 37% of patients received 8 cycles, and15% received more than 8 cycles up to 17 cycles.

The most common adverse reactions (≥ 20%) observed were cytokine release syndrome, neutropenia,pyrexia, hypophosphatemia and headache. The most common serious adverse reactions (≥ 2%)observed included cytokine release syndrome (CRS) (21% by ASTCT grading system), pyrexia (5%),and pneumonia (3%). Nine of 218 patients (4.1%) discontinued Lunsumio due to an adverse event.

CRS was the only adverse reaction that led to discontinuation in more than one patient (2 patients[0.9%]).

The adverse reactions are listed below by MedDRA system organ class (SOC) and categories offrequency. 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 notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 5 Adverse reactions occurring in patients treated with Lunsumio

System organ class/preferred term oradverse reaction All grades Grade 3 - 4

Upper respiratory tract infection Common Common

Urinary tract infection Common Common

Pneumonia Common Common

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Tumour flare Common Common

Neutropenia1 Very common Very common

Anaemia Very common Common

Thrombocytopenia2 Very common Common

Febrile neutropenia Common Common

Haemophagocytic lymphohistiocytosis5 Uncommon Uncommon

Cytokine release syndrome3 Very common Common

Hypophosphataemia Very common Very common

Hypokalaemia Very common Common

Hypomagnesaemia Very common Very rare

Tumour lysis syndrome Uncommon Uncommon

System organ class/preferred term oradverse reaction All grades Grade 3 - 4

Headache Very common Uncommon

Immune effector cell-associatedneurotoxicity syndrome4,5 Common Very rare

Diarrhoea Very common Very rare

Rash Very common Uncommon

Pruritus Very common Very rare

Dry skin Very common Very rare

Pyrexia Very common Common

Chills Very common Uncommon

Alanine aminotransferase, increased Very common Common

Aspartate aminotransferase, increased Common Common1 Neutropenia includes neutropenia and neutrophil count decreased2 Thrombocytopenia includes thrombocytopenia and platelet count decreased3 By American Society for Transplant and Cellular Therapy4 Consistent with the medical concept of ICANS according to American Society for Transplant and

Cellular Therapy and includes confusional state, ICANS, lethargy, encephalopathy, depressed levelof consciousness, and memory impairment5 The frequency calculation is based on additional clinical studies

CRS (ASTCT grading system) of any grade occurred in 39% (86/218) of patients, with grade 2occurring in 14%, grade 3 occurring in 2.3%, and grade 4 occurring in 0.5% of patients treated with

Lunsumio. The one patient with the grade 4 event was a patient with FL in the leukemic phase whoalso 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 1was 5 hours (range: 1-73 hours), Cycle 1 Day 8 was 28 hours (range: 5-81 hours), Cycle 1 Day 15 was25 hours (range: 0.1-391 hours), and Cycle 2 Day 1 was 46 hours (range: 12-82 hours). CRS resolvedin 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 includedpyrexia (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% receivedtocilizumab alone, 6% received corticosteroids alone, and 4% received both tocilizumab andcorticosteroids. Among the 10% of patients who received tocilizumab (with or without acorticosteroid), 86% received only one dose of tocilizumab, with no more than two doses oftocilizumab administered for a single CRS event. In patients experiencing Grade 2 CRS, 48% ofpatients were treated with symptomatic management without corticosteroids or tocilizumab, 18%received tocilizumab alone, 21% received corticosteroids alone, and 12% received both corticosteroidsand tocilizumab. Patients with grade 3 or grade 4 CRS received tocilizumab, corticosteroids,vasopressors and/or oxygen supplementation. Three percent of patients experienced hypotensionand/or hypoxia without fever following Lunsumio administration; 2% of patients received tocilizumaband/or corticosteroids in the absence of fever.

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

Neutropenia of any grade occurred in 28% of patients, including 24% Grade 3-4 events. The mediantime to onset of first neutropenia/neutrophil count decreased events was 48 days (range: 1-280 days),with median duration of 8 days (range: 1-314 days). Of the 60 patients who had neutropenia/neutrophilcount decreased events 68% received treatment G-CSF to treat the events.

Serious infections of any grade occurred in 17% of patients. 1.8% of patients experienced seriousinfections concurrently with grade 3-4 neutropenia. The median time to onset of first serious infectionwas 50 days (range: 1-561 days), with median duration of 12 days (range: 2-174 days). Grade 5 eventsoccurred in 0.9% of patients, which included pneumonia and sepsis.

Immune Effector Cell-Associated Neurotoxicity Syndrome

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) occurred in 2.1% (20/949) ofpatients, 19 patients had Grade 1-2 events and 1 patient had Grade 3 event. The majority of eventsoccurred during the first cycle of treatment. The majority of cases resolved. The median time to onsetfrom initial dose was 17 days (range: 1 to 48 days). The median duration was 3 days (range: 1-20days).

Tumour flare (including pleural effusion and tumour inflammation) occurred in 4% of patients, whichincluded 1.8% grade 2 and 2.3% grade 3 events. The median time to onset was 13 days (range5-84 days), and median duration was 10 days (range 1-77 days).

Tumour Lysis Syndrome (TLS)

TLS occurred in 0.9% of patients, concurrent with CRS. One patient with follicular lymphoma was inthe leukemic phase who experienced Grade 4 TLS. TLS onset was on days 2 and 24, and resolvedwithin 4 and 6 days, respectively.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions,and appropriate symptomatic treatment instituted.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents; monoclonalantibodies,

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 bindingto CD20 on B-cells and CD3 on T-cells. Engagement of both arms of mosunetuzumab results in theformation of an immunologic synapse between a target B cell and a cytotoxic T cell leading to T-cellactivation. Subsequent directed release of perforin and granzymes from T-cell activation through theimmunologic synapsis induce B-cell lysis leading to cell death.

Lunsumio caused B-cell depletion (defined as CD19 B-cell counts < 0.07 x 109/L) andhypogammaglobulinemia (defined as IgG levels < 500 mg/dL).

An open-label, multicentre, multi-cohort study (GO29781) was conducted to evaluate Lunsumio inpatients with relapsed or refractory B-cell non-Hodgkin's lymphoma for whom there was no availabletherapy expected to improve survival. In the follicular lymphoma (FL) cohort (n=90), patients withrelapsed or refractory FL (Grade 1-3A) were required to have received at least two prior systemictherapies, including an anti-CD20 monoclonal antibody and an alkylating agent. Patients with FL

Grade 3b and patients with transformed FL at study entry were not eligible; those with a history oftransformed FL but FL Grade 1-3A at study entry were included in the FL cohort.

The study excluded patients with Eastern Cooperative Oncology Group (ECOG) performance status≥ 2, significant cardiovascular disease (such as New York Heart Association Class III or IV cardiacdisease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina),significant active pulmonary disease, impaired renal functions (Creatinine clearance[CrCl] < 60 mL/min with elevated serum creatinine level), active autoimmune disease requiringimmunosuppressive therapy, active infections (i.e., chronic active EBV, acute or chronic hepatitis C,hepatitis B, HIV), progressive multifocal leukoencephalopathy, current or a history of CNS lymphomaor CNS disease, a history of macrophage activation syndrome/hemophagocytic lymphohistiocytosis,prior allogeneic stem cell transplant, or prior organ transplantation.

Patients received Lunsumio intravenously in a 21-day Cycle as follows:

* Cycle 1 Day 1: 1 mg

* Cycle 1 Day 8: 2 mg

* Cycle 1 Day 15: 60 mg

* Cycle 2 Day 1: 60 mg

* Cycle 3 and beyond Day 1: 30 mg

The median number of cycles was 8, 59% received 8 cycles, and 18% received more than 8 cycles upto 17 cycles.

The median age was 60 years (range 29 to 90 years) with 31% being > age 65, and 7.8% being ≥ age75. Sixty-one percent were male, 82% were white, 9% were Asian, 4% were Black, 100% had an

ECOG performance status of 0 or 1 and 34% of patients had bulky disease (at least one lesion > 6 cm).

The median number of prior therapies was 3 (range: 2-10), with 38% receiving 2 prior therapies, 31%receiving 3 prior therapies and 31% receiving more than 3 prior therapies.

All patients received prior anti-CD20 and alkylator therapies, 21% received autologous stem celltransplant, 19% received PI3K inhibitors, 9% received prior rituximab plus lenalidomide therapy, and3% received CAR-T therapies. Seventy-nine percent of patients were refractory to prior anti-CD20monoclonal antibody therapy and 53% were refractory to both anti-CD20 monoclonal antibody andalkylator therapy. Sixty-nine percent of patients were refractory to the last prior therapy and 52% hadprogression of disease within 24 months of first systemic therapy.

The primary efficacy endpoint was complete response (CR) as assessed by an independent reviewfacility (IRF) according to standard criteria for NHL (Cheson 2007). The efficacy results aresummarised in Table 6.

Table 6 Summary of efficacy in patients with relapsed/refractory FL

Efficacy parameter Lunsumio

N=90

Median observation time 18.3 months (range 2 - 27 months)

Complete Response (CR), n (%), 54 (60.0)(95% CI) (49.1, 70.2)

Objective Response Rate (ORR), n (%) 72 (80.0)(95% CI) (70.3, 87.7)

Partial Response (PR) n (%) 18 (20.0)(95% CI) (12.3, 29.8)

Duration of Response (DOR)1

Patients with event, n (%) 29 (40.3)

Median, months (95% CI) 22.8 (9.7, NR)

K-M event-free proportion12 months 61.8(95% CI) (50.0, 73.7)18 months 56.9(95% CI) (44.1, 69.6)

Duration of Complete Response (DOCR)2

Patients with event, n (%) 16 (29.6)

Median, months (95% CI) NR (14.6, NR)

K-M event-free proportion,12 months 71.4(95% CI) (57.9, 84.9)18 months 63.7(95% CI) (48.0, 79.4)

CI=confidence interval; K-M=Kaplan-Meier; NR=not reached.

Clinical Cut-off: 27 August 2021

Hypothesis testing was conducted on the primary endpoint of IRF assessed CR rate.1 DOR is defined as the time from the initial occurrence of a documented PR or CR until the patientexperiences an event (documented disease progression or death due to any cause, whichever occursfirst).2 DOCR is defined as the time from the initial occurrence of a documented CR until the patientexperiences an event (documented disease progression or death due to any cause, whichever occursfirst).

The median follow-up for DOR was 14.9 months. Additional exploratory efficacy outcomes includedthe median time to first response (1.4 months, range: 1.1 - 8.9) and the median time to first completeresponse (3.0 months, range: 1.1- 18.9).

The immunogenicity of mosunetuzumab was evaluated using an enzyme-linked immunosorbent assay(ELISA). No patients tested positive for anti-mosunetuzumab antibodies in 418 ADA-evaluablepatients who received Lunsumio single-agent intravenous treatments in Study GO27981. Based on theavailable information, the clinical relevance of anti-mosunetuzumab antibodies could not be assessed.

The European Medicines Agency has waived the obligation to submit results of studies with Lunsumioin all subsets of the paediatric population for the treatment of mature B-cell neoplasms (see section 4.2for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.

Mosunetuzumab pharmacokinetic (PK) exposure increased in an approximately dose-proportionalmanner over the dose range studied, from 0.05 to 60 mg. The population pharmacokinetic followingintravenous administrations of Lunsumio was described by a 2-compartment PK model with time-dependent clearance, which was parameterized as descending to a steady-state plateau (CLss) from abaseline value (CLbase) at the start of treatment according to transitional half-life of 16.3 days.

Moderate to high pharmacokinetic variability for mosunetuzumab was observed and characterized byinter-individual variability (IIV) ranging from 18% to 86% coefficient of variation (CV) formosunetuzumab PK parameters: IIV was estimated for CLbase (63% CV), central volume ofdistribution (31% CV), peripheral volume of distribution (25% CV), CLss (18% CV), and transitionalhalf-life (86% CV).

After the first two Cycles (i.e., 42 days) of the dosing with Lunsumio, the serum concentration reachesthe Cmax at the end of dose of Cycle 2 Day 1 of the Lunsumio intravenous infusion with an averagemaximal concentration of 17.9 µg/mL and %CV of 49.6%. The average total two cycles (42 days)mosunetuzumab exposure AUC was 126 day*µg/mL with %CV of 44.4%.

Lunsumio is administered intravenously.

The population estimate of central volume of distribution for mosunetuzumab was 5.49 L withintravenous infusion of Lunsumio. Because mosunetuzumab is an antibody, protein binding studieswere not conducted.

The metabolic pathway of mosunetuzumab has not been directly studied. Like other proteintherapeutics, mosunetuzumab is expected to be degraded into small peptides and amino acids viacatabolic pathways.

Based on a population pharmacokinetic analysis, the estimated mean CLss and baseline clearance(CLbase) were 1.08 L/day and 0.584 L/day, respectively. The terminal half-life estimate was 16.1 daysat steady state based on population pharmacokinetic model estimates. The results obtained in study

GO29781 indicate that mosunetuzumab serum concentration reaches the Cmax at the end of theintravenous infusion and declines in a bi-exponential fashion.

Age did not have an effect on the pharmacokinetics of mosunetuzumab based on a populationpharmacokinetic analysis with patients aged 19-96 years (n=439). No clinically important differencewas observed in the pharmacokinetics of mosunetuzumab for patients in this age group.

Like other therapeutic proteins, bodyweight was positively associated with mosunetuzumab estimatedclearance and volume of distribution. However, based on exposure-response analysis and clinicalexposure 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 ismarginally 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 mosunetuzumabpharmacokinetics.

No dedicated studies have been conducted to determine the effect of renal impairment on thepharmacokinetics of mosunetuzumab. The renal elimination of intact mosunetuzumab, an IgGmonoclonal antibody, is expected to be low and of minor importance.

The population PK analysis of mosunetuzumab showed that creatinine clearance (CrCl) does notaffect pharmacokinetics of mosunetuzumab. Pharmacokinetics of mosunetuzumab in patients withmild (CrCl 60 to 89 mL/min, n=178) or moderate (CrCl 30 to 59 mL/min, n=53) renal impairmentwere similar to those in patients with normal renal function (CrCl ≥ 90 mL/min, n=200).

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 was not studied in patients withend-stage renal disease and/or who are on dialysis.

No specific studies have been conducted to determine the effect of hepatic impairment on thepharmacokinetics of mosunetuzumab. IgGs are mainly eliminated via intracellular catabolism andhepatic impairment is not expected to influence clearance of mosunetuzumab.

The population PK analysis of mosunetuzumab showed that hepatic impairment does not affectpharmacokinetics of mosunetuzumab. Pharmacokinetics of mosunetuzumab in patients with mildhepatic impairment (total bilirubin > ULN to 1.5 x ULN or AST > ULN, n=53) were similar to thosein patients with normal hepatic function (n=384). The number of patients with moderate hepaticimpairment is limited (total bilirubin > 1.5-3 x ULN, any AST, n=2) and no patients with severehepatic impairment have been studied.

No studies have been conducted to investigate the pharmacokinetics of mosunetuzumab in thepaediatric population (< 18 years old).

Key nonclinical findings with mosunetuzumab identified in single- and repeat-dose toxicity studies upto 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 inother organs that were likely secondary to cytokine release and immune cell activation, and increasedsusceptibility to infection following chronic dosing due to sustained B-cell depletion.

All of the findings were considered pharmacologically-mediated effects and reversible. Across studiesthere was a single incidence of convulsion in one animal at Cmax and AUC exposures (time-averagedover 7 days) of 3.3- and 1.8- fold higher, respectively, than those in patients receiving Lunsumio at therecommended dose and schedule in Study GO29781.

An assessment of the male and female reproductive organs was included in a 26-week chronic toxicitystudy in sexually mature cynomolgus monkeys administered by intravenous infusion. Mosunetuzumabhad 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 onlow placental transfer of antibodies during the first trimester, the mechanism of action and availabledata of mosunetuzumab, and the data on the anti-CD20 antibody class, the risk for teratogenicity islow. Studies with mosunetuzumab in non-pregnant animals have demonstrated that prolonged B-celldepletion 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.

6 PHARMACEUTICAL PARTICULARS

L-histidine

L-methionine

Acetic acid (pH adjustment)

Sucrose

Polysorbate 20 (E 432)

Water for injections

* Do not mix Lunsumio with, or administer through the same infusion line, as other medicinalproducts.

* Do not use solvents other than sodium chloride 9 mg/mL (0.9%) solution for injection orsodium chloride 4.5 mg/mL (0.45%) solution for injection to dilute Lunsumio since its use hasnot been tested.

* No incompatibilities have been observed between Lunsumio and intravenous infusion bags withproduct contacting materials of polyvinyl chloride (PVC), or polyolefins (PO) such aspolyethylene (PE) and polypropylene (PP). In addition, no incompatibilities have been observedwith infusion sets or infusion aids with product contacting materials of PVC, PE, polyurethane(PUR), polybutadiene (PBD), silicone, acrylonitrile butadiene styrene (ABS), polycarbonate(PC), polyetherurethane (PEU), fluorinated ethylene propylene (FEP), or polytetrafluorethylene(PTFE), or with drip chamber filter membrane composed of polyamide (PA).

* Do not use an in-line filter.

Unopened vial3 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C - 8 °C and 24 hoursat 9 °C - 30 °C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user and would normallynot be longer than 24 hours at 2 °C to 8 °C, unless dilution has taken place in controlled and validatedaseptic conditions.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product,see section 6.3.

Type I glass-vial with a butyl rubber stopper and an aluminium seal with a plastic dark grey flip-offcap containing 1 mg of concentrate for solution for infusion.

Pack of one vial.

Type I glass-vial with a butyl rubber stopper and an aluminium seal with a plastic light blue flip-offcap containing 30 mg of concentrate for solution for infusion.

Pack of one vial.

Lunsumio contains no preservative and is intended for single-dose only. Proper aseptic techniquethroughout the handling of this medicinal product should be followed. Do not shake.

Lunsumio must be diluted into a PVC or polyolefin (PO) such as polyethylene (PE) and polypropyleneinfusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection or sodium chloride 4.5mg/mL (0.45%) solution for injection by a healthcare professional using aseptic technique prior toadministration.

Use sterile needle and syringe to prepare Lunsumio. Discard any unused portion.

A dedicated infusion line should be used during intravenous administration.

Do not use an in-line filter to administer Lunsumio.

Drip chamber filters can be used to administer Lunsumio.

Preparation for infusion1. Withdraw and discard a volume of sodium chloride 9 mg/mL (0.9%) solution for injection orsodium chloride 4.5 mg/mL (0.45%) solution for injection equal to the volume of the Lunsumiorequired for the patient’s dose from the infusion bag according to the Table 7 below.2. Withdraw the required volume of Lunsumio from the vial using a sterile syringe and dilute intothe infusion bag. Discard any unused portion left in the vial.

Table 7: Dilution of Lunsumio

Volume of Lunsumio insodium chloride 9mg/mL (0.9%) or 4.5

Dose of mg/mL (0.45%) solution

Day of treatment Lunsumio for injection Size of infusion bag

Cycle 1 Day 1 1 mg 1 mL 50 mL or 100 mL

Day 8 2 mg 2 mL 50 mL or 100 mL

Day 15 60 mg 60 mL 100 mL or 250 mL

Cycle 2 Day 1 60 mg 60 mL 100 mL or 250 mL

Cycle 3 Day 1 30 mg 30 mL 100 mL or 250 mLandbeyond3. Gently mix the infusion bag by slowly inverting the bag. Do not shake.4. Inspect the infusion bag for particulates and discard if present.5. Apply the peel-off label from the leaflet to the infusion bag.

For storage conditions of the infusion bags, see section 6.3.

The release of pharmaceuticals into the environment should be minimised. Medicinal products shouldnot be disposed of via wastewater and disposal through household waste should be avoided.

The following points should be strictly adhered to regarding the use and disposal of syringes and othermedicinal sharps:

* Needles and syringes should never be reused.

* Place all used needles and syringes into a sharps container (puncture-proof disposablecontainer).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/22/1649/001

EU/1/22/1649/002

Date of first authorisation: 3 June 2022

Date of latest renewal: 19 April 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.