COLUMVI 2.5mg 1mg / ml perfusive solution concentrate medication leaflet

Columvi 2.5 mg concentrate for solution for infusion

Columvi 10 mg concentrate for solution for infusion

Columvi 2.5 mg concentrate for solution for infusion

Each vial of 2.5 mL of concentrate contains 2.5 mg of glofitamab at a concentration of 1 mg/mL.

Columvi 10 mg concentrate for solution for infusion

Each vial of 10 mL of concentrate contains 10 mg of glofitamab at a concentration of 1 mg/mL.

Glofitamab is a humanised anti-CD20/anti-CD3 bispecific monoclonal antibody produced in Chinesehamster ovary (CHO) cells by recombinant DNA technology.

Each 2.5 mL vial of Columvi contains 1.25 mg (0.5 mg/mL) of polysorbate 20.

Each 10 mL vial of Columvi contains 5 mg (0.5 mg/mL) of polysorbate 20.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Colourless, clear solution with a pH of 5.5 and osmolality of 270-350 mOsm/kg.

Columvi in combination with gemcitabine and oxaliplatin is indicated for the treatment of adultpatients with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified (DLBCL

NOS) who are ineligible for autologous stem cell transplant (ASCT).

Columvi as monotherapy is indicated for the treatment of adult patients with relapsed or refractorydiffuse large B-cell lymphoma (DLBCL), after two or more lines of systemic therapy.

Columvi must only be administered under the supervision of a healthcare professional experienced inthe diagnosis and treatment of cancer patients and who has access to appropriate medical support tomanage severe reactions associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

At least 1 dose of tocilizumab for use in the event of CRS must be available prior to Columvi infusionat Cycles 1 and 2. Access to an additional dose of tocilizumab within 8 hours of use of the previoustocilizumab dose must be ensured (see section 4.4).

Pre-treatment with obinutuzumab

All patients in study NP30179 and in study GO41944 (STARGLO) received a single 1 000 mg dose ofobinutuzumab as pre-treatment on Cycle 1 Day 1 (7 days prior to initiation of Columvi treatment) tolower the circulating and lymphoid B cells (see Table 2, Delayed or Missed Doses, and section 5.1).

Obinutuzumab was administered as an intravenous infusion at 50 mg/h. The rate of infusion wasescalated in 50 mg/h increments every 30 minutes to a maximum of 400 mg/h.

Refer to the obinutuzumab prescribing information for complete information on premedication,preparation, administration and management of adverse reactions of obinutuzumab.

Premedication and prophylaxis

Cytokine release syndrome prophylaxis

Columvi should be administered to well-hydrated patients. Recommended premedication for CRS (seesection 4.4) is outlined in Table 1.

Table 1. Premedication before Columvi infusion

Treatment cycle (Day) Patients requiringpremedication Premedication Administration20 mg intravenous Completed at least 1 hour

Cycle 1 (Day 8, Day 15); dexamethasone prior to Columvi infusion

Cycle 2 (Day 1); All patients Oral analgesic /

Cycle 3 (Day 1) anti-pyretic2 At least 30 minutesbefore Columvi infusion

Anti-histamine3

Oral analgesic /

All patients anti-pyretic2 At least 30 minutesbefore Columvi infusion

Anti-histamine3

All subsequent infusions Patients whoexperienced CRS 20 mg intravenous Completed at least 1 hourwith the previous dexamethasone1, 4 prior to Columvi infusiondose1 If patient has an intolerance to dexamethasone or dexamethasone is unavailable, administer 100 mgprednisone/prednisolone or 80 mg methylprednisolone.2 For example, 1 000 mg paracetamol.3 For example, 50 mg diphenhydramine.4 To be administered in addition to the premedication required for all patients.

Columvi dosing begins with a step-up dosing schedule (which is designed to decrease the risk of

CRS), leading to the recommended dose of 30 mg.

Columvi monotherapy dose step-up schedule

Columvi must be administered as an intravenous infusion according to the dose step-up scheduleleading to the recommended dose of 30 mg (as shown in Table 2), after completion of pre-treatmentwith obinutuzumab on Cycle 1 Day 1. Each cycle is 21 days.

Table 2. Columvi monotherapy dose step-up schedule for patients with relapsed or refractory

DLBCL

Treatment cycle, Day Dose of Columvi Duration of infusion

Cycle 1 Day 1 Pre-treatment with obinutuzumab 1000 mg1(Pre-treatment and Day 8 2.5 mgstep-up dose) Day 15 10 mg 4 hours2

Cycle 2 Day 1 30 mg

Cycle 3 to 12 Day 1 30 mg 2 hours31 Refer to “Pre-treatment with obinutuzumab” described above.2 For patients who experience CRS with their previous dose of Columvi, the duration of infusion may beextended up to 8 hours (see section 4.4).3 At the discretion of the treating physician, if the previous infusion was well tolerated. If the patient experienced

CRS with a previous dose, the duration of infusion should be maintained at 4 hours.

Columvi dose step-up schedule in combination with gemcitabine and oxaliplatin

Columvi must be administered as an intravenous infusion according to the dose step-up scheduleleading to the recommended dose of 30 mg (as shown in Table 3), after completion of pre-treatmentwith obinutuzumab on Cycle 1 Day 1.

Columvi is given in combination with gemcitabine and oxaliplatin at Cycles 1-8 and as monotherapyat Cycles 9-12. Each cycle is 21 days.

Table 3. Columvi dose step-up schedule in combination with gemcitabine and oxaliplatin forpatients with relapsed or refractory DLBCL

Treatment cycle, Day Dose of Columvi Dose of Dose of(duration of infusion) gemcitabine oxaliplatin

Day 1 Pre-treatment with obinutuzumab 1000 mga

Cycle 1 Day 2 - 1000 mg/m2 b 100 mg/m2 b(Pre-treatment andstep-up dose) Day 8 2.5 mg (4 hours)c - -

Day 15 10 mg (4 hours)c

Cycle 2 Day 1 30 mg (4 hours)c,d 1000 mg/m2 b,d 100 mg/m2 b,d

Cycle 3 to 8 Day 1 30 mg (2 hours)d,e 1000 mg/m2 b,d 100 mg/m2 b,d

Cycle 9 to 12 Day 1 30 mg (2 hours)e - -a Refer to “Pre-treatment with obinutuzumab” described above.b Cycles 1-8: Administer gemcitabine before oxaliplatin.c For patients who experience CRS with their previous dose of Columvi, the time of infusion may be extended upto 8 hours (see section 4.4).d Cycles 2-8: Administer Columvi before gemcitabine and oxaliplatin. Gemcitabine and oxaliplatin may be givenon Day 1 or 2.e Infusion time may be shortened to 2 hours at the discretion of the treating physician, if the previous infusionwas well tolerated. If the patient experienced CRS with a previous dose, the duration of infusion should bemaintained at 4 hours.

Patient monitoring

* When Columvi is given as monotherapy, patients must be monitored for signs and symptoms ofpotential CRS during all Columvi infusions and for at least 10 hours after completion of theinfusion of the first Columvi dose (2.5 mg on Cycle 1 Day 8) (see section 4.8).

* When Columvi is given in combination with gemcitabine and oxaliplatin, patients must bemonitored for signs and symptoms of potential CRS during all Columvi infusions and for4 hours after completion of the first Columvi dose (2.5 mg on Cycle 1 Day 8) (see section 4.8).

Patients who experienced Grade ≥ 2 CRS with their previous infusion should be monitored aftercompletion of the infusion (see Table 4 in section 4.2).

All patients must be monitored for signs and symptoms of CRS and immune effector cell-associatedneurotoxicity syndrome (ICANS) following Columvi administration.

All patients must be counselled on the risk, signs and symptoms of CRS and ICANS and advised tocontact the healthcare provider immediately should they experience signs and symptoms of CRSand/or ICANS at any time (see section 4.4).

Treatment with Columvi monotherapy is recommended for a maximum of 12 cycles or until diseaseprogression or unmanageable toxicity, whichever occurs first. Each cycle is 21 days.

Treatment with Columvi in combination with gemcitabine and oxaliplatin is recommended for8 cycles, followed by 4 cycles of Columvi monotherapy for a maximum of 12 cycles of Columvi intotal or until disease progression or unmanageable toxicity, whichever occurs first. Each cycle is21 days.

During step-up dosing (weekly dosing):

* Following pre-treatment with obinutuzumab, if the Columvi 2.5 mg dose is delayed by morethan 1 week, then repeat pre-treatment with obinutuzumab.

* Following Columvi 2.5 mg dose or 10 mg dose, if there is a Columvi treatment-free interval of2 weeks to 6 weeks, then repeat the last tolerated Columvi dose and resume the planned step-updosing.

* Following Columvi 2.5 mg dose or 10 mg dose, if there is a Columvi treatment-free interval ofmore than 6 weeks, then repeat pre-treatment with obinutuzumab and Columvi step-up dosing(see Cycle 1 in Table 2 and Table 3).

After Cycle 2 (30 mg dose):

* If there is a Columvi treatment-free interval of more than 6 weeks between cycles, then repeatpre-treatment with obinutuzumab and Columvi step-up dosing (see Cycle 1 in Table 2 and

Table 3), and then resume the planned treatment cycle (30 mg dose).

No dose reductions of Columvi are recommended.

Management of cytokine release syndrome

CRS should be identified based on the clinical presentation (see sections 4.4 and 4.8). Patients shouldbe evaluated for other causes of fever, hypoxia, and hypotension, such as infections or sepsis. If CRSis suspected, it should be managed according to the CRS management recommendations based on

American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading in Table 4.

Table 4. ASTCT CRS grading and CRS management guidance

Grade1 CRS management For next scheduled

Columvi infusion

Grade 1 If CRS occurs during infusion: * Ensure symptoms are

Fever ≥ 38 °C * Interrupt infusion and treat symptoms resolved for at least

* Restart infusion at slower rate when 72 hours prior to nextsymptoms resolve infusion

* If symptoms recur, discontinue current * Consider slowerinfusion infusion rate2

If CRS occurs post-infusion:

*

Treat symptoms

If CRS lasts more than 48 h after symptomaticmanagement:

* Consider corticosteroids3

*

Consider tocilizumab4

For CRS with concurrent ICANS, refer to

Table 5.

Grade 2 If CRS occurs during infusion: * Ensure symptoms are

Fever ≥ 38 °C and/or * Discontinue current infusion and treat resolved for at leasthypotension not symptoms 72 hours prior to nextrequiring vasopressors * Administer corticosteroids3 infusionand/or hypoxia * Consider tocilizumab4 * Consider slowerrequiring low-flow 2oxygen by nasal If CRS occurs post-infusion: infusion rate

* Monitor patientscannula or blow-by * Treat symptoms 5

* Administer corticosteroids3 post-infusion

* 4

Consider tocilizumab

For CRS with concurrent ICANS, refer to

Table 5.

For Grade 2: Tocilizumab use

Do not exceed 3 doses of tocilizumab in a period of 6 weeks.

If no prior use of tocilizumab or if 1 dose of tocilizumab was used within the last 6 weeks:

* Administer first dose of tocilizumab4

* If no improvement within 8 hours, administer second dose of tocilizumab4

* After 2 doses of tocilizumab, consider alternative anti-cytokine therapy and/or alternativeimmunosuppressant therapy

If 2 doses of tocilizumab were used within the last 6 weeks:

* Administer only one dose of tocilizumab4

* If no improvement within 8 hours, consider alternative anti-cytokine therapy and/or alternativeimmunosuppressant therapy

Grade1 CRS management For next scheduled

Columvi infusion

Grade 3 If CRS occurs during infusion: * Ensure symptoms are

Fever ≥ 38 °C and/or * Discontinue current infusion and treat resolved for at leasthypotension requiring symptoms 72 hours prior to nexta vasopressor (with or * Administer corticosteroids3 infusionwithout vasopressin) *

Administer tocilizumab4 * Consider slowerand/or hypoxia 2requiring high-flow If CRS occurs post-infusion: infusion rateoxygen by nasal * Treat symptoms * Monitor patientscannula, face mask, * Administer corticosteroids3 post-infusion

*

* Administer tocilizumab4 If Grade ≥ 3 CRSnon-rebreather mask, recurs at subsequentor Venturi mask For CRS with concurrent ICANS, refer to infusion, stop infusion

Table 5. immediately andpermanentlydiscontinue Columvi

Grade 4 If CRS occurs during infusion or post-infusion:

Fever ≥ 38 °C and/or * Permanently discontinue Columvi and treat symptomshypotension requiring * Administer corticosteroids3multiple vasopressors *

Administer tocilizumab4(excluding For CRS with concurrent ICANS, refer to Table 5.vasopressin) and/orhypoxia requiringoxygen by positivepressure (e.g., CPAP,

BiPAP, intubation, andmechanicalventilation)

For Grade 3 and Grade 4: Tocilizumab use

Do not exceed 3 doses of tocilizumab in a period of 6 weeks.

If no prior use of tocilizumab or if 1 dose of tocilizumab was used within the last 6 weeks:

* Administer first dose of tocilizumab4

* If no improvement within 8 hours or rapid progression of CRS, administer second dose oftocilizumab4

* After 2 doses of tocilizumab, consider alternative anti-cytokine therapy and/or alternativeimmunosuppressant therapy

If 2 doses of tocilizumab were used within the last 6 weeks:

* Administer only one dose of tocilizumab4

* If no improvement within 8 hours or rapid progression of CRS, consider alternative anti-cytokinetherapy and/or alternative immunosuppressant therapy1 ASTCT consensus grading criteria (Lee 2019).2 Duration of infusion may be extended up to 8 hours, as appropriate for that cycle (see Table 2).3 Corticosteroids (e.g., 10 mg intravenous dexamethasone, 100 mg intravenous prednisolone, 1-2 mg/kgintravenous methylprednisolone per day, or equivalent).4 Tocilizumab 8 mg/kg intravenously (not to exceed 800 mg), as administered in Study NP30179.5 See section 4.8 for frequency and time to onset of Grade ≥ 2 CRS following Columvi 10 mg and 30 mg doses.

Management of immune effector cell-associated neurotoxicity syndrome (ICANS)

At the first sign of ICANS, based on the type and severity, consider supportive therapy, neurologyevaluation, and withholding Columvi (see Table 5). Rule out other causes of neurologic symptoms. If

ICANS is suspected, it should be managed according to the recommendations in Table 5.

Table 5. ICANS grading and management guidance

Grade1 Presenting symptoms2 ICANS management

Concurrent CRS No concurrent CRS

Grade 1 ICE3 score 7-9 * Manage CRS per Table 4. * Monitor neurologic

* Monitor neurologic symptoms and consider

Or depressed level of symptoms and consider neurology consultationconsciousness4: neurology consultation and evaluation, perawakens spontaneously and evaluation, per physician discretion.

physician discretion.

W ithhold Columvi until ICANS resolves.

Consider non-sedating, anti-seizure medicinal products( e.g., levetiracetam) for seizure prophylaxis.

Grade 2 ICE3 score 3-6 * Administer tocilizumab * Administerper Table 4 for dexamethasone5 10 mg

Or depressed level of management of CRS. intravenously everyconsciousness4: * If no improvement after 6 hours.awakens to voice starting tocilizumab, * Continue dexamethasoneadminister use until resolution todexamethasone5 10 mg Grade 1 or less, thenintravenously every taper.6 hours if not alreadytaking othercorticosteroids. Continuedexamethasone use untilresolution to Grade 1 orless, then taper.

W ithhold Columvi until ICANS resolves.

Consider non-sedating, anti-seizure medicinal products(e.g., levetiracetam) for seizure prophylaxis. Considerneurology consultation and other specialists for furthere valuation, as needed.

Grade 3 ICE3 score 0-2 * Administer tocilizumab * Administer

Or depressed level of per Table 4 for dexamethasone5 10 mgconsciousness4: management of CRS. intravenously everyawakens only to tactile * In addition, administer 6 hours.

stimulus; dexamethasone5 10 mg * Continue dexamethasoneintravenously with the use until resolution to

Or seizures4, either: first dose of tocilizumab, Grade 1 or less, then

* any clinical seizure, and repeat dose every taper.

focal or generalised 6 hours, if not alreadythat resolves rapidly, taking otheror corticosteroids. Continue

* non-convulsive dexamethasone use untilseizures on resolution to Grade 1 orelectroencephalogramless, then taper.(EEG) that resolvewith intervention; Withhold Columvi until ICANS resolves.

For Grade 3 ICANS events which do not improve within

Or raised intracranial 7 days, consider permanently discontinuing Columvi.pressure: focal/localoedema on Consider non-sedating, anti-seizure medicinal productsneuroimaging4 (e.g., levetiracetam) for seizure prophylaxis. Considerneurology consultation and other specialists for furtherevaluation, as needed.

Grade1 Presenting symptoms2 ICANS management

Concurrent CRS No concurrent CRS

Grade 4 ICE3 score 0 * Administer tocilizumab * Administer

Or depressed level of per Table 4 for dexamethasone5 10 mgconsciousness4, either: management of CRS. intravenously every

* patient is unarousable * As above, or consider 6 hours.

or requires vigorous administration of * Continue dexamethasoneor repetitive tactile methylprednisolone use until resolution tostimuli to arouse, or 1 000 mg per day Grade 1 or less, then

* stupor or coma; intravenously with first taper.dose of tocilizumab, and * Alternatively, consider

Or seizures4, either: continue administration of

* life-threatening methylprednisolone methylprednisoloneprolonged seizure 1 000 mg per day 1 000 mg per day(> 5 minutes), or intravenously for 2 or intravenously for 3 days;

* repetitive clinical or more days. if symptoms improve,electrical seizures then manage as above.without return tobaseline in between;

Permanently discontinue Columvi.

Or motor findings4: Consider non-sedating, anti-seizure medicinal products

* deep focal motor (e.g., levetiracetam) for seizure prophylaxis. Considerweakness such as neurology consultation and other specialists for furtherhemiparesis or evaluation, as needed. In case of raised intracranialparaparesis; pressure/cerebral oedema, refer to institutional guidelines

Or raised intracranial f or management.pressure/cerebraloedema4, withsigns/symptoms, suchas:

* diffuse cerebraloedema onneuroimaging, or

* decerebrate ordecorticate posturing,or

* cranial nerve VIpalsy, or

* papilloedema, or

*

Cushing’s triad1 ASTCT consensus grading criteria for ICANS (Lee 2019).2 Management is determined by the most severe event, not attributable to any other cause.3 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 3 objects, e.g., point to clock, pen, button = 3 points);

Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out yourtongue” = 1 point);

Writing (ability to write a standard sentence = 1 point);

Attention (count backwards from 100 by ten = 1 point).

If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.4 Attributable to no other cause.5 All references to dexamethasone administration are dexamethasone or equivalent.

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

No dose adjustment is required in patients with mild hepatic impairment (total bilirubin > upper limitof normal [ULN] to ≤ 1.5 × ULN or aspartate transaminase [AST] > ULN). Columvi has not beenstudied in patients with moderate or severe hepatic impairment (see section 5.2).

No dose adjustment is required in patients with mild or moderate renal impairment (CrCL 30 to< 90 mL/min). Columvi has not been studied in patients with severe renal impairment (seesection 5.2).

The safety and efficacy of Columvi in children below 18 years of age have not been established. Nodata are available.

Columvi is for intravenous use only.

Columvi must be diluted by a healthcare professional using aseptic technique, prior to intravenousadministration. It must be administered as an intravenous infusion through a dedicated infusion line.

Columvi must not be administered as an intravenous push or bolus.

For instructions on dilution of Columvi before administration, see section 6.6.

Hypersensitivity to the active substance, to obinutuzumab, or to any of the excipients listed insection 6.1.

For specific contraindications on obinutuzumab, please refer to the obinutuzumab prescribinginformation.

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

CD20-negative disease

There are limited data available on patients with CD20-negative DLBCL treated with Columvi and itis possible that patients with CD20-negative DLBCL may have less benefit compared to patients with

CD20-positive DLBCL. The potential risks and benefits associated with treatment of patients with

CD20-negative DLBCL with Columvi should be considered.

Cytokine release syndrome

CRS, including life-threatening reactions, has been reported in patients receiving Columvi (seesection 4.8).

The most common manifestations of CRS were pyrexia, tachycardia, hypotension, chills and hypoxia.

Infusion-related reactions may be clinically indistinguishable from manifestations of CRS.

Most CRS events occurred following the first dose of Columvi. Elevated liver function tests (AST andalanine transaminase [ALT] > 3 × ULN and/or total bilirubin > 2 × ULN) concurrent with CRS havebeen reported after Columvi use (see section 4.8).

Patients in studies NP30179 and GO41944 (STARGLO) were pre-treated with obinutuzumab to lowerthe circulating and lymphoid B cells, 7 days prior to initiation of Columvi therapy. All patients shouldbe premedicated with an anti-pyretic, antihistamine, and a glucocorticoid (see Table 1).

At least 1 dose of tocilizumab for use in the event of CRS must be available prior to Columvi infusionat Cycles 1 and 2. Access to an additional dose of tocilizumab within 8 hours of use of the previoustocilizumab dose must be ensured.

When Columvi is given as monotherapy, patients must be monitored during all Columvi infusions andfor at least 10 hours after completion of the first infusion.

When Columvi is given in combination with gemcitabine and oxaliplatin, patients must be monitoredduring all Columvi infusions and for 4 hours after completion of the first infusion.

For complete information on monitoring, see section 4.2. Patients must be counselled to seekimmediate medical attention should signs or symptoms of CRS occur at any time (see Patient cardbelow).

Patients should be evaluated for other causes of fever, hypoxia and hypotension, such as infections orsepsis. CRS should be managed based on the patient’s clinical presentation and according to the CRSmanagement guidance provided in Table 4 (section 4.2).

Immune effector cell-associated neurotoxicity syndrome

Serious cases of immune effector cell-associated neurotoxicity syndrome (ICANS) which could belife-threatening or fatal have occurred following treatment with Columvi (see section 4.8).

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

CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusion, depressedlevel of consciousness, disorientation, seizure, aphasia, and dysgraphia.

Patients should be monitored for signs and symptoms of ICANS following Columvi administrationand treated promptly. Patients must be counselled to seek immediate medical attention should signs orsymptoms occur at any time (see Patient card below).

At the first signs or symptoms of ICANS, manage according to the ICANS guidance provided in

Table 5. Treatment with Columvi should be withheld or discontinued permanently as recommended.

The prescriber must inform the patient of the risk of CRS and ICANS and the signs and symptoms of

CRS and ICANS. Patients must be instructed to seek immediate medical attention if they experiencesigns and symptoms of CRS and ICANS. Patients should be provided with the patient card andinstructed to carry the card at all times. This card describes symptoms of CRS and ICANS which, ifexperienced, should prompt the patient to seek immediate medical attention.

Interaction with CYP450 substrates

The initial release of cytokines associated with the start of Columvi treatment could suppress CYP450enzymes and lead to fluctuations in concentrations of concomitantly administered drugs. On initiationof Columvi therapy, patients being treated with CYP450 substrates with a narrow therapeutic indexshould be monitored as fluctuations in the concentration of concomitant drugs may lead to toxicity,loss of effect or adverse events (see section 4.5).

Serious infections (such as sepsis and pneumonia) have occurred in patients treated with Columvi (seesection 4.8).

Columvi must not be administered to patients with an active infection. Caution should be exercisedwhen considering the use of Columvi in patients with a history of chronic or recurrent infection, thosewith underlying conditions that may predispose them to infections, or those who have had significantprior immunosuppressive treatment. Patients should be monitored before and during Columvitreatment for the emergence of possible bacterial, fungal, and new or reactivated viral infections andtreated appropriately.

Columvi should be temporarily withheld in the presence of an active infection until the infection hasresolved. Patients should be instructed to seek medical advice if signs or symptoms suggestive of aninfection occur.

Febrile neutropenia has been reported during treatment with Columvi. Patients with febrileneutropenia should be evaluated for infection and treated promptly.

Tumour flare has been reported in patients receiving Columvi (see section 4.8). Manifestationsincluded localised pain and swelling.

Consistent with the mechanism of action of Columvi, tumour flare is likely due to the influx of T cellsinto tumour sites following Columvi administration and may mimic progression of disease. Tumourflare does not imply treatment failure or represent tumour progression.

Specific risk factors for tumour flare have not been identified, however, there is a heightened risk ofcompromise and morbidity due to mass effect secondary to tumour flare in patients with bulkytumours located in close proximity to airways and/or a vital organ. Monitoring and evaluation fortumour flare at critical anatomical sites is recommended in patients treated with Columvi and managedas clinically indicated. Corticosteroids and analgesics should be considered to treat tumour flare.

Tumour lysis syndrome (TLS) has been reported in patients receiving Columvi (see section 4.8).

Patients with high tumour burden, rapidly proliferative tumours, renal dysfunction or dehydration areat greater risk of tumour lysis syndrome.

Patients at risk should be monitored closely by appropriate laboratory and clinical tests for electrolytestatus, hydration and renal function. Appropriate prophylactic measures with anti-hyperuricaemics(e.g., allopurinol or rasburicase) and adequate hydration should be considered prior to obinutuzumabpre-treatment and prior to Columvi infusion.

Management of TLS may include aggressive hydration, correction of electrolyte abnormalities,anti-hyperuricaemic therapy and supportive care.

The safety of immunisation with live vaccines during or following Columvi therapy has not beenstudied. Immunisation with live vaccines is not recommended during Columvi therapy.

Polysorbates

This medicinal product contains 1.25 mg of polysorbate 20 in each 2.5 mL vial and 5 mg ofpolysorbate 20 in each 10 mL vial, which is equivalent to 0.5 mg/mL.

Polysorbates may cause allergic reactions.

No interaction studies have been performed. No interactions with Columvi are expected via thecytochrome P450 enzymes, other metabolising enzymes or transporters.

The initial release of cytokines associated with the start of Columvi treatment could suppress CYP450enzymes. The highest drug-drug interaction risk is during the period of one week following each of thefirst 2 doses of Columvi (i.e., Cycle 1 Day 8 and 15) in patients who are receiving concomitant

CYP450 substrates with a narrow therapeutic index (e.g., warfarin, cyclosporine). On initiation of

Columvi therapy, patients being treated with CYP450 substrates with a narrow therapeutic indexshould be monitored.

The pharmacokinetics (PK) of glofitamab are not affected by co-administration with gemcitabine oroxaliplatin.

Female patients of childbearing potential must use highly effective contraceptive methods duringtreatment with Columvi and for at least 2 months following the last dose of Columvi.

There are no data on the use of Columvi in pregnant women. No reproductive toxicity studies havebeen performed in animals (see section 5.3).

Glofitamab is an immunoglobulin G (IgG). IgG is known to cross the placenta. Based on itsmechanism of action, glofitamab is likely to cause foetal B-cell depletion when administered to apregnant woman.

Columvi is not recommended during pregnancy and in women of childbearing potential not usingcontraception. Female patients receiving Columvi should be advised of the potential harm to thefoetus. Female patients should be advised to contact the treating physician, should pregnancy occur.

It is not known whether glofitamab is excreted in human milk. No studies have been conducted toassess the impact of glofitamab on milk production or its presence in breast milk. Human IgG isknown to be present in human milk. The potential for absorption of glofitamab and the potential foradverse reactions in the breast-feeding child is unknown. Women should be advised to discontinuebreast-feeding during treatment with Columvi and for 2 months after the final dose of Columvi.

No human data on fertility are available. No fertility assessments in animals have been performed toevaluate the effect of glofitamab on fertility (see section 5.3).

Columvi has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving Columvi are at risk of depressed level ofconsciousness (see section 4.4). Patients should be instructed to avoid driving or operating machinesfor 48 hours after each of the first two doses during the step-up dosing and in the event of new onset ofany symptoms of ICANS (confusion, disorientation, depressed level of consciousness) and/or CRS(pyrexia, tachycardia, hypotension, chills, hypoxia) until symptoms resolve (see sections 4.4 and 4.8).

Columvi monotherapy

The most common adverse reactions (≥ 20%) were cytokine release syndrome, neutropenia, anaemia,thrombocytopenia, and rash.

The most common serious adverse reactions reported in ≥ 2% of patients were cytokine releasesyndrome (22.1%), sepsis (4.1%), COVID-19 (3.4%), tumour flare (3.4%), COVID-19 pneumonia(2.8%), febrile neutropenia (2.1%), neutropenia (2.1%), and pleural effusion (2.1%).

Permanent discontinuation of Columvi due to an adverse reaction occurred in 5.5% of patients. Themost common adverse reactions leading to permanent discontinuation of Columvi were COVID-19(1.4%) and neutropenia (1.4%).

Columvi in combination with gemcitabine and oxaliplatin

The most common adverse reactions (≥ 20%) were thrombocytopenia, cytokine release syndrome,neutropenia, anaemia, nausea, peripheral neuropathy, diarrhoea, aspartate aminotransferase increased,alanine aminotransferase increased, rash, lymphopenia, pyrexia, and vomiting.

The most common serious adverse reactions reported in ≥ 2% of patients were cytokine releasesyndrome (20.3%), pyrexia (6.4%), pneumonia (5.8%), COVID-19 (5.8%), thrombocytopenia (4.7%),respiratory tract infection (3.5%), sepsis (2.3%), febrile neutropenia (2.3%), and diarrhoea (2.3%).

Permanent discontinuation of Columvi due to an adverse reaction occurred in 20.9% of patients. Themost common adverse reactions leading to permanent discontinuation of Columvi were COVID-19(11.6%), sepsis (1.2%), and pneumonitis (1.2%).

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with Columvimonotherapy (n=145) in study NP30179 are listed in Table 6. Patients received a median of 5 cyclesof Columvi treatment (range: 1 to 13 cycles).

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with Columvi incombination with gemcitabine and oxaliplatin (n=172) in study GO41944 (STARGLO) are listed in

Table 7. Patients received a median of 11 cycles of Columvi treatment (range: 1 to 13 cycles).

The adverse reactions are listed by MedDRA system organ class and categories of frequency. Thefollowing categories of frequency have been used: 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).

Within each frequency grouping, adverse reactions are presented in the order of decreasingseriousness.

Table 6. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with

Columvi monotherapy

System organ class Adverse reaction All grades Grade 3−4

Viral infections1 Very common Common*

Bacterial infections2 Common Common

Upper respiratory tract infections3 Common Very rare**

Infections and Sepsis4 Common Common*infestations Lower respiratory tract infections5 Common Very rare**

Pneumonia Common Uncommon

Urinary tract infection6 Common Uncommon

Fungal infections7 Common Very rare**

Neoplasms benign,malignant andunspecified (incl Tumour flare Very common Commoncysts and polyps)

Neutropenia Very common Very Common

Blood and Anaemia Very common Commonlymphatic system Thrombocytopenia Very common Commondisorders Lymphopenia Common Common

Febrile neutropenia8 Common Common

Immune systemdisorders Cytokine release syndrome9 Very common Common

Hypophosphataemia Very common Common

Hypomagnesaemia Very common Very rare**

Metabolism and Hypocalcaemia Very common Very rare**nutrition disorders Hypokalaemia Very common Uncommon

Hyponatraemia Common Common

Tumour lysis syndrome Common Common

Psychiatricdisorders Confusional state Common Very rare**

Headache Very common Very rare**

Immune effector cell-associated

Nervous system neurotoxicity syndrome10 Common Uncommon*disorders Somnolence Common Uncommon

Tremor Common Very rare**

Myelitis11 Uncommon Uncommon

Constipation Very common Very rare**

Gastrointestinal Diarrhoea Very common Very rare**disorders Nausea Very common Very rare**

Gastrointestinal haemorrhage12 Common Common

Vomiting Common Very rare**

Skin andsubcutaneous Rash13 Very common Commontissue disorders

General disordersand administration Pyrexia Very common Very rare**site conditions

System organ class Adverse reaction All grades Grade 3−4

Alanine aminotransferase increased Common Common

Aspartate aminotransferase increased Common Common

Investigations Blood alkaline phosphatase increased Common Common

Gamma-glutamyltransferase increased Common Common

Blood bilirubin increased Common Uncommon

Hepatic enzyme increased Common Common

* Grade 5 reactions reported. See Description of selected adverse reactions.

** No Grade 3-4 events were reported.1 Includes COVID-19, COVID-19 pneumonia, herpes zoster, influenza, and ophthalmic herpes zoster.2 Includes vascular device infection, bacterial infection, Campylobacter infection, biliary tract infectionbacterial, urinary tract infection bacterial, Clostridium difficile infection, Escherichia infection, and peritonitis.3 Includes upper respiratory tract infection, sinusitis, nasopharyngitis, chronic sinusitis, and rhinitis.4 Includes sepsis and septic shock.5 Includes lower respiratory tract infection and bronchitis.6 Includes urinary tract infection and Escherichia urinary tract infection.7 Includes oesophageal candidiasis and oral candidiasis.8 Includes febrile neutropenia and neutropenic infection.9 Based on ASTCT consensus grading (Lee 2019).10 ICANS based on Lee 2019 and includes somnolence, cognitive disorder, confusional state, delirium, anddisorientation.11 Myelitis occurred concurrently with CRS.12 Includes gastrointestinal haemorrhage, large intestinal haemorrhage, and gastric haemorrhage.13 Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative,erythema, palmar erythema, pruritis, and rash erythematous.

Table 7. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with

Columvi in combination with gemcitabine and oxaliplatin

System organ class Adverse reaction All grades Grade 3−4

COVID-191 Very common Common*

Respiratory tract infections2 Very common Common*

Pneumonia3 Very common Common*

Infections and Cytomegalovirus infections4 Common Uncommoninfestations Herpes viral infections Common Uncommon

Urinary tract infection6 Common Common

Sepsis7 Common Common*

Candida infections8 Common Very rare**

Pneumocystis jirovecii pneumonia Uncommon Uncommon

Neoplasms benign,malignant and 9unspecified (incl Tumour flare Common Very rare**cysts and polyps)

Thrombocytopenia Very common Very common

Blood and Neutropenia Very common Very commonlymphatic system Anaemia Very common Very commondisorders Lymphopenia Very common Very common

Febrile neutropenia Common Common

Immune systemdisorders Cytokine release syndrome10 Very common Common

Hypokalaemia Very common Common

Hyponatraemia Very common Uncommon

Metabolism and Hypomagnesaemia Common Very rare**nutrition disorders Hypocalcaemia Common Uncommon

Hypophosphataemia Common Common

Tumour lysis syndrome Common Common

Peripheral neuropathy11 Very common Common

Nervous system Immune effector cell-associatedneurotoxicity syndrome12 Common Uncommondisorders Headache Common Very rare**

Tremor Uncommon Very rare**

Respiratory,thoracic and ,mediastinal Pneumonitis Common Very rare* **disorders

Nausea Very common Uncommon

Diarrhoea Very common Common

Gastrointestinal Vomiting Very common Uncommondisorders Abdominal pain13 Very common Common

Constipation Very common Very rare**

Colitis14 Common Common

Pancreatitis15 Common Common

Skin andsubcutaneous Rash16 Very common Uncommontissue disorders

Musculoskeletaland connective Musculoskeletal pain17 Very common Commontissue disorders

System organ class Adverse reaction All grades Grade 3−4

General disordersand administration Pyrexia Very common Uncommonsite conditions

Aspartate aminotransferase increased Very common Common

Alanine aminotransferase increased Very common Common

Blood alkaline phosphatase increased Very common Uncommon

Investigations Gamma-glutamyltransferase increased Very common Common

Blood lactate dehydrogenase Very commonincreased Very rare**

Blood bilirubin increased18 Common Very rare**

Hepatic enzyme increased Uncommon Very rare**

* Grade 5 reactions reported. See Description of selected adverse reactions.

** No Grade 3-4 events were reported.1 Includes COVID-19, COVID-19 pneumonia, and SARS-CoV-2 test positive.2 Includes upper respiratory tract infection, lower respiratory tract infection, respiratory tract infection, andrespiratory tract infection bacterial.3 Includes pneumonia, pneumonia bacterial, and pneumonia pneumococcal.4 New onset or reactivation. Includes cytomegalovirus infection, cytomegalovirus test positive, cytomegalovirusinfection reactivation and cytomegalovirus viraemia.5 New onset or reactivation. Includes herpes zoster and herpes virus infection.6 Includes urinary tract infection and urosepsis.7 Includes sepsis, streptococcal sepsis, septic shock, and enterococcal sepsis.8 Includes oral candidiasis and candida infection.9 Includes tumour flare and tumour pain.10 Based on ASTCT consensus grading (Lee 2019).11 Includes neuropathy peripheral, peripheral sensory neuropathy, dysaesthesia, paraesthesia, hypoaesthesia,peripheral motor neuropathy, and polyneuropathy.12 Includes confusional state, delirium, and ICANS.13 Includes abdominal pain, abdominal discomfort, abdominal pain upper, abdominal pain lower, andgastrointestinal pain.14 Includes colitis, colitis ischaemic, and enterocolitis.15 Includes pancreatitis and pancreatitis acute.16 Includes rash, rash pruritic, rash maculo-papular, erythema, pruritus, rash erythematous, urticaria, anderythema multiforme.17 Includes arthralgia, musculoskeletal pain, back pain, bone pain, myalgia, neck pain, pain in extremity,musculoskeletal chest pain, and non-cardiac chest pain.18 Includes blood bilirubin increased and hyperbilirubinaemia.

The descriptions below reflect information for significant adverse reactions for Columvi monotherapyand/or combination therapy. Details for the significant adverse reactions for Columvi when given incombination are presented separately if clinically relevant differences were noted in comparison to

Columvi monotherapy.

Cytokine release syndrome

Columvi monotherapy

Any grade CRS (by ASTCT criteria) occurred in 67.6% of patients who received Columvimonotherapy, with Grade 1 CRS reported in 50.3% of patients, Grade 2 CRS in 13.1% of patients,

Grade 3 CRS in 2.8% of patients and Grade 4 CRS in 1.4% of patients. CRS occurred more than oncein 32.4% (47/145) of patients; 36/47 patients experienced multiple Grade 1 CRS events only. Therewere no fatal cases of CRS. CRS resolved in all patients except one. One patient discontinuedtreatment due to CRS.

In patients with CRS, the most common manifestations of CRS included pyrexia (99.0%), tachycardia(25.5%), hypotension (23.5%), chills (14.3%) and hypoxia (12.2%). Grade 3 or higher eventsassociated with CRS included hypotension (3.1%), hypoxia (3.1%), pyrexia (2.0%) and tachycardia(2.0%).

CRS of any grade occurred in 54.5% of patients following the first 2.5 mg dose of Columvi at Cycle 1

Day 8 with median time to onset (from start of infusion) of 12.6 hours (range: 5.2 to 50.8 hours) andmedian duration of 31.8 hours (range: 0.5 to 316.7 hours); in 33.3% of patients following the 10 mgdose at Cycle 1 Day 15 with median time to onset of 26.8 hours (range: 6.7 to 125.0 hours) andmedian duration of 16.5 hours (range: 0.3 to 109.2 hours); and in 26.8% of patients following the30 mg dose at Cycle 2 with median time to onset of 28.2 hours (range: 15.0 to 44.2 hours) and medianduration of 18.9 hours (range: 1.0 to 180.5 hours). CRS was reported in 0.9% of patients at Cycle 3and in 2% of patients beyond Cycle 3.

Grade ≥ 2 CRS occurred in 12.4% of patients following the first Columvi dose (2.5 mg) with mediantime to onset of 9.7 hours (range: 5.2 to 19.1 hours) and median duration of 50.4 hours (range: 6.5 to316.7 hours). Following Columvi 10 mg dose at Cycle 1 Day 15, the incidence of Grade ≥ 2 CRSdecreased to 5.2% of patients with median time to onset of 26.2 hours (range: 6.7 to 144.2 hours) andmedian duration of 30.9 hours (range: 3.7 to 227.2 hours). Grade ≥ 2 CRS following Columvi 30 mgdose at Cycle 2 Day 1 occurred in one patient (0.8%) with time to onset of 15.0 hours and duration of44.8 hours. No Grade ≥ 2 CRS was reported beyond Cycle 2.

In 145 patients, 7 patients (4.8%) experienced elevated liver function tests (AST and ALT > 3 × ULNand/or total bilirubin > 2 × ULN) reported concurrently with CRS (n=6) or with disease progression(n=1).

Among the 25 patients who experienced Grade ≥ 2 CRS after Columvi, 22 (88.0%) receivedtocilizumab, 15 (60.0%) received corticosteroids and 14 (56.0%) received both tocilizumab andcorticosteroids. Ten patients (40.0%) received oxygen. All 6 patients (24.0%) with Grade 3 or 4 CRSreceived a single vasopressor.

Hospitalisations due to patients experiencing CRS following Columvi administration occurred in22.1% of patients and the reported median duration of hospitalisation was 4 days (range: 2 to 15 days).

Columvi in combination with gemcitabine and oxaliplatin

Any grade CRS (by ASTCT criteria) occurred in 44.2% of patients who received Columvi withgemcitabine and oxaliplatin, with Grade 1 CRS reported in 31.4% of patients, Grade 2 CRS in 10.5%of patients, and Grade 3 CRS in 2.3% of patients. CRS occurred more than once in 21.5% (37/172) ofpatients; 30/37 patients experienced multiple Grade 1 CRS events only. There were no Grade 4 or fatalcases of CRS. CRS resolved in all patients except one. One patient discontinued treatment due to CRS.

In patients with CRS, the most common manifestations of CRS included pyrexia (98.7%), hypotension(22.4%), chills (17.1%) and hypoxia (14.5%). Grade 3 or higher events associated with CRS includedhypotension (6.6%), hypoxia (5.3%), pyrexia (3.9%), chills (1.3%) and diarrhoea (1.3%).

CRS of any grade occurred in 34.9% of patients following the first 2.5 mg dose of Columvi at Cycle 1

Day 8 with median time to onset (from start of infusion) of 12.6 hours (range: 4.4 to 54.7 hours) andmedian duration of 19.8 hours (range: 2.0 to 168.0 hours); in 14.4% of patients following the 10 mgdose at Cycle 1 Day 15 with median time to onset of 22.8 hours (range: 7.4 to 81.2 hours) and medianduration of 10.6 hours (range: 1.0 to 248.5 hours); and in 9.3% of patients following the 30 mg dose at

Cycle 2 with median time to onset of 23.5 hours (range: 14.7 to 33.4 hours) and median duration of18.4 hours (range: 8.3 to 137.0 hours). CRS was reported in 6.7% of patients at Cycle 3 and in 11.0%of patients beyond Cycle 3.

Grade ≥ 2 CRS occurred in 10.5% of patients following the first Columvi dose (2.5 mg) with mediantime to onset of 12.0 hours (range: 4.4 to 30.5 hours) and median duration of 42.3 hours (range: 3.5 to143.7 hours). The majority (14/18) of patients who experienced Grade ≥ 2 CRS had onset of CRSwithin 8 hours of the start of the first Columvi dose (2.5 mg). Following Columvi 10 mg dose at

Cycle 1 Day 15, the incidence of Grade ≥ 2 CRS decreased to 1.8% of patients with median time toonset of 22.3 hours (range: 7.4 to 22.8 hours) and median duration of 37.0 hours (range: 34.8 to248.5 hours). There were no Grade ≥ 2 CRS events following Columvi 30 mg dose at Cycle 2 Day 1.

Three patients (2.0%) had Grade ≥ 2 CRS beyond Cycle 2 (all Grade 2 events).

Of the 172 patients, 2 patients (1.2%) experienced elevated liver function tests (AST and

ALT > 3 × ULN) reported concurrently with CRS.

Out of the 76 patients with any grade CRS, 28 patients (36.8%) were treated with tocilizumab,39 patients (51.3%) were treated with corticosteroids, and 18 patients (23.7%) received bothtocilizumab and corticosteroids.

Among the 22 patients who experienced Grade ≥ 2 CRS after Columvi, 16 (72.7%) receivedtocilizumab, 15 (68.2%) received corticosteroids, and 12 (54.5%) received both tocilizumab andcorticosteroids. Eleven patients (50.0%) received oxygen. All 4 patients (18.2%) with Grade 3 CRSreceived a single vasopressor.

Hospitalisations due to patients experiencing CRS following Columvi administration occurred in19.8% of patients and the reported median duration of hospitalisation was 5 days (range: 2 to 85 days).

Immune effector cell-associated neurotoxicity syndrome

ICANS, including Grade 3 and higher, was reported in clinical trials and with post-marketingexperience. The most frequent clinical manifestations of ICANS were confusion, depressed level ofconsciousness, disorientation, seizure, aphasia, and dysgraphia. Based on the available data, the onsetof neurologic toxicity was concurrent with CRS in the majority of cases.

The observed time to onset of the majority of ICANS was 1-7 days with median of 2 days after themost recent dose. Only few events were reported to have occurred more than one month after theinitiation of Columvi.

Serious infections were reported in 15.9% of patients who received Columvi monotherapy. The mostfrequent serious infections reported in ≥ 2% of patients were sepsis (4.1%), COVID-19 (3.4%), and

COVID-19 pneumonia (2.8%). Infection-related deaths were reported in 4.8% of patients (due tosepsis, COVID-19 pneumonia and COVID-19). Four patients (2.8%) experienced serious infectionsconcurrently with Grade 3 or 4 neutropenia.

Serious infections were reported in 22.7% of patients who received Columvi with gemcitabine andoxaliplatin. The most frequent serious infections reported in ≥ 2% of patients were pneumonia (5.8%),

COVID-19 (4.7%), and lower respiratory tract infection (2.9%). Infection-related deaths were reportedin 3.5% of patients (due to COVID-19, pneumonia, respiratory tract infection, and septic shock). Onepatient (0.6%) experienced a serious infection (pneumonia) concurrently with Grade 3 neutropenia.

Pneumonitis

Pneumonitis events (excluding pneumonia of infectious aetiology) were reported in 2 patients (1.2%)who received Columvi with gemcitabine and oxaliplatin, both of which were fatal events. The mediantime to onset of pneumonitis from the first Columvi dose was 168 days (range: 102 to 255 days).

Colitis events (excluding infectious aetiology) were reported in 4/172 patients (2.3%) who received

Columvi with gemcitabine and oxaliplatin. Two patients (1.2%) had Grade 3 events. The median timeto onset of colitis from the first Columvi dose was 154 days (range: 115 to 187 days).

Cytomegalovirus (CMV) events were reported in 10 patients (5.8%) who received Columvi withgemcitabine and oxaliplatin, with 1 patient (0.6%) experiencing Grade 3 CMV viraemia. Oralcandidiasis was reported in 3 patients (1.7%) all of which were Grade 1-2 events. Pneumocystisjirovecii pneumonia (Grade 3) was reported in 1 patient (0.6%), the same patient with Grade 3 CMVviraemia. Borellia meningitis (Grade 2) was reported in 1 patient (0.6%).

Neutropenia (including neutrophil count decreased) was reported in 40.0% of patients and severeneutropenia (Grade 3 or 4) was reported in 29.0% of patients who received Columvi monotherapy.

The median time to onset of the first neutropenia event was 29 days (range: 1 to 203 days). Prolongedneutropenia (lasting longer than 30 days) occurred in 11.7% of patients. The majority of patients withneutropenia (79.3%) were treated with G-CSF. Febrile neutropenia was reported in 3.4% of patients.

Tumour flare was reported in 11.7% of patients who received Columvi monotherapy, including

Grade 2 tumour flare in 4.8% of patients and Grade 3 tumour flare in 2.8% of patients. Tumour flarewas reported involving lymph nodes in the head and neck presenting with pain and involving lymphnodes in the thorax with symptoms of breathlessness due to development of pleural effusion. Mosttumour flare events (16/17) occurred during Cycle 1, and no tumour flare events were reported beyond

Cycle 2. The median time to onset of tumour flare of any grade was 2 days (range: 1 to 16 days), andthe median duration was 3.5 days (range: 1 to 35 days).

Among the 11 patients who experienced Grade ≥ 2 tumour flare, 2 patients (18.2%) receivedanalgesics, 6 patients (54.5%) received corticosteroids and analgesics including morphine derivatives,1 patient (9.1%) received corticosteroids and anti-emetics, and 2 patients (18.2%) did not requiretreatment. All tumour flare events resolved except in one patient with a Grade ≥ 2 event. No patientsdiscontinued treatment due to tumour flare.

TLS was reported in 2 patients (1.4%) who received Columvi monotherapy and was Grade 3 inseverity in both cases. The median time to onset of TLS onset was 2 days, and the median durationwas 4 days (range: 3 to 5 days).

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.

There is no experience with overdose in clinical trials. In case of overdose, patients should be closelymonitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatmentinstituted.

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drugconjugates, ATC code: L01FX28

Glofitamab is a bispecific monoclonal antibody that binds bivalently to CD20 expressed on the surfaceof B cells and monovalently to CD3 in the T-cell receptor complex expressed on the surface of T cells.

By simultaneous binding to CD20 on the B cell and CD3 on the T cell, glofitamab mediates theformation of an immunological synapse with subsequent T-cell activation and proliferation, secretionof cytokines and release of cytolytic proteins that results in the lysis of CD20-expressing B cells.

Pharmacodynamics

In study NP30179, 84% (84/100) of patients were already B-cell depleted (< 70 cells/µL) before pre-treatment with obinutuzumab. The proportion of patients with B-cell depletion increased to 100%(94/94) after obinutuzumab pre-treatment prior to Columvi treatment initiation, and B-cell countsremained low during Columvi treatment.

During Cycle 1 (step-up dosing), transient increases in plasma IL-6 levels were observed at 6 hourspost Columvi infusion, which remained elevated at 20 hours post-infusion and returned to baselineprior to the next infusion.

In study GO41944 (STARGLO), 63.9% (115/180) of patients were already B-cell depleted(< 70 cells/µL) before pre-treatment with obinutuzumab. The proportion of patients with B-celldepletion increased to 79.4% (143/180) after obinutuzumab pre-treatment prior to Columvi treatmentinitiation, and B-cell counts remained low during Columvi treatment.

In study NP30179, 16/145 patients who were exposed to Columvi experienced a post-baseline QTcvalue > 450 ms. One of these cases was assessed to be of clinical significance by the investigator. Nopatients discontinued treatment due to QTc prolongation.

In study GO41944 (STARGLO), 16/172 patients who were exposed to Columvi experienced a post-baseline QTc value > 450 ms. No patients discontinued treatment due to QTc prolongation.

Relapsed or refractory DLBCL

Columvi monotherapy

An open-label multicentre, multi-cohort trial (NP30179) was conducted to evaluate Columvi inpatients with relapsed or refractory B-cell non-Hodgkin's lymphoma. In the single-arm monotherapy

DLBCL cohort (n=108), patients with relapsed or refractory DLBCL were required to have received atleast two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and ananthracycline agent. Patients with FL3b and Richter transformation were not eligible. Patients wereexpected to present CD20-positive DLBCL, but biomarker eligibility was not a requirement forinclusion (see section 4.4).

The study excluded patients with ECOG performance status ≥ 2, significant cardiovascular disease(such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within thelast 6 months, unstable arrhythmias, or unstable angina), significant active pulmonary disease,impaired renal functions (CrCL < 50 mL/min with elevated serum creatinine level), activeautoimmune disease requiring immunosuppressive therapy, active infections (i.e., chronic active EBV,acute or chronic hepatitis C, hepatitis B, HIV), progressive multifocal leukoencephalopathy, current ora history of CNS lymphoma or CNS disease, a history of macrophage activation syndrome /hemophagocytic lymphohistiocytosis, prior allogeneic stem cell transplant, prior organ transplantation,or hepatic transaminases ≥ 3 × ULN.

All patients received pre-treatment with obinutuzumab at Cycle 1 Day 1. Patients received 2.5 mg of

Columvi at Cycle 1 Day 8, 10 mg of Columvi at Cycle 1 Day 15, and 30 mg of Columvi at Cycle 2

Day 1 as per the step-up dosing schedule. Patients continued to receive 30 mg of Columvi on Day 1 of

Cycles 3 to 12. The duration of each cycle was 21 days. Patients received a median of 5 cycles of

Columvi treatment (range: 1 to 13 cycles); 34.7% received 8 or more cycles and 25.7% received12 cycles of Columvi treatment.

The baseline demographic and disease characteristics were: median age 66 years (range: 21 to90 years) with 53.7% aged 65 years or older and 15.7% aged 75 years or older; 69.4% males; 74.1%white, 5.6% Asian and 0.9% Black or African American; 5.6% Hispanic or Latino; and ECOGperformance status of 0 (46.3%) or 1 (52.8%). Most patients (71.3%) had DLBCL not otherwisespecified, 7.4% had DLBCL transformed from follicular lymphoma, 8.3% had high-grade B-celllymphoma (HGBCL) or another histology transformed from follicular lymphoma, 7.4% had HGBCL,and 5.6% had primary mediastinal large B-cell lymphoma (PMBCL). The median number of priorlines of therapy was 3 (range: 2 to 7); 39.8% of patients received 2 prior lines and 60.2% received 3 ormore prior lines of therapy. All patients had received prior chemotherapy (all patients receivedalkylator therapy and 98.1% of patients received anthracycline therapy) and all patients had receivedprior anti-CD20 monoclonal antibody therapy; 35.2% of patients had received prior CAR T-celltherapy, and 16.7% of patients had received autologous stem cell transplant. Most patients (89.8%)had refractory disease, 60.2% of patients had primary refractory disease and 83.3% of patients wererefractory to their last prior therapy.

The primary efficacy outcome measure was complete response (CR) rate as assessed by anindependent review committee (IRC) using 2014 Lugano criteria. The overall median duration offollow-up was 15 months (range: 0 to 21 months). The secondary efficacy outcome measures includedoverall response rate (ORR), duration of response (DOR), duration of complete response (DOCR), andtime to first complete response (TFCR) as assessed by IRC.

Efficacy results are summarised in Table 8.

Table 8. Summary of efficacy in patients with relapsed or refractory DLBCL

Efficacy endpoints Columvi

N=108

Complete response

Patients with CR, n (%) 38 (35.2)95% CI [26.24, 44.96]

Overall response rate

Patients with CR or PR, n (%) 54 (50.0)95% CI [40.22, 59.78]

Duration of complete response1

Median DOCR, months [95% CI] NE [18.4, NE]

Range, months 02−20212-month DOCR, % [95% CI]3 74.6 [59.19, 89.93]

Duration of response4

Median duration, months [95% CI] 14.4 [8.6, NE]

Range, months 02−202

Time to first complete response

Median TFCR, days [95% CI] 42 [41, 47]

Range, days 31-308

CI=confidence interval; NE=not estimable; PR=partial response.

Hypothesis testing was conducted on the primary endpoint of IRC-assessed CR rate.1 DOCR is defined as the date of first complete response until disease progression or death due to any cause.2 Censored observations.3 Event-free rates based on Kaplan-Meier estimates.4 DOR is defined as the date of first response (PR or CR) until disease progression or death due to any cause.

The median follow-up for DOR was 12.8 months (range: 0 to 20 months).

Columvi in combination with gemcitabine and oxaliplatin

The efficacy of Columvi in combination with gemcitabine and oxaliplatin (Columvi+GemOx) wasevaluated in study GO41944 (STARGLO), an open-label multicentre, randomised clinical trial in274 patients with relapsed or refractory DLBCL not otherwise specified (DLBCL NOS).

The study included patients with DLBCL NOS who received only one prior line of therapy who werenot candidates for autologous stem cell transplant (ASCT), or who had received ≥ 2 prior therapies.

Patients were required to have ECOG performance status ≤ 2, CrCL ≥ 30 mL/min, hepatictransaminases ≤ 2.5 × ULN, no significant cardiovascular disease (such as New York Heart

Association Class III or IV cardiac disease, myocardial infarction within the last 3 months, unstablearrhythmias, or unstable angina) and no current or prior CNS lymphoma or CNS disease, no activeautoimmune disease requiring immunosuppressive therapy, no active infections (i.e., chronic active

EBV, active hepatitis B, hepatitis C), and no history of any of the following: HIV, progressivemultifocal leukoencephalopathy, hemophagocytic lymphohistiocytosis, prior allogeneic stem celltransplant, or prior organ transplantation. Patients with HGBCL, PMBCL, or history of transformationof indolent disease to DLBCL were excluded.

Patients who received only one prior line of therapy were not considered candidates for transplant ifthey met at least one of the following criteria: age ≥ 70 years, ECOG performance status 2, leftventricular ejection fraction ≤ 40%, insufficient response to salvage therapy prior to ASCT,

CrCL ≤ 45 mL/min, other comorbidities or criteria that preclude use of transplant based on localpractice standards or in the investigator’s opinion, or patient refusal of high-dose chemotherapy and/ortransplant.

Patients were randomised 2:1 to receive Columvi+GemOx (N=183) or rituximab in combination withgemcitabine plus oxaliplatin (R-GemOx; N=91) for 8 cycles, followed by 4 additional cycles of

Columvi monotherapy for patients in the Columvi+GemOx arm. Randomisation was stratified bynumber of previous lines of systemic therapy for DLBCL (1 vs. ≥ 2) and outcome of last systemictherapy (relapsed vs. refractory).

In the Columvi+GemOx arm, patients received pre-treatment with obinutuzumab at Cycle 1 Day 1followed by 2.5 mg of Columvi at Cycle 1 Day 8, 10 mg of Columvi at Cycle 1 Day 15, and 30 mg of

Columvi at Cycle 2 Day 1 as per the step-up dosing schedule. Patients continued to receive 30 mg of

Columvi on Day 1 of Cycles 3 to 12. Gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) wereadministered intravenously on Day 2 of Cycle 1 and then on Day 1 of subsequent cycles, up to

Cycle 8. The duration of each cycle was 21 days in both arms. Patients received a median of 11 cyclesof Columvi treatment (range: 1 to 13 cycles); 64.5% received 8 or more cycles and 44.8% received12 cycles of Columvi treatment.

The baseline demographic and disease characteristics were: median age 68 years (range: 20 to88 years) with 62.8% aged 65 years or older and 23.7% aged 75 years or older; 57.7% males; 42%white, 50% Asian, and 1.1% Black or African American; 5.8% Hispanic or Latino; and ECOGperformance status of 0 (43.3%), 1 (46.6%), or 2 (10.1%). The majority of patients (62.8%) hadreceived 1 prior line of systemic therapy; 37.2% of patients received 2 or more prior lines. All patientshad received prior chemotherapy and most (98.5%) had received prior anti-CD20 monoclonalantibody therapy; 7.7% of patients had received prior CAR T-cell therapy, and 4.0% of patients hadreceived autologous stem cell transplant. The majority of patients (66.8%) had refractory disease,55.8% of patients had primary refractory disease, and 60.6% of patients were refractory to their lastprior therapy. The most common reasons why patients were not considered candidates for transplantincluded age (42.3%), patient refused high-dose chemotherapy and/or transplant (34.7%), andinsufficient response to salvage therapy (9.9%).

The primary efficacy outcome measure was overall survival (OS). At the time of the prespecifiedprimary analysis, a statistically significant improvement in OS was observed for patients randomisedto the Columvi+GemOx arm compared to patients randomised to R-GemOx (HR 0.59, 95% CI: 0.40,0.89; p-value=0.011). Median OS in the R-GemOx arm was 9.0 months (95% CI: 7.3, 14.4) and wasnot reached in the Columvi+GemOx arm (95% CI: 13.8, NE). Statistically significant improvements inprogression-free survival (PFS) and CR rate, as assessed by an IRC, were also observed with

Columvi+GemOx over R-GemOx. Median PFS was 12.1 months (95% CI: 6.8, 18.3) in the

Columvi+GemOx arm versus 3.3 months (95% CI: 2.5, 5.6) in the R-GemOx arm (HR 0.37, 95% CI:0.25, 0.55; p-value<0.001). The rate of complete response was 50.3% with Columvi+GemOx versus22.0% with R-GemOx, a difference of 28.3% (p-value<0.001).

Overall survival, PFS, and CR results from an updated analysis conducted after an additional10.5 months of follow-up continue to demonstrate benefit of Columvi+GemOx over R-GemOx. Thekey results are summarised in Table 9. Kaplan-Meier plots for OS and PFS from the updated analysisare presented in Figure 1 and Figure 2, respectively. Exploratory subgroup analysis at the time of theupdated analysis showed an OS hazard ratio of 1.09 (95% CI: 0.54, 2.18) and PFS hazard ratio of 0.84(95% CI: 0.44, 1.59) for patients enrolled in Europe.

Table 9. Efficacy in patients with relapsed or refractory DLBCL treated with Columvi incombination with gemcitabine and oxaliplatin (ITT)

Updated analysis(median observation time=20.7 months)

Efficacy endpoints

Columvi+GemOx R-GemOx

N=183 N=91

Overall survival

Number (%) of deaths 80 (43.7) 52 (57.1)

Median (95% CI), months 25.5 (18.3, NE) 12.9 (7.9, 18.5)

HR (95% CI) 0.62 (0.43, 0.88)

Progression-free survival - IRC-assessed

Number (%) of patients with events 90 (49.2) 54 (59.3)

Median (95% CI), months 13.8 (8.7, 20.5) 3.6 (2.5, 7.1)

HR (95% CI) 0.40 (0.28, 0.57)

Complete response rate - IRC-assessed

Responders (%) 107 (58.5) 23 (25.3)

Difference in response rate (95% CI), % 33.2 (20.9, 45.5)

Objective response rate - IRC-assessed

Responders (%) (CR, PR) 125 (68.3) 37 (40.7)

Difference in response rate (95% CI), % 27.7 (14.7, 40.6)

CI=confidence interval; HR=hazard ratio; NE=not estimable.

Figure 1. Kaplan-Meier plot of overall survival in study GO41944 (STARGLO, updatedanalysis; ITT)

Figure 2. Kaplan Meier plot of IRC-assessed progression-free survival in study GO41944(STARGLO, updated analysis; ITT)

Across studies, of 608 patients, only 4 patients (0.7%) were negative for anti-glofitamab antibodies atbaseline and became positive following treatment. Due to the limited number of patients withantibodies against glofitamab, no conclusions can be drawn concerning a potential effect ofimmunogenicity on efficacy or safety.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Columvi 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).

Non-compartmental analyses indicate that glofitamab serum concentration reaches the maximal level(Cmax) at the end of infusion and declines in a bi-exponential fashion. Glofitamab exhibits linear anddose-proportional pharmacokinetics over the dose range studied (0.005 to 30 mg) and is independentof time.

Columvi is administered as an intravenous infusion. Peak concentration of glofitamab (Cmax) wasreached at the end of the infusion.

Following intravenous administration, the central volume of distribution was 3.34 L, which is close tototal serum volume. The peripheral volume of distribution was 2.35 L.

The metabolism of glofitamab has not been studied. Antibodies are cleared principally by catabolism.

The glofitamab serum concentration-time data are described by a population pharmacokinetic modelwith two compartments, and both time-independent clearance and time-varying clearance.

The time-independent clearance pathway was estimated as 0.633 L/day and the initial time-varyingclearance pathway as 0.814 L/day, with an exponential decay over time (Kdes ~ 1.5/day). The estimateddecay half-life from the initial total clearance value to the time-independent clearance only wasestimated as 0.471 days.

The effective half-life in the linear phase (i.e., after the contribution of time-varying clearance hascollapsed to a negligible amount) is 7.92 days (geometric mean, 95% CI: 4.69, 11.90) based on thepopulation pharmacokinetic analysis.

No differences in glofitamab exposure were noted in patients 65 years of age and older and thoseunder 65 years based on population pharmacokinetic analysis.

The population pharmacokinetic analysis of glofitamab showed that creatinine clearance does notaffect the pharmacokinetics of glofitamab. The pharmacokinetics of glofitamab in patients with mildor moderate renal impairment (CrCL 30 to < 90 mL/min) were similar to those in patients with normalrenal function. Columvi has not been studied in patients with severe renal impairment.

Population pharmacokinetic analyses showed mild hepatic impairment does not affect thepharmacokinetics of glofitamab. The pharmacokinetics of glofitamab in patients with mild hepaticimpairment (total bilirubin > ULN to ≤ 1.5 × ULN or AST > ULN) were similar to those with normalhepatic functions. Columvi has not been studied in patients with moderate or severe hepaticimpairment.

Effects of age, gender and body weight

No clinically significant differences in the pharmacokinetics of glofitamab were observed based onage (21 years to 90 years), gender and body weight (31 kg to 148 kg).

No studies have been conducted to establish the carcinogenic potential and mutagenic potential ofglofitamab.

No fertility assessments in animals have been performed to evaluate the effect of glofitamab.

No reproductive and developmental toxicity studies in animals have been performed to evaluate theeffect of glofitamab. Based on low placental transfer of antibodies during the first trimester, themechanism of action of glofitamab (B-cell depletion, target-dependent T-cell activation, and cytokinerelease), the available safety data with glofitamab and data on other anti-CD20 antibodies, the risk forteratogenicity is low. Prolonged B-cell depletion can lead to increased risk of opportunistic infection,which may cause foetal loss. Transient CRS associated with Columvi administration may also beharmful to the foetus (see section 4.6).

In a study in cynomolgus monkeys, animals experiencing severe CRS after a single intravenous doseof glofitamab (0.1 mg/kg) without obinutuzumab pre-treatment had erosions in the gastrointestinaltract and inflammatory cell infiltrates in spleen and sinusoids of the liver and sporadically in someother organs. These inflammatory cell infiltrates were likely secondary to cytokine-induced immunecell activation. Pre-treatment with obinutuzumab resulted in the attenuation of glofitamab-inducedcytokine release and related adverse effects by depleting B cells in peripheral blood and lymphoidtissue. This allowed at least 10 times higher doses of glofitamab (1 mg/kg) in cynomolgus monkeysresulting in a Cmax of up to 3.74 times the human Cmax at the recommended 30 mg dose.

All findings with glofitamab were considered pharmacologically mediated effects and reversible.

Studies longer than 4 weeks were not performed, as glofitamab was highly immunogenic incynomolgus monkeys and led to loss of exposure and loss of the pharmacologic effect.

As all relapsed or refractory DLBCL patients to be treated have been exposed to anti-CD20 treatmentbefore, the majority will likely have low levels of circulating B cells due to residual effects of prioranti-CD20 therapy, before treatment with obinutuzumab. Therefore, the animal model without priorrituximab (or other anti-CD20) treatment may not fully reflect the clinical context.

L-histidine

L-histidine hydrochloride monohydrate

L-methionine

Sucrose

Polysorbate 20 (E432)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial30 months.

Diluted solution for intravenous infusion

Chemical and physical in-use stability have been demonstrated for a maximum of 72 hours at 2 °C to8 °C and 24 hours at 30 °C followed by a maximum infusion time of 8 hours.

From a microbiological point of view, the diluted solution should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 °C to 8 °C, unless dilution has taken place incontrolled and validated aseptic 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.

Columvi 2.5 mg concentrate for solution for infusion2.5 mL concentrate for solution for infusion in a 6 mL vial (colourless Type I glass) with stopper(butyl rubber).

Pack size of 1 vial.

Columvi 10 mg concentrate for solution for infusion10 mL concentrate for solution for infusion in a 15 mL vial (colourless Type I glass) with stopper(butyl rubber).

Pack size of 1 vial.

Columvi diluted solution can be administered via intravenous bag infusion or intravenous syringeinfusion.

* Columvi contains no preservative and is intended for single use only.

* Columvi must be diluted by a healthcare professional using aseptic technique, prior tointravenous administration.

* Visually inspect the Columvi vial for particulate matter or discolouration prior toadministration. Columvi is a colourless, clear solution. Discard the vial if the solution is cloudy,discoloured or contains visible particles.

* Withdraw the appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection orsodium chloride 4.5 mg/mL (0.45%) solution for injection, as described in Table 10, from theinfusion bag using a sterile needle and syringe and discard.

* Withdraw the required volume of Columvi concentrate for the intended dose from the vial usinga sterile needle and syringe and dilute into the infusion bag (see Table 10). Discard any unusedportion left in the vial.

* The final glofitamab concentration after dilution must be 0.1 mg/mL to 0.6 mg/mL.

* Gently invert the infusion bag to mix the solution in order to avoid excessive foaming. Do notshake.

* Inspect the infusion bag for particulates and discard if present.

* Prior to the start of the intravenous infusion, the content of the infusion bag should be at roomtemperature (25 °C).

* When administering Columvi using syringe infusion, withdraw the entire content of the infusionbag into a syringe. Alternatively, a two-syringe method using a connector can be used to preparethe dose for the syringe pump infusion.

Table 10. Dilution of Columvi for infusion

Volume of sodiumchloride 9 mg/mL (0.9%)

Dose of Columvi to Size of infusion or 4.5 mg/mL (0.45%) Volume of Columvibe administered bag solution for injection to concentrate to bebe withdrawn and addeddiscarded2.5 mg 50 mL 27.5 mL 2.5 mL100 mL 77.5 mL 2.5 mL10 mg 50 mL 10 mL 10 mL100 mL 10 mL 10 mL30 mg 50 mL 30 mL 30 mL100 mL 30 mL 30 mL

Only administer as an intravenous infusion.

Do not administer as an intravenous push or bolus.

Administer as an intravenous infusion through a dedicated infusion line via intravenous bag infusionor intravenous syringe infusion, both using a pump, over a maximum of 8 hours.

The Columvi infusion bag or syringe may empty before the recommended duration of infusion isreached. To ensure the entire dose of Columvi is administered, clear the infusion line by replacing theemptied Columvi infusion bag or syringe with an infusion bag or syringe containing sodium chloride9 mg/mL (0.9%) solution for injection or sodium chloride 4.5 mg/mL (0.45%) solution for injectionconnected to the same infusion line. Continue the infusion at the same rate until the recommendedinfusion duration is reached according to Table 2.

Incompatibilities

Only sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for injection should be used todilute Columvi, since other solvents have not been tested.

When diluted with sodium chloride 9 mg/mL (0.9%) solution for injection, Columvi is compatiblewith intravenous infusion bags composed of polyvinyl chloride (PVC), polyethylene (PE),polypropylene (PP) or non-PVC polyolefin. When diluted with sodium chloride 4.5 mg/mL (0.45%)solution for injection, Columvi is compatible with intravenous infusion bags composed of PVC.

When diluted with sodium chloride 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) solution for injection,

Columvi is compatible with syringes composed of PP.

No incompatibilities have been observed with infusion sets with product-contacting surfaces ofpolyurethane (PUR), PVC, PE, polybutadiene (PBD), polyetherurethane (PEU), polycarbonate (PC),silicone, polytetrafluoroethylene (PTFE) or acrylonitrile butadiene styrene (ABS), and in-line filtermembranes composed of polyethersulfone (PES) or polysulfone. The use of in-line filter membranes isoptional.

Columvi vial is for single use only.

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/1/23/1742/001

EU/1/23/1742/002

Date of first authorisation: 7 July 2023

Date of latest renewal: 27 May 2024

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

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