ADCETRIS 50mg powder for concentrate infusion solution medication leaflet

ADCETRIS 50 mg powder for concentrate for solution for infusion.

Each vial contains 50 mg of brentuximab vedotin.

After reconstitution (see section 6.6), each mL contains 5 mg of brentuximab vedotin.

ADCETRIS is an antibody-drug conjugate composed of a CD30-directed monoclonal antibody(recombinant chimeric immunoglobulin G1 [IgG1], produced by recombinant DNA technology in

Chinese Hamster ovary cells) that is covalently linked to the antimicrotubule agent monomethylauristatin E (MMAE).

Each vial contains approximately 13.2 mg of sodium.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

White to off-white cake or powder.

ADCETRIS is indicated for adult patients with previously untreated CD30+ Stage III or IV Hodgkinlymphoma (HL) in combination with doxorubicin, vinblastine and dacarbazine (AVD) (seesections 4.2 and 5.1).

ADCETRIS is indicated for the treatment of adult patients with CD30+ HL at increased risk of relapseor progression following autologous stem cell transplant (ASCT) (see section 5.1).

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory CD30+ Hodgkinlymphoma (HL):

1. following ASCT, or2. following at least two prior therapies when ASCT or multi-agent chemotherapy is not atreatment option.

ADCETRIS in combination with cyclophosphamide, doxorubicin and prednisone (CHP) is indicatedfor adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) (seesection 5.1).

ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory sALCL.

ADCETRIS is indicated for the treatment of adult patients with CD30+ cutaneous T-cell lymphoma(CTCL) after at least 1 prior systemic therapy (see section 5.1).

ADCETRIS should be administered under the supervision of a physician experienced in the use ofanti-cancer agents.

The recommended dose in combination with chemotherapy (doxorubicin [A], vinblastine [V] anddacarbazine [D] [AVD]) is 1.2 mg/kg administered as an intravenous infusion over 30 minutes ondays 1 and 15 of each 28-day cycle for 6 cycles (see section 5.1).

Primary prophylaxis with growth factor support (G-CSF), beginning with the first dose, isrecommended for all adult patients with previously untreated HL receiving combination therapy (seesection 4.4).

Refer to the summary of product characteristics (SmPC) of chemotherapy agents given in combinationwith ADCETRIS for patients with previously untreated HL.

The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every3 weeks.

ADCETRIS treatment should start following recovery from ASCT based on clinical judgment. Thesepatients should receive up to 16 cycles (see section 5.1).

The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every3 weeks.

The recommended starting dose for the retreatment of patients who have previously responded totreatment with ADCETRIS is 1.8 mg/kg administered as an intravenous infusion over 30 minutesevery 3 weeks. Alternatively, treatment may be started at the last tolerated dose (see section 5.1).

Treatment should be continued until disease progression or unacceptable toxicity (see section 4.4).

Patients who achieve stable disease or better should receive a minimum of 8 cycles and up to amaximum of 16 cycles (approximately 1 year) (see section 5.1).

The recommended dose in combination with chemotherapy (cyclophosphamide [C], doxorubicin [H]and prednisone [P] [CHP]) is 1.8 mg/kg administered as an intravenous infusion over 30 minutesevery 3 weeks for 6 to 8 cycles (see section 5.1).

Primary prophylaxis with G-CSF, beginning with the first dose, is recommended for all adult patientswith previously untreated sALCL receiving combination therapy (see section 4.4).

Refer to the SmPCs of chemotherapy agents given in combination with ADCETRIS for patients withpreviously untreated sALCL.

The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every3 weeks.

The recommended starting dose for the retreatment of patients who have previously responded totreatment with ADCETRIS is 1.8 mg/kg administered as an intravenous infusion over 30 minutesevery 3 weeks. Alternatively, treatment may be started at the last tolerated dose (see section 5.1).

Treatment should be continued until disease progression or unacceptable toxicity (see section 4.4).

Patients who achieve stable disease or better should receive a minimum of 8 cycles and up to amaximum of 16 cycles (approximately 1 year) (see section 5.1).

The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every3 weeks.

Patients with CTCL should receive up to 16 cycles (see section 5.1).

If the patient’s weight is more than 100 kg, the dose calculation should use 100 kg (see section 6.6).

Complete blood counts should be monitored prior to administration of each dose of this treatment (seesection 4.4).

Patients should be monitored during and after infusion (see section 4.4).

If neutropenia develops during treatment it should be managed by dose delays. See Table 1 and

Table 2 for appropriate dosing recommendations for monotherapy and combination therapy,respectively (see also section 4.4).

Table 1: Dosing recommendations for neutropenia with monotherapy

Severity grade of neutropenia Modification of dosing schedule(signs and symptoms [abbreviateddescription of CTCAEa])

Grade 1 (< LLN-1500/mm3 Continue with the same dose and schedule.< LLN-1.5 x 109/L) or

Grade 2 (< 1500-1000/mm3< 1.5-1.0 x 109/L)

Grade 3 (< 1,000-500/mm3 Withhold dose until toxicity returns to ≤ Grade 2 or baseline< 1.0-0.5 x 109/L) or then resume treatment at the same dose and scheduleb.

Grade 4 (< 500/mm3 Consider G-CSF or GM-CSF in subsequent cycles for< 0.5 x 109/L) patients who develop Grade 3 or Grade 4 neutropenia.

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0;see Neutrophils/granulocytes; LLN = lower limit of normal.

b. Patients who develop Grade 3 or Grade 4 lymphopenia may continue treatment without interruption.

Table 2: Dosing recommendations for neutropenia during combination therapy

Severity grade of neutropenia Modification of dosing schedule(signs and symptoms[abbreviated description of

CTCAEa])

Grade 1 (< LLN-1500/mm3 Primary prophylaxis with G-CSF, beginning with the first< LLN-1.5 x 109/L) or dose, is recommended for all adult patients receiving

Grade 2 (< 1500-1000/mm3 combination therapy. Continue with the same dose and< 1.5-1.0 x 109/L) schedule.

Grade 3 (< 1,000-500/mm3< 1.0-0.5 x 109/L) or

Grade 4 (< 500/mm3< 0.5 x 109/L)

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03;see Neutrophils/granulocytes; LLN = lower limit of normal.

If peripheral sensory or motor neuropathy emerges or worsens during treatment see Table 3 and 4 forappropriate dosing recommendations for monotherapy and combination therapy, respectively (seesection 4.4).

Table 3: Dosing recommendations for new or worsening peripheral sensory or motorneuropathy with monotherapy

Severity of peripheral sensory or Modification of dose and schedulemotor neuropathy(signs and symptoms [abbreviateddescription of CTCAEa])

Grade 1 (paraesthesia and/or loss of Continue with the same dose and schedule.reflexes, with no loss offunction)

Grade 2 (interfering with function but Withhold dose until toxicity returns to ≤ Grade 1 ornot with activities of daily baseline, then restart treatment at a reduced dose ofliving) 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Grade 3 (interfering with activities of Withhold dose until toxicity returns to ≤ Grade 1 ordaily living) baseline, then restart treatment at a reduced dose of1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Grade 4 (sensory neuropathy that is Discontinue treatment.disabling or motor neuropathythat is life threatening or leadsto paralysis)

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0;see neuropathy: motor; neuropathy: sensory; and neuropathic pain.

Table 4: Dosing recommendations for new or worsening peripheral sensory or motorneuropathy during combination therapy

Combination therapy Combination therapywith AVD with CHP

Severity of peripheral sensory or motor Modification of dose and Modification of dose andneuropathy schedule schedule(signs and symptoms [abbreviateddescription of CTCAEa])

Grade 1 (paraesthesia and/or loss of Continue with the same Continue with the samereflexes, with no loss of function) dose and schedule. dose and schedule.

Grade 2 (interfering with function but not Reduce dose to 0.9 mg/kg Sensory neuropathy:with activities of daily living) up to a maximum of Continue treatment at same90 mg every 2 weeks. dose level.

Motor neuropathy:

Reduce dose to 1.2 mg/kg,up to a maximum of120 mg every 3 weeks.

Grade 3 (interfering with activities of daily Withhold treatment with Sensory neuropathy:living) ADCETRIS until toxicity Reduce dose to 1.2 mg/kgis ≤ Grade 2, then restart up to a maximum oftreatment at a reduced 120 mg every 3 weeks.dose to 0.9 mg/kg up to a Motor neuropathy:maximum of 90 mg every Discontinue treatment.2 weeks.

Grade 4 (sensory neuropathy which is Discontinue treatment. Discontinue treatment.disabling or motor neuropathy thatis life-threatening or leads toparalysis)

a. Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03;see neuropathy: motor; neuropathy: sensory; and neuropathic pain.

Patients with renal impairment should be closely monitored for adverse events. There is no clinicaltrial experience using ADCETRIS in combination with chemotherapy in patients with renalimpairment, where serum creatinine is ≥ 2.0 mg/dL and/or creatinine clearance or calculated creatinineclearance is ≤ 40 mL/minute. Use of ADCETRIS in combination with chemotherapy should beavoided in patients with severe renal impairment.

Patients with hepatic impairment should be closely monitored for adverse events. The recommendedstarting dose in patients with mild hepatic impairment receiving ADCETRIS in combination with

AVD is 0.9 mg/kg administered as an intravenous infusion over 30 minutes every 2 weeks. Therecommended starting dose in patients with mild hepatic impairment receiving ADCETRIS incombination with CHP is 1.2 mg/kg administered as an intravenous infusion over 30 minutes every3 weeks. There is no clinical trial experience using ADCETRIS in combination with chemotherapy inpatients with hepatic impairment, where total bilirubin is > 1.5 times the upper limit of normal (ULN)(unless due to Gilbert syndrome), or aspartate aminotransferase (AST) or alanine aminotransferase(ALT) are > 3 times the ULN, or > 5 times the ULN if their elevation may be reasonably ascribed tothe presence of HL in the liver. Use of ADCETRIS in combination with chemotherapy should beavoided in patients with moderate and severe hepatic impairment.

The recommended starting dose in patients with severe renal impairment is 1.2 mg/kg administered asan intravenous infusion over 30 minutes every 3 weeks. Patients with renal impairment should beclosely monitored for adverse events (see section 5.2).

The recommended starting dose in patients with hepatic impairment is 1.2 mg/kg administered as anintravenous infusion over 30 minutes every 3 weeks. Patients with hepatic impairment should beclosely monitored for adverse events (see section 5.2).

The dosing recommendations for patients aged 65 and older are the same as for adults. Currentlyavailable data are described in sections 4.8, 5.1 and 5.2.

The safety and efficacy of ADCETRIS in children less than 18 years have not been established.

Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on aposology can be made.

The recommended dose of ADCETRIS is infused over 30 minutes.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

ADCETRIS must not be administered as an intravenous push or bolus. ADCETRIS should beadministered through a dedicated intravenous line and it must not be mixed with other medicinalproducts (see section 6.2).

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

Combined use of bleomycin and ADCETRIS causes pulmonary toxicity (see section 4.5).

John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy(PML) and death can occur in ADCETRIS-treated patients. PML has been reported in patients whoreceived this treatment after receiving multiple prior chemotherapy regimens. PML is a raredemyelinating disease of the central nervous system that results from reactivation of latent JCV and isoften fatal.

Patients should be closely monitored for new or worsening neurological, cognitive, or behaviouralsigns or symptoms, which may be suggestive of PML. ADCETRIS should be held for any suspectedcase of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhancedmagnetic resonance imaging of the brain and cerebrospinal fluid analysis for JCV DNA by polymerasechain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML.

Additional follow up and evaluation may be warranted if no alternative diagnosis can be established.

ADCETRIS dosing should be permanently discontinued if a diagnosis of PML is confirmed.

The physician should be particularly alert to symptoms suggestive of PML that the patient may notnotice (e.g., cognitive, neurological, or psychiatric symptoms).

Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have beenreported.

Patients should be closely monitored for new or worsening abdominal pain, which may be suggestiveof acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation forserum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriatediagnostic measures. ADCETRIS should be held for any suspected case of acute pancreatitis.

ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Cases of pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratorydistress syndrome (ARDS), some with fatal outcomes, have been reported in patients receiving

ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk ofpulmonary toxicity cannot be ruled out. In the event of new or worsening pulmonary symptoms (e.g.cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients should be treatedappropriately. Consider holding ADCETRIS dosing during evaluation and until symptomaticimprovement.

Serious infections such as pneumonia, staphylococcal bacteraemia, sepsis/septic shock (including fataloutcomes) and herpes zoster, cytomegalovirus (CMV) (reactivation) and opportunistic infections suchas Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with

ADCETRIS. Patients should be carefully monitored during treatment for the emergence of possibleserious and opportunistic infections.

Immediate and delayed infusion-related reactions (IRR), as well as anaphylactic reactions, have beenreported.

Patients should be carefully monitored during and after infusion. If an anaphylactic reaction occurs,administration of ADCETRIS should be immediately and permanently discontinued and appropriatemedical therapy should be administered.

If an IRR occurs, the infusion should be interrupted and appropriate medical management instituted.

The infusion may be restarted at a slower rate after symptom resolution. Patients who haveexperienced a prior IRR should be premedicated for subsequent infusions. Premedication may includeparacetamol, an antihistamine and a corticosteroid.

IRRs are more frequent and more severe in patients with antibodies to brentuximab vedotin (seesection 4.8).

Tumour lysis syndrome (TLS) has been reported with ADCETRIS. Patients with rapidly proliferatingtumour and high tumour burden are at risk of tumour lysis syndrome. These patients should bemonitored closely and managed according to best medical practice. Management of TLS may includeaggressive hydration, monitoring of renal function, correction of electrolyte abnormalities,anti-hyperuricaemic therapy, and supportive care.

ADCETRIS may cause peripheral neuropathy, both sensory and motor. ADCETRIS-inducedperipheral neuropathy is typically an effect of cumulative exposure to this medicinal product and isreversible in most cases. In clinical trials, the majority of patients had resolution or improvement oftheir symptoms (see section 4.8). Patients should be monitored for symptoms of neuropathy, such ashypoesthesia, hyperesthesia, paraesthesia, discomfort, a burning sensation, neuropathic pain orweakness. Patients experiencing new or worsening peripheral neuropathy may require a delay and adose reduction of ADCETRIS or discontinuation of treatment (see section 4.2).

Grade 3 or Grade 4 anaemia, thrombocytopenia, and prolonged (≥ 1 week) Grade 3 or Grade 4neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior toadministration of each dose. If Grade 3 or Grade 4 neutropenia develops, refer to section 4.2.

Febrile neutropenia (fever of unknown origin without clinically or microbiologically documentedinfection with an absolute neutrophil count < 1.0 x 109/L, fever ≥ 38.5 0C; ref CTCAE v3) has beenreported with treatment with ADCETRIS. Complete blood counts should be monitored prior toadministration of each dose of treatment. Patients should be monitored closely for fever and managedaccording to best medical practice if febrile neutropenia develops.

In combination therapy with AVD or CHP, advanced age was a risk factor for febrile neutropenia.

When ADCETRIS is administered in combination with AVD or CHP, primary prophylaxis with

G-CSF, beginning with the first dose, is recommended for all adult patients regardless of age.

Cases of SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) anddrug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with

ADCETRIS. Fatal outcomes have been reported for SJS and TEN. If SJS, TEN or DRESS occur,

ADCETRIS should be discontinued and appropriate medical therapy should be administered.

Gastrointestinal (GI) complications including intestinal obstruction, ileus, enterocolitis, neutropeniccolitis, erosion, ulcer, perforation and haemorrhage, some with fatal outcomes, have been reported inpatients treated with ADCETRIS. In the event of new or worsening GI symptoms, perform a promptdiagnostic evaluation and treat appropriately.

Hepatotoxicity in the form of elevations in alanine aminotransferase (ALT) and aspartateaminotransferase (AST) has been reported with ADCETRIS. Serious cases of hepatotoxicity,including fatal outcomes, have also occurred. Pre-existing liver disease, comorbidities, andconcomitant medications may also increase the risk. Liver function should be tested before initiatingthe treatment and routinely monitored in patients receiving ADCETRIS. Patients experiencinghepatotoxicity may require a delay, change in dose or discontinuation of ADCETRIS.

Hyperglycaemia has been reported during clinical trials in patients with an elevated Body Mass Index(BMI) with or without a history of diabetes mellitus. However, any patient who experiences an eventof hyperglycaemia should have their serum glucose closely monitored. Anti-diabetic treatment shouldbe administered as appropriate.

Extravasation during intravenous infusion has occurred. Given the possibility of extravasation, it isrecommended to closely monitor the infusion site for possible infiltration during drug administration.

There is limited experience in patients with renal and hepatic impairment. Available data indicate that

MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by lowserum albumin concentrations (see section 5.2).

The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) andprimary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high levelevidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in thesubtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. Thesedata suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes.

Nevertheless, ADCETRIS should be used with caution in other CD30+ CTCL patients after carefulconsideration of the potential benefit-risk on an individual basis (see section 5.1).

This medicinal product contains 13.2 mg sodium per vial, equivalent to 0.7% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

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

Interaction with medicinal products metabolised through CYP3A4 route (CYP3A4inhibitors/inducers)

Co-administration of brentuximab vedotin with ketoconazole, a strong CYP3A4 and P-gp inhibitor,increased the exposure to the antimicrotubule agent MMAE by approximately 73%, and did not alterthe plasma exposure to brentuximab vedotin. Therefore, co-administration of brentuximab vedotinwith strong CYP3A4 and P-gp inhibitors may increase the incidence of neutropenia. If neutropeniadevelops, refer to Tables 1 and 2 for dosing recommendations for neutropenia (see section 4.2).

Co-administration of brentuximab vedotin with rifampicin, a strong CYP3A4 inducer, did not alter theplasma exposure to brentuximab vedotin. Though PK data are limited, co-administration of rifampicinappeared to reduce plasma concentrations of MMAE metabolites that could be assayed.

Co-administration of midazolam, a CYP3A4 substrate, with brentuximab vedotin did not alter themetabolism of midazolam; therefore brentuximab vedotin is not expected to alter the exposure tomedicines that are metabolised by CYP3A4 enzymes.

The serum and plasma pharmacokinetic characteristics of antibody drug conjugate (ADC) and MMAErespectively following administration of brentuximab vedotin in combination with AVD were similarto that in monotherapy.

Co-administration of brentuximab vedotin did not affect the plasma exposure of AVD.

The serum and plasma pharmacokinetic characteristics of ADC and MMAE, respectively, followingadministration of brentuximab vedotin in combination with CHP were similar to that in monotherapy.

Co-administration of brentuximab vedotin is not expected to affect the exposure of CHP.

There were no formal drug-drug interaction studies with brentuximab vedotin and bleomycin (B). In aphase 1 dose finding and safety study (SGN35-009), unacceptable pulmonary toxicity (including2 fatal events) was noted in 11 of 25 patients (44%) treated with brentuximab vedotin plus ABVD. Nopulmonary toxicity or fatal events were reported with brentuximab vedotin + AVD. Therefore,co-administration of ADCETRIS with bleomycin is contraindicated (see section 4.3).

Women of childbearing potential should be using two methods of effective contraception duringtreatment with ADCETRIS and until 6 months after treatment.

There are no data from the use of ADCETRIS in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

ADCETRIS should not be used during pregnancy unless the benefit to the mother outweighs thepotential risks to the foetus. If a pregnant woman needs to be treated she should be clearly advised onthe potential risk to the foetus.

See the fertility section below pertaining to advice for women whose male partners are being treatedwith ADCETRIS.

There are no data as to whether brentuximab vedotin or its metabolites are excreted in human milk.

A risk to the newborn/infant cannot be excluded.

A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from thistherapy, taking into account a potential risk of breast-feeding for the child and the benefit of therapyfor the woman.

In non-clinical studies, brentuximab vedotin treatment has resulted in testicular toxicity, and may altermale fertility. MMAE has been shown to have aneugenic properties (see section 5.3). Therefore, menbeing treated with this medicine are advised to have sperm samples frozen and stored before treatment.

Men being treated with this medicine are advised not to father a child during treatment and for up to6 months following the last dose.

ADCETRIS may have a moderate influence on the ability to drive and use machines (e.g. dizziness),see section 4.8.

The safety profile of ADCETRIS is based on available clinical trial data, the Named Patient Program(NPP), and post-marketing experience to date. Frequencies of adverse reactions described below andin Table 5 have been determined based on data generated from clinical studies.

In the pooled dataset of ADCETRIS as monotherapy across HL, sALCL and CTCL studies(SG035-0003, SG035-0004, SGN35-005, SGN35-006, C25001, C25006 and C25007, see section 5.1)the most frequent adverse reactions (≥ 10%) were infections, peripheral sensory neuropathy, nausea,fatigue, diarrhoea, pyrexia, neutropenia, upper respiratory tract infection, arthralgia, rash, cough,vomiting, pruritus, peripheral motor neuropathy, infusion-related reactions, constipation, dyspnoea,myalgia, weight decreased, and abdominal pain.

Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adversedrug reactions was ≤ 1%.

Adverse events led to treatment discontinuation in 24% of patients receiving ADCETRIS.

The safety data in patients retreated with ADCETRIS (SGN35-006, see section 5.1) were consistentwith those observed in the combined pivotal phase 2 studies, with the exception of peripheral motorneuropathy, which had a higher incidence (28% vs. 9% in the pivotal phase 2 studies) and wasprimarily Grade 2. Patients also had a higher incidence of arthralgia, Grade 3 anaemia, and back paincompared to patients observed in the combined pivotal phase 2 studies.

The safety data in patients with relapsed or refractory HL who had not received an autologous stemcell transplant and were treated with the recommended dose of 1.8 mg/kg every three weeks in asingle-arm phase 4 study (n = 60), the phase 1 dose escalation and clinical pharmacology studies(n = 15 patients) and in the NPP (n = 26 patients) (see section 5.1) were consistent with the safetyprofile of the pivotal clinical studies.

For safety information of chemotherapy agents given in combination with ADCETRIS (doxorubicin,vinblastine and dacarbazine (AVD) or cyclophosphamide, doxorubicin and prednisone (CHP)), referto their summary of product characteristics.

In the studies of ADCETRIS as combination therapy in 662 patients with previously untreatedadvanced HL (C25003) and 223 patients with previously untreated CD30+ peripheral T-celllymphoma (PTCL) (SGN35-014), the most common adverse reactions (≥ 10%) were: infections,neutropenia, peripheral sensory neuropathy, nausea, constipation, vomiting, diarrhoea, fatigue,pyrexia, alopecia, anaemia, weight decreased, stomatitis, febrile neutropenia, abdominal pain,decreased appetite, insomnia, bone pain, rash, cough, dyspnoea, arthralgia, myalgia, back pain,peripheral motor neuropathy, upper respiratory tract infection, and dizziness.

In patients receiving ADCETRIS combination therapy, serious adverse reactions occurred in 34% ofpatients. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (15%),pyrexia (5%), and neutropenia (3%).

Adverse events led to treatment discontinuation in 10% of patients. Adverse events that led totreatment discontinuation in ≥ 2% of patients included peripheral sensory neuropathy, and peripheralneuropathy.

Adverse reactions for ADCETRIS are listed by MedDRA System Organ Class and Preferred Term(see Table 5). Within each System Organ Class, adverse reactions are listed under frequencycategories of: 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); not known (cannot be estimatedfrom the available data). Within each frequency grouping, adverse reactions are presented in the orderof decreasing seriousness.

Table 5: Adverse reactions to ADCETRIS

System organ class Adverse reactions (monotherapy) Adverse reactions(combination therapy)

Very common: Infectiona, upper respiratory tract infection Infectiona, upper respiratory tractinfection

Common: Herpes zoster, pneumonia, herpes simplex, Pneumonia, oral candidiasis,oral candidiasis sepsis/septic shock, herpes zoster

Uncommon: Pneumocystis jiroveci pneumonia, Herpes simplex, Pneumocystisstaphylococcal bacteraemia, cytomegalovirus jiroveci pneumoniainfection or reactivation, sepsis/septic shock

Frequency not known: Progressive multifocal leukoencephalopathy

Very common: Neutropenia Neutropeniaa, anaemia, febrileneutropenia

Common: Anaemia, thrombocytopenia Thrombocytopenia

Uncommon: Febrile neutropenia

Uncommon: Anaphylactic reaction Anaphylactic reaction

Very common: Decreased appetite

Common: Hyperglycaemia Hyperglycaemia

Uncommon: Tumour lysis syndrome Tumour lysis syndrome

Very common: Insomnia

Very common: Peripheral sensory neuropathy, peripheral Peripheral sensory neuropathya,motor neuropathy peripheral motor neuropathya,dizziness

Common: Dizziness

Uncommon: Demyelinating polyneuropathy

Very common: Cough, dyspnoea Cough, dyspnoea

Very common: Nausea, diarrhoea, vomiting, constipation, Nausea, constipation, vomiting,abdominal pain diarrhoea, abdominal pain,stomatitis

Uncommon: Pancreatitis acute Pancreatitis acute

System organ class Adverse reactions (monotherapy) Adverse reactions(combination therapy)

Common: Alanine aminotransferase/aspartate Alanine aminotransferase/aspartateaminotransferase (ALT/AST) increased aminotransferase (ALT/AST)increased

Very common: Rasha, pruritus Alopecia, rasha

Common: Alopecia Pruritus

Uncommon: Stevens-Johnson syndrome/toxic epidermal Stevens-Johnson syndromebnecrolysis

Not known: Drug reaction with eosinophilia and systemicsymptoms (DRESS)

Very common: Arthralgia, myalgia Bone pain, arthralgia, myalgia,back pain

Common: Back pain

Very common: Fatigue, pyrexia, infusion-related reactionsa Fatigue, pyrexia

Common: Chills Infusion-related reactionsa, chills

Not known: Infusion site extravasationc

Very common: Weight decreased Weight decreased

a. Represents pooling of preferred terms.

b. Toxic epidermal necrolysis was not reported in the combination therapy setting.

c. Extravasation may result in related reactions include skin redness, pain, swelling, blistering, exfoliation, or cellulitis ator surrounding the infusion site.

In clinical trials, neutropenia led to dose delays in 13% of patients. Grade 3 neutropenia was reportedin 13% and Grade 4 neutropenia was reported in 5% of patients. One patient required dose reductionand 1 patient discontinued treatment for neutropenia.

Severe and prolonged (≥ 1 week) neutropenia can occur with this treatment which may increase therisk of patients developing serious infections. Febrile neutropenia reported in < 1% of the patients (seesection 4.2).

In the pivotal phase 2 population (SG035-0003 and SG035-0004), the median duration of Grade 3 or

Grade 4 neutropenia was limited (1 week); 2% of patients had Grade 4 neutropenia that lasted≥ 7 days. Less than half of the patients in the pivotal phase 2 population with Grade 3 or Grade 4neutropenia had temporally associated infections, and the majority of temporally associated infectionswere Grade 1 or Grade 2.

In the clinical trials of ADCETRIS as combination therapy, neutropenia led to dose delays in 19% ofpatients. Grade 3 neutropenia was reported in 17% and Grade 4 neutropenia was reported in 41% ofpatients. Two percent of patients required dose reduction and < 1% discontinued one of more of thestudy drugs due to neutropenia.

Febrile neutropenia was reported in 20% of the patients who did not receive primary prophylaxis with

G-CSF (see section 4.2). The frequency of febrile neutropenia was 13% in patients who receivedprimary prophylaxis with G-CSF.

In clinical trials, serious infections and opportunistic infections occurred in 10% of patients, sepsis orseptic shock occurred in < 1% of the patients. The most commonly reported opportunistic infectionswere herpes zoster and herpes simplex.

In the clinical trials of ADCETRIS as combination therapy, serious infections including opportunisticinfections occurred in 15% of patients; sepsis, neutropenic sepsis, septic shock or bacteraemiaoccurred in 4% of the patients. The most commonly reported opportunistic infections were herpesviral infections.

In clinical trials treatment emergent neuropathy occurred in 57% of the population, peripheral motorneuropathy occurred in 13% of patients. Peripheral neuropathy led to treatment discontinuation in15%, dose reductions in 15%, and dose delays in 16% of patients. For patients who experiencedperipheral neuropathy the median time of onset of peripheral neuropathy was 12 weeks. The medianduration of treatment for patients who discontinued due to peripheral neuropathy was 11 cycles.

Among patients who experienced peripheral neuropathy in the pivotal phase 2 studies (SG035-0003and SG035-0004) and randomised phase 3 monotherapy studies (SGN35-005 and C25001), themedian follow up time from end of treatment until last evaluation ranged from 48.9 to 98 weeks. Atthe time of last evaluation, most of the patients (82-85%) who experienced peripheral neuropathy hadresolution or improvement of their peripheral neuropathy symptoms. The median time from onset toresolution or improvement for all events ranged from 16 to 23.4 weeks.

In patients with relapsed or refractory HL or sALCL who were retreated with ADCETRIS(SGN35-006), the majority of patients (80%) also had improvement or resolution of their peripheralneuropathy symptoms at the time of last evaluation.

In the clinical trial of ADCETRIS as combination therapy with AVD, treatment emergent neuropathyoccurred in 67% of the population; peripheral motor neuropathy occurred in 11% of patients.

Peripheral neuropathy led to treatment discontinuation in 7%, dose reductions in 21%, and dose delaysin 1% of patients. For patients who experienced peripheral neuropathy the median time of onset ofperipheral neuropathy was 8 weeks. Patients who discontinued due to peripheral neuropathy received amedian of 8 doses of ADCETRIS+AVD (A+AVD) before discontinuation of one or more agents.

Among patients who experienced peripheral neuropathy, the median follow up time from end oftreatment until last evaluation was approximately 286 weeks. At the time of last evaluation, most ofthe patients (86%) who experienced peripheral neuropathy had resolution or improvement of theirperipheral neuropathy symptoms. The median time from onset to resolution or improvement ofperipheral neuropathy events was 17 weeks (ranged from 0 weeks to 283 weeks).

In the clinical trial of ADCETRIS as combination therapy with CHP, treatment emergent neuropathyoccurred in 52% of the population; peripheral motor neuropathy occurred in 9% of patients. Peripheralneuropathy led to treatment discontinuation in 1%, dose reductions in 7% and dose delays in < 1% ofpatients. For patients who experienced peripheral neuropathy the median time of onset was 9.1 weeks.

Patients who discontinued due to peripheral neuropathy received a median of 5 doses of

ADCETRIS + CHP (A+CHP) before discontinuation of one or more agents.

Among patients who experienced peripheral neuropathy, the median follow up time from end oftreatment until last evaluation was approximately 177 weeks. At the time of last evaluation, 64% whoexperienced peripheral neuropathy had resolution or improvement of their peripheral neuropathysymptoms. The median time from onset to resolution or improvement of peripheral neuropathy eventswas 19.0 weeks (ranged from 0 weeks to 205 weeks).

IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus and cough werereported in 12% of patients. Anaphylactic reactions have been reported (see section 4.4). Symptoms ofan anaphylactic reaction may include, but are not limited to, urticaria, angioedema, hypotension andbronchospasm.

IRRs, such as headache, rash, back pain, vomiting, chills, nausea, dyspnoea, pruritus, cough, infusionsite pain and pyrexia were reported in 8% of patients. Anaphylactic reactions have been reported (seesection 4.4). Symptoms of an anaphylactic reaction may include, but are not limited to, urticaria,angioedema, hypotension and bronchospasm.

In clinical trials, patients were periodically tested for antibodies to brentuximab vedotin using asensitive electrochemiluminescent immunoassay. There was a higher incidence of infusion-relatedreactions observed in patients with antibodies to brentuximab vedotin relative to patients who testedtransiently positive or negative.

The presence of antibodies to brentuximab vedotin did not correlate with a clinically meaningfulreduction in serum brentuximab vedotin levels and did not result in a decrease in the efficacy ofbrentuximab vedotin. While the presence of antibodies to brentuximab vedotin does not necessarilypredict the development of an IRR, there was a higher incidence of IRRs observed in patients withpersistently positive anti-drug antibodies (ADA) relative to patients with transiently positive ADA andnever positive ADA.

There was a trend of increased clearance of brentuximab vedotin in paediatric patients confirmedpositive for ADAs. No patients aged < 12 years (0 of 11) and 2 patients aged ≥ 12 years (2 of 23)became persistently ADA positive.

The rate of ADA positivity was low in Study C25004; 4 patients (aged ≥ 12 years) of 59 patientsbecame transiently ADA positive, and no patients became persistently ADA positive. Due to the smallnumber of transiently ADA positive patients, the impact of ADA on efficacy is inconclusive.

Safety was evaluated in a phase 1/2 study in paediatric patients aged 7-17 years of age (n = 36) withrelapsed or refractory (r/r) HL and sALCL (see section 5.1). In this study in 36 patients, no new safetyconcerns were reported.

Safety was evaluated in an open-label, multicenter trial in 59 paediatric patients aged 6-17 years of agewith previously untreated advanced-stage classical CD30+ HL in combination with chemotherapy (seesection 5.1). In this study, no new safety concerns were reported. The most common serious adversereaction reported in this study was febrile neutropenia (17%). G-CSF prophylaxis was considered atthe physician’s discretion. Peripheral neuropathy events (per Standardized MedDRA Query) werereported in 24% of paediatric patients in this study.

The safety profile in elderly patients is generally in line with that of adult patients. However, elderlypatients may be more susceptible to events such as pneumonia, neutropenia and febrile neutropenia.

In older patients (≥ 60 years of age; n = 186 [21%]), the incidence of adverse events was similar acrosstreatment arms. More serious adverse events and dose modifications (including dose delays,reductions, and discontinuations) were reported in the older patients compared with the overall studypopulation. Advanced age was a risk factor for febrile neutropenia in patients in both arms. Olderpatients who received G-CSF primary prophylaxis had lower incidence of neutropenia and febrileneutropenia than those who did not receive G-CSF primary prophylaxis.

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 known antidote for overdose of ADCETRIS. In case of overdose, the patient should beclosely monitored for adverse reactions, particularly neutropenia, and supportive treatment should beadministered (see section 4.4).

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, ATC code: L01FX05.

Brentuximab vedotin is an ADC that delivers an antineoplastic agent that results in apoptotic celldeath selectively in CD30-expressing tumour cells. Nonclinical data suggest that the biologicalactivity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on thecell surface initiates internalisation of the ADC-CD30 complex, which then traffics to the lysosomalcompartment. Within the cell, a single defined active species, MMAE, is released via proteolyticcleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cellcycle arrest and results in apoptotic death of the CD30-expressing tumour cell.

Classical HL, sALCL and subtypes of CTCL (including MF and pcALCL) express CD30 as anantigen on the surface of their malignant cells. This expression is independent of disease stage, line oftherapy or transplant status. These features make CD30 a target for therapeutic intervention. Becauseof the CD30-targeted mechanism of action brentuximab vedotin is able to overcome chemo-resistanceas CD30 is consistently expressed in patients who are refractory to multi-agent chemotherapy,irrespective of prior transplant status. The CD30-targeted mechanism of action of brentuximabvedotin, the consistent expression of CD30 throughout the classical HL, sALCL and CD30+ CTCLdisease and therapeutic spectrums and clinical evidence in CD30-positive malignancies followingmultiple lines of treatment provide a biologic rationale for its use in patients with relapsed andrefractory classical HL, sALCL with or without prior ASCT and CD30+ CTCL after at least 1 priorsystemic therapy.

Contributions to the mechanism of action by other antibody associated functions have not beenexcluded.

Forty-six (46) patients with CD30-expressing haematologic malignancies were evaluable of the52 patients who received 1.8 mg/kg of brentuximab vedotin every 3 weeks as part of a phase 1,single-arm, open-label, multicenter cardiac safety study. The primary objective was to evaluate theeffect of brentuximab vedotin on cardiac ventricular re-polarization and the predefined primaryanalysis was the change in QTc from baseline to multiple time points in Cycle 1.

The upper 90% confidence interval (CI) around the mean effect on QTc was < 10 msec at each of the

Cycle 1 and Cycle 3 post-baseline time points. These data indicate the absence of clinically relevant

QT prolongation due to brentuximab vedotin administered at a dose of 1.8 mg/kg every 3 weeks inpatients with CD30-expressing malignancies.

The efficacy and safety of ADCETRIS were evaluated in a randomised, open-label, 2-arm, multicentertrial in 1334 patients with previously untreated advanced HL in combination with chemotherapy(doxorubicin [A], vinblastine [V] and dacarbazine [D] [AVD]). Patients with nodular lymphocytepredominant HL (NLPHL) were excluded from the study. All patients had a histologically confirmed

CD30-expressing disease. Sixty-two percent of patients had extranodal site involvement. Of the1334 patients, 664 patients were randomised to the ADCETRIS + AVD arm and 670 patients wererandomised to the ABVD (doxorubicin [A], bleomycin [B], vinblastine [V] and dacarbazine [D]) armand stratified by number of International Prognostic Factor Project (IPFP) risk factors and region.

Patients were treated on days 1 and 15 of each 28-day cycle with 1.2 mg/kg of ADCETRISadministered as an intravenous infusion over 30 minutes + doxorubicin 25 mg/m2,vinblastine 6 mg/m2, and dacarbazine 375 mg/m2. The median number of cycles received was 6(range, 1 to 6 cycles). Table 6 provides a summary of the baseline patient and disease characteristics.

There were no relevant differences in the patient and disease characteristics between the two arms.

Table 6: Summary of baseline patient and disease characteristics in the phase 3 previouslyuntreated HL study

Patient Characteristics ADCETRIS + AVD ABVDn = 664 n = 670

Median age (range) 35 years (18-82) 37 years (18-83)

Patients ≥ 65 years old n (%) 60 (9) 62 (9)

Gender, n (%) 378M (57) 398M (59)2 86F (43) 2 72F (41)

ECOG status, n (%)0 376 (57) 378 (57)1 260 (39) 263 (39)2 28 (4) 27 (4)

Missing 0 2

Disease Characteristics

Median time from HL diagnosis to first dose (range) 0.92 mo (0.1-21.4) 0.89 mo (0.0-81.4)

Disease stagea at initial diagnosis of HL, n (%)

III 237 (36) 246 (37)

IV 425 (64) 421 (63)

Not applicable 1 (< 1) 1 (< 1)

Missing 0 2 (< 1 )

Extranodal involvement at time of diagnosis, n (%) 411 (62) 416 (62)

IPFPb risk factors, n (%)0-1 141 (21) 141 (21)2-3 354 (53) 351 (52)4-7 169 (25) 178 (27)

Bone marrow involvement at time of diagnosis or 147(22) 151 (23)study entry, n (%)

B symptomsa n (%) 400 (60) 381 (57)a Per Ann Arbor Staging.bIPFP = International Prognostic Factor Project.

The primary endpoint in Study C25003 was modified PFS (mPFS) per independent review facility(IRF), defined as time from randomisation to disease progression, death, or evidence of non-completeresponse (non-CR) after completion of first-line therapy per IRF followed by subsequent anticancertherapy. Timing of the modified event was the date of the first PET scan post completion of first-linetherapy demonstrating the absence of complete response (CR), defined as Deauville score of ≥ 3. Themedian modified PFS by IRF assessment was not reached in either treatment arm. The results in theintent-to-treat (ITT) population showed a statistically significant improvement in modified PFS for

ADCETRIS+ AVD, with a stratified hazard ratio of 0.770 (95% CI, 0.603; 0.983, p = 0.035),indicating a 23% reduction in the risk of modified PFS events for ADCETRIS+ AVD versus ABVD.

Table 7 provides the efficacy results for modified PFS and overall survival (OS) in the ITT population.

Table 7: Efficacy results for previously untreated HL patients treated with 1.2 mg/kg of

ADCETRIS + AVD on days 1 and 15 of a 28-day cycle (ITT)

Intent to Treat (ITT) Population

ADCETRIS + ABVD Stratified Hazard Ratio

AVD n = 670 and p-valuen = 664

Number of events (%) 117 (18) 146 (22)0.77(95% CI [0.60, 0.98])

Estimated mPFSa per IRF at 82.1 77.2 p-value = 0.0352 Year (%) (95% CI [78.8, (95% CI [73.7,85.0]) 80.4])0.73

Overall Survivalb Number ofdeaths (%) 28 (4) 39 (6) (95% CI [0.45, 1.18])p-value = 0.199aAt the time of analysis, the median modified PFS follow-up time for both arms was 24.6 months.bData from an interim OS analysis.

Figure 1: Modified progression-free survival per IRF in the ITT population (ADCETRIS + AVDvs. ABVD)1.00.80.60.4

Log-rank test p-value: 0.035

Hazard ratio (95% CI): 0.770 ( 0.603, 0.983)0.2 Num of events A+AVD: 117 ABVD: 146

A+AVD Censored

ABVD Censored0.00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

Time (Months) from Randomization

Number of Patients-at-Risk

A+AVD 664 637 623 600 541 528 513 493 463 439 347 328 309 196 185 169 96 85 77 26 24 21 4 4 4 0 0

ABVD 670 636 626 593 521 490 474 459 432 413 326 306 292 177 164 153 76 66 62 16 13 12 1 1 1 0 0

Other secondary efficacy endpoints including CR rate and ORR at the end of randomisation regimen,

CR rate at the end of first-line therapy, and the rate of PET negativity at the end of Cycle 2, durationof response (DOR), duration of complete remission (DOCR), disease-free survival (DFS) andevent-free survival (EFS) all trended in favour of ADCETRIS + AVD in the ITT population.

Pre‑specified subgroup analyses of modified PFS per IRF showed no clinically meaningful differencebetween the two treatment arms in the elderly population (patients ≥ 60 years of age [n = 186][HR = 1.00, 95% CI (0.58, 1.72)] and ≥ 65 years of age [n = 122] [HR = 1.01, 95% CI (0.53, 1.94)])and patients without extranodal sites (n = 445) (HR = 1.04, 95% CI [0.67, 1.62]).

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As of a 01 June 2021 cut-off date, approximately 5 years after enrollment of the last patient, the resultsin the ITT population showed a statistically significant improvement in OS in the ADCETRIS + AVDarm compared with patients treated with ABVD [HR = 0.59, 95% CI (0.396, 0.879)], see Figure 2.

In the Stage III population, OS results indicated a 14% reduction in the risk of death in the A+AVDarm compared with patients in the ABVD arm (HR = 0.86, 95% CI [0.452, 1.648]); in the Stage IVpopulation there was a 52% reduction in the risk of death (HR = 0.48, 95% CI [0.286, 0.799]). Asubgroup analysis of OS showed no clinically meaningful difference between the two treatment armsfor patients without extranodal sites (n = 445) (HR = 1.18, 95% CI [0.641, 2.187]).

Median OS was not reached for either A+AVD or ABVD patients [95%◦CI (NE, NE)].

Figure 2: Overall survival (ADCETRIS + AVD vs. ABVD) (ITT, 6 years median follow up)1.00.80.60.4

Log-rank test p-value: 0.009

Hazard ratio (95% CI): 0.590 ( 0.396, 0.879)0.2 Num of events A+AVD: 39 ABVD: 64

A+AVD Censored0.0 ABVD Censored0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102

Time (Months) from Randomization

Number of Patients-at-Risk

A+AVD 664 638 626 612 598 584 572 557 538 517 494 461 350 209 97 27 4 0

ABVD 670 634 614 604 587 567 545 527 505 479 454 411 308 191 84 11 1 0

A descriptive analysis of OS was performed using data with median follow-up of over 7 years for OS.

In the ITT population, a lower proportion of patients randomized to A + AVD had died (44 deaths,7%) compared with patients randomized to ABVD (67 deaths, 10%; HR = 0.61, 95% CI [0.414,0.892]). Similar proportions of Stage III patients randomized to A+AVD (20 deaths, 8%) and ABVD(20 deaths, 8%) had died (HR = 1.00, 95% CI [0.540, 1.866]). A lower proportion of Stage IV patientsrandomized to A + AVD (24 deaths, 6%) had died compared with patients randomized to ABVD(46 deaths, 11%; HR = 0.48, 95% CI [0.291, 0.784]).

In the ITT population, 33% fewer patients treated with ADCETRIS + AVD in the ITT populationreceived subsequent salvage chemotherapy (n = 66) and high-dose chemotherapy and transplant(n = 36) compared with those treated with ABVD (n = 99 and n = 54, respectively). In the Stage IVpopulation, 35% fewer patients treated with ADCETRIS + AVD received subsequent salvagechemotherapy (n = 45) compared with those treated with ABVD (n = 69) and 22% fewer patientstreated with ADCETRIS + AVD received high-dose chemotherapy and transplant (n = 29) comparedwith those treated with ABVD (n = 37).

The efficacy and safety of ADCETRIS were evaluated in a randomised, double-blind,placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progressionfollowing ASCT. Patients with known cerebral/meningeal disease, including history of PML wereexcluded from the study. See Table 8 for patient characteristics. Of the 329 patients, 165 patients wererandomised to the treatment arm and 164 patients were randomised to the placebo arm. In the study,patients were to receive their first dose after recovery from ASCT (between days 30-45 following

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ASCT). Patients were treated with 1.8 mg/kg of ADCETRIS or matching placebo intravenously over30 minutes every 3 weeks for up to 16 cycles.

Eligible patients were required to have at least one of the following risk factors:

* HL that was refractory to frontline treatment

* Relapsed or progressive HL that occurred < 12 months from the end of frontline treatment

* Extranodal involvement at time of pre-ASCT relapse, including extranodal extension of nodalmasses into adjacent vital organs.

Table 8: Summary of baseline patient and disease characteristics in the phase 3 HL post-ASCT

Study

Patient characteristics ADCETRIS Placebon = 165 n = 164

Median age, years (range) 33 years (18-71) 32 years (18-76)

Gender 76M (46%)/89F (54%) 97M (59%)/67F (41%)

ECOG status0 87 (53%) 97 (59%)1 77 (47%) 67 (41%)2 1 (1%) 0

Disease characteristics

Median number of prior chemotherapy 2 (2-8) 2 (2-7)regimens (range)

Median time from HL diagnosis to first dose 18.7 mo (6.1-204.0) 18.8 mo (7.4-180.8)(range)

Disease stage at initial diagnosis of HL

Stage I 1 (1%) 5 (3%)

Stage II 73 (44%) 61 (37%)

Stage III 48 (29%) 45 (27%)

Stage IV 43 (26%) 51 (31%)

Unknown 0 2 (1%)

PET scan Status prior to ASCT

FDG-AVID 64 (39%) 51 (31%)

FDG-NEGATIVE 56 (34%) 57 (35%)

NOT DONE 45 (27%) 56 (34%)

Extranodal involvement at time of 54 (33%) 53 (32%)pre-ASCT relapse

B symptomsa 47 (28%) 40 (24%)

Best response to salvage therapy pre-ASCTb

Complete Response 61 (37%) 62 (38%)

Partial Response 57 (35%) 56 (34%)

Stable Disease 47 (28%) 46 (28%)

HL Status after the end of frontline standardchemotherapyb

Refractory 99 (60%) 97 (59%)

Relapse occurred <12 months 53 (32%) 54 (33%)

Relapse occurred ≥ 12 months 13 (8%) 13 (8%)

a. For refractory disease, or upon progression or relapse after frontline therapy.

b. Stratification factors at randomisation.

Efficacy results as of the primary analysis of the primary endpoint are shown in Table 9. The primaryendpoint of PFS per IRF was met and showed a difference in median PFS of 18.8 months in favour ofthe treatment arm.

Table 9: Efficacy results in HL patients at increased risk of relapse or progression following

ASCT treated with 1.8 mg/kg of ADCETRIS every 3 weeks (ITT, primary analysis)

ADCETRIS Placebo Stratified Hazardn = 165 n = 164 Ratio

Median per IRF0.5742.9 months 24.1 months (95% CI [0.40, 0.81])

Progression (95% CI [30.4, 42.9]) (95% CI [11.5, -]) Stratified log-rank test

Free Survivala p = 0 .001

Median per Investigator

Not reached 15.8 months 0.5(95% CI [26.4, -]) (95% CI [8.5, -]) (95% CI [0 .36, 0.70])b

Overall Number of deaths (%)

Survival 28 (17) 25 (15) 1.15(95% CI [0.67, 1.97]

a. At the time of the primary analysis, the median follow-up time for both arms was 30 months (range, 0 to 50).

b. Stratified log-rank test was not performed for PFS per Investigator.

Pre-specified subgroup analyses of PFS per IRF were performed by patients’ best response topre-ASCT salvage therapy, HL status after frontline therapy, age, gender, baseline weight, baseline

ECOG performance status, number of treatments pre-ASCT, geographic region, pre-ASCT PETstatus, B symptom status after failure of frontline therapy, and pre-ASCT extranodal disease status.

The analyses showed a consistent trend towards benefit for patients who received ADCETRIScompared with patients who received placebo with the exception of patients ≥65 years of age (n = 8).

No differences were observed in quality of life between the treatment and placebo arms. Medicalresource utilization (MRU) analysis showed that hospitalizations and outpatient visits, as well asworking days/other activities missed by patients and caregivers were lower with ADCETRIScompared with placebo in patients with HL at increased risk of relapse.

An updated analysis conducted after 3 years of follow-up showed a sustained PFS improvement per

IRF (HR = 0.58 [95% CI (0.41, 0.81)]).

As of study closure, approximately 10 years after enrollment of the first patient, PFS per investigatorcontinued to show a benefit (HR = 0.51 [95% CI (0.37, 0.71)]). Overall survival results wereconsistent with those reported at the time of primary analysis (HR = 1.11 [95% CI (0.72, 1.70)]).

Figure 3 shows PFS per investigator in the ITT population as of study closure.

Figure 3: Kaplan-Meier Plot of PFS per investigator (ITT, study closure)20 Stratified

Median (Months) Hazard10 N Events (CI%) Ratio (CI%)

Placebo+BSC 164 94 15.8( 8.5, 27.0)0 BV+BSC 165 67 62.1( 34.3, 98.4) 0.510 (0.370, 0.705)0 9 18 27 36 45 54 63 72 81 90 99 108

Time (Months)

N at Risk (Events)

Pla+BSC 164 (0) 91 (68) 73 (83) 29 (90) 19 (90) 11 (91) 7 (92) 5 (93) 4 (93) 2 (93) 1 (94) 0 (94) 0 (94)

BV+BSC 165 (0) 131 (28) 105 (49) 47 (58) 32 (61) 17 (63) 11 (63) 9 (64) 6 (64) 3 (64) 2 (65) 1 (66) 0 (67)

Post-hoc analyses were performed for the primary analysis of the primary endpoint to evaluate theimpact of increased risk (number of risk factors) on clinical benefit (Table 10). Representative riskfactors for these analyses were:

* HL that occurred <12 months or HL that was refractory to frontline therapy

* Best response of PR or SD to most recent salvage therapy as determined by CT and/or PETscanning

* Extranodal disease at pre-ASCT relapse

* B symptoms at pre-ASCT relapse

* Two or more prior salvage therapies.

The results of these post-hoc analyses suggest increased clinical benefit for patients with two or morerisk factors but no difference based on any of the individual risk factors. No benefit in terms of PFS or

OS has been observed in patients with one risk factor for relapse or progression.

Percent of Subjects Free of PD or Death

Table 10: Summary of PFS per IRF and OS by number of risk factors in the phase 3 HLpost-ASCT Study (primary analysis)

Progression Free Survival per IRF

Number of Risk Number of Risk Number of Risk

Factors = 1 Factors ≥ 2 Factors ≥ 3

ADCETRIS Placebo ADCETRIS Placebo ADCETRIS Placebon = 21 n = 28 n = 144 n = 136 n = 82 n = 84

Number of 9 (43) 7 (25) 51 (35) 68 (50) 32 (39) 49 (58)patients withdiseaseprogressionor deatha (%)

Stratified 1.65 0.49 0.43

Hazard

Ratio (95% CI [0.60, 4.55])b (95% CI [0.34, 0.71]) (95% CI [0.27, 0.68])

Overall Survival

Number of Risk Number of Risk Number of Risk

Factors = 1 Factors ≥ 2 Factors ≥ 3

ADCETRIS Placebo ADCETRIS Placebo ADCETRIS Placebon = 21 n = 28 n = 144 n = 136 n = 82 n = 84

Number of 5 (24) 1 (4) 23 (16) 24 (18) 15 (18) 16 (19)deathsc (%)

Stratified 7.94 0.94 0.92

Hazard

Ratio (95% CI [0.93, 68.06])b (95% CI [0.53, 1.67]) (95% CI [0.45, 1.88])

a. Death without either prior progression or more than one missed assessment visit.

b. Indicates results from non-stratified analysis.

c. Events are death due to any cause.

At the time of the updated analysis (3 years of follow-up) for patients with 2 or more risk factors, thehazard ratio for PFS per IRF was 0.49 (95% CI [0.34, 0.71]) and the hazard ratio for PFS perinvestigator was 0.41 (95% CI [0.29, 0.58]) (see Figures 4 and 5).

Figure 4: Kaplan-Meier Plot of PFS per IRF in Patients with ≥ 2 Risk Factors (3-year follow-up)

Figure 5: Kaplan-Meier Plot of PFS per Investigator in Patients with ≥ 2 Risk Factors (3-yearfollow-up)

As of study closure, approximately 10 years after enrollment of the first patient, the hazard ratio for

PFS per investigator for patients with 2 or more risk factors was 0.41 (95% CI [0.29, 0.58]). Thehazard ratio for PFS per investigator for patients with 3 or more risk factors was 0.38 (95% CI [0.25,0.59]). Overall survival results remained consistent with those observed as of the primary analysis.

The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal open-label,single-arm, multicenter study in 102 patients with relapsed or refractory HL. See Table 11 below for asummary of baseline patient and disease characteristics.

Table 11: Summary of baseline patient and disease characteristics in the phase 2 relapsed orrefractory HL study

Patient characteristics n = 102

Median age, years (range) 31 years (15-77)

Gender 48M (47%)/54F (53%)

ECOG status0 42 (41%)1 60 (59%)

Prior ASCT 102 (100%)

Prior chemotherapy Regimens 3.5 (1-13)

Time from ASCT to first post-transplant relapse 6.7 mo (0-131)

Histologically confirmed CD30-expressing disease 102 (100%)

Disease characteristics

Primary Refractory to frontline therapya 72 (71%)

Refractory to most recent therapy 43 (42%)

Baseline B symptoms 35 (33%)

Stage III at initial diagnosis 27 (26%)

Stage IV at initial diagnosis 20 (20%)

a. Primary refractory HL is defined as a failure to achieve a complete remission to, or progressed within 3 months ofcompleting frontline therapy.

Eighteen (18) patients (18%) received 16 cycles of ADCETRIS; and the median number of cyclesreceived was 9 (ranging from 1 to 16).

Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the

Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response wasassessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Responseassessments were performed at cycles 2, 4, 7, 10, 13, and 16 with PET at cycles 4 and 7.

The objective response rate (ORR) per IRF assessment was 75% (76 of 102 patients in theintent-to-treat [ITT] set) and tumour reduction was achieved in 94% of patients. Complete remission(CR) was 33% (34 of 102 patients in the ITT set). The median overall survival (OS) is 40.5 months(the median observation time (time to death or last contact) from first dose was 35.1 months (range1.8 to 72.9+ months). The estimated overall survival rate at 5 years was 41% (95% CI [31%, 51%]).

The investigator assessments were generally consistent with the independent review of the scans. Ofthe patients treated, 8 responding patients went on to receive an allogeneic SCT. For further efficacyresults see Table 12.

Table 12: Efficacy results in relapsed or refractory Hodgkin lymphoma patients treated with1.8 mg/kg of ADCETRIS every 3 weeks

Best clinical response (n = 102 ) IRF n (%) 95% CI

Objective response rate (CR + PR) 76 (75) 64.9, 82.6

Complete remission (CR) 34 (33) 24.3, 43.4

Partial remission (PR) 42 (41) NA

Disease control rate (CR + PR + SD) 98 (96) 90.3, 98.9

Duration of response Median per IRF 95% CI

Objective response rate (CR + PR)a 6.7 months 3.6, 14.8

Complete remission (CR) 27.9 months 10.8, NEb

Overall survival 95% CI

Median 40.5 months 28.7, 61.9

Estimated 5-year OS Rate 41% 31%, 51%

a. The range of DOR was 1.2+ months to 43+ months and the median follow-up time from first dose for patients whoachieved objective response (OR) per IRF was 9.0 months.

b. Not estimable.

An exploratory intra-patient analysis showed that approximately 64% of the HL patients treated with

ADCETRIS as part of the SG035-0003 clinical study experienced an improvement in clinical benefitas measured by longer progression free survival (PFS) compared with their most recent prior line oftherapy.

Of the 35 patients (33%) who had B symptoms at baseline, 27 patients (77%) experienced resolutionof all B symptoms at a median time of 0.7 months from initiation of ADCETRIS.

Data in HL Patients Who Are Not Stem Cell Transplant (SCT) Candidates

A phase 4 single-arm study was conducted in patients with relapsed or refractory HL (n = 60) who hadreceived at least one prior chemotherapeutic regimen and at the time of treatment initiation with

ADCETRIS were not considered candidates for SCT or multiagent chemotherapy. Eligible patientswere not to have received a prior SCT. The median number of cycles was 7 (range 1 to 16 cycles).

Patients were treated with 1.8 mg/kg of ADCETRIS every 3 weeks.

At the time of the primary analysis of the primary endpoint, per IRF, the objective response rate(ORR) in the ITT population was 50% (95% CI, 37; 63%). A best overall response of CR was reportedfor 7 patients (12%); PR was reported for 23 patients (38%). Among these 30 patients, the mediantime to response, defined as the time from first dose to the soonest of PR or CR, was 6 weeks (range, 5to 39 weeks). The median time to best overall response, defined as the time from first dose to theclinical best response of CR or PR, was 11 weeks (range, 5 to 60 weeks). Twenty-eight patients (47%)went on to receive SCT after a median of 7 cycles (range, 4 to 16 cycles) of ADCETRIS treatment.

The 32 patients (53%) who did not receive subsequent SCT also received ADCETRIS for a median of7 cycles (range, 1 to 16 cycles).

Of the 60 patients in the study, 49 patients (82%) received > 1 prior cancer-related treatment and11 patients (18%) received 1 prior cancer-related treatment. Per IRF, the ORR was 51%(95% CI [36%, 66%]) for the patients who had received > 1 prior cancer-related treatment and 45%(95% CI [17%, 77%]) for the patients who had received 1 prior cancer-related treatment. For thepatients who received > 1 prior cancer-related treatment, a best overall response of CR was reportedfor 6 patients (12%); PR was reported for 19 patients (39%). For the patients who received 1 priorcancer-related treatment, CR was reported for 1 patient (9%) and PR was reported for 4 patients(36%). Out of the 49 patients receiving > 1 line of prior treatment, 22 patients (45%) receivedsubsequent SCT; of the 11 patients who had received 1 prior treatment, 6 patients (55%) receivedsubsequent SCT.

Data were also collected from patients (n = 15) in phase 1 dose escalation and clinical pharmacologystudies, and from patients (n = 26) in a NPP, with relapsed or refractory HL who had not received an

ASCT, and who were treated with 1.8 mg/kg of ADCETRIS every 3 weeks.

Baseline patient characteristics showed failure from multiple prior chemotherapy regimens (median of3 with a range of 1 to 7) before first administration with ADCETRIS. Fifty nine percent (59%) ofpatients had advanced stage disease (Stage III or IV) at initial diagnosis.

Results from these phase 1 studies and from the NPP experience showed, that in patients with relapsedor refractory HL without prior ASCT, clinically meaningful responses can be achieved as evidencedby an investigator-assessed, objective response rate of 54% and a complete remission rate of 22% aftera median of 5 cycles of ADCETRIS.

The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with

ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Twenty patients with relapsed orrefractory HL received a starting dose of 1.8 mg/kg and one patient received a starting dose of1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The mediannumber of cycles was 7 (range, 2 to 37 cycles). Of the 20 evaluable patients with HL, 6 patients (30%)achieved a CR and 6 patients (30%) achieved a PR with ADCETRIS retreatment, for an ORR of 60%.

The median duration of response was 9.2 and 9.4 months in patients who achieved OR (CR+PR) and

CR, respectively.

The efficacy and safety of ADCETRIS were evaluated in a randomised, double-blind, double-dummy,active-controlled, multicenter trial of 452 patients with previously untreated CD30+ PTCL incombination with cyclophosphamide [C], doxorubicin [H] and prednisone [P] (CHP). For enrollment,the trial required CD30 expression ≥ 10% per immunohistochemistry. Only patients with CD30+

PTCLs who were eligible for a cyclophosphamide [C], doxorubicin [H], vincristine [O] andprednisone [P] (CHOP)-based regimen were included. The combination of ADCETRIS + CHP has notbeen studied in all PTCL subtypes. See Table 13 for enrolled PTCL subtypes. Of the 452 patients,226 were randomised to treatment with ADCETRIS + CHP and 226 patients were randomised totreatment with CHOP. Randomisation was stratified by ALK-positive sALCL versus all othersubtypes and by the International Prognostic Index (IPI) score. Patients were treated with 1.8 mg/kg of

ADCETRIS administered as an intravenous infusion over 30 minutes on day 1 of each 21-day cycle +

CHP (cyclophosphamide 750 mg/m2 every 3 weeks by IV infusion; doxorubicin 50 mg/m2 every3 weeks by IV infusion; and prednisone 100 mg on Days 1 to 5 of each 3-week cycle, orally) for 6 to8 cycles. The median number of cycles received was 6 (range, 1 to 8 cycles); 70% of patients received6 cycles of treatment, and 18% received 8 cycles of treatment. Table 13 provides a summary ofbaseline patient and disease characteristics.

Table 13: Summary of baseline patient and disease characteristics in the phase 3 previouslyuntreated PTCL study (ITT and sALCL)

ITT Population sALCL Populationb

Patient characteristics ADCETRIS ADCETRIS+ CHP CHOP + CHP CHOPn = 226 n = 226 n = 162 n = 154

Median age (range) 58.0 (18-85) 58.0 (18-83) 55.0 (18-85) 54.0 (18-83)

Patients ≥ 65 years old (%) 69 (31) 70 (31) 38 (23) 36 (23)

Male sex, n (%) 133 (59) 151 (67) 95 (59) 110 (71)

ECOG status, n (%)0 84 (37) 93 (41) 58 (36) 53 (34)1 90 (40) 86 (38) 62 (38) 61 (40)2 51 (23) 47 (21) 41 (25) 40 (26)

Disease characteristics

Diagnosis, per local assessment,n (%)asALCL 162 (72) 154 (68) 162 (100) 154 (100)

ALK-positive 49 (22) 49 (22) 49 (30) 49 (32)

ALK-negative 113 (50) 105 (46) 113 (70) 105 (68)

Peripheral T-cell lymphoma (PTCL- 29 (13) 43 (19) NA NA

NOS)

Angioimmunoblastic T-cell 30 (13) 24 (11) NA NAlymphoma (AITL)

Adult T-cell leukemia/lymphoma 4 (2) 3 (1) NA NA(ATLL)

Enteropathy-associated T-cell 1 (0) 2 (1) NA NAlymphoma (EATL)

Median time from diagnosis to first 0.8 (0, 19) 0.9 (0, 10) 0.8 (0, 19) 0.9 (0, 10)dose, months (range)

Disease stage at initial diagnosis of

PTCL, n (%)

Stage I 12 (5) 9 (4) 12 (7) 7 (5)

Stage II 30 (13) 37 (16) 22 (14) 27 (18)

Stage III 57 (25) 67 (30) 29 (18) 46 (30)

Stage IV 127 (56) 113 (50) 99 (61) 74 (48)

IPI score0 8 (4) 16 (7) 7 (4) 14 (9)1 45 (20) 32 (14) 34 (21) 18 (12)2 74 (33) 78 (35) 58 (36) 60 (39)3 66 (29) 66 (29) 37 (23) 40 (26)4 29 (13) 25 (11) 22 (14) 16 (10)5 4 (2) 9 (4) 4 (2) 6 (4)

Extranodal involvement at time ofdiagnosis, n (%)≤ 1 site 142 (63) 146 (65) 94 (58) 95 (62)> 1 site 84 (37) 80 (35) 68 (42) 59 (38)

Baseline bone marrow biopsy-lymphoma involvement, n (%)

Yes 30 (13) 34 (15) 15 (9) 13 (8)

No 196 (87) 192 (85) 147 (91) 141 (92)

a. As per the 2008 WHO classification.

b. For patients with locally-diagnosed sALCL.

The primary endpoint in SGN35-014 was PFS per IRF, defined as the time from the date ofrandomisation to the date of first documentation of progressive disease, death due to any cause, orreceipt of subsequent anticancer chemotherapy to treat residual or progressive disease, whicheveroccurs first. Receipt of post-treatment consolidative radiotherapy, post-treatment chemotherapy for thepurpose of mobilising peripheral blood stem cells, or consolidative autologous or allogeneic stem celltransplant were not considered as disease progression or as having started new anticancer therapy.

Key secondary endpoints included PFS per IRF for patients with centrally-confirmed sALCL, CR rateper IRF following the completion of study treatment, OS and ORR per IRF following the completionof study treatment which were tested by a fixed sequence testing procedure following the statisticalsignificance of PFS per IRF.

The primary endpoint and alpha-protected, key secondary endpoints, which were evaluatedhierarchically, were met. The median PFS per IRF for the ITT population was 48.2 months on the

ADCETRIS + CHP arm versus 20.8 months on the CHOP arm. The stratified hazard ratio was0.71 (95% CI: 0.54; 0.93, p = 0.011), indicating a 29% reduction in the risk of PFS events for

ADCETRIS + CHP versus CHOP. For overall survival, the stratified hazard ratio was0.66 (95% CI: 0.46; 0.95, p = 0.024), a 34% reduction in the risk of OS events for ADCETRIS + CHPversus CHOP.

PFS per IRF for patients with centrally-confirmed sALCL was a pre-specified key secondary endpoint.

The median PFS per IRF was 55.7 months on the ADCETRIS + CHP arm versus 54.2 months on the

CHOP arm. The stratified hazard ratio was 0.59 (95% CI: 0.42; 0.84), compatible with a statisticallysignificant 41% reduction in the risk of PFS events for ADCETRIS + CHP versus CHOP(p-value = 0.003), see Figure 6 and Table 14.

Subgroup analyses were performed for patients with locally-diagnosed sALCL. For overall survival,the stratified hazard ratio was 0.54 (95% CI: 0.34; 0.87), a 46% reduction in the risk of OS events for

ADCETRIS + CHP versus CHOP, see Figure 7. At the end of treatment, the CR rate by IRFassessment was 71.0% for patients on the ADCETRIS + CHP arm compared with 53.2% for patientson the CHOP arm with a difference of 17.7% (95% CI: 7.2%; 28.3%). At the end of treatment, the

ORR rate by IRF assessment was 87.7% for patients on the ADCETRIS + CHP arm compared with70.8% for patients on the CHOP arm with a difference of 16.9% (95% CI: 8.1%; 25.7%). In thesubgroup of patients with ALK+ sALCL and ALK- sALCL the stratified hazard ratio for PFS per IRFwas 0.29 (95% CI: 0.11; 0.79) and 0.65 (95% CI: 0.44; 0.95), respectively.

Table 14: Efficacy results in patients with previously untreated sALCL with 1.8 mg/kg of

ADCETRIS on day 1 of a 3-week cycle (primary analysis)

ADCETRIS + CHP CHOPn = 162a n = 154a

PFS per IRF

Number of patients with a PFS event, n (%) 56 (34) 73 (48)

Median PFS, months (95% CI) 55.66 (48.20, NE) 54.18 (13.44, NE)

Hazard ratio (95% CI)b 0.59 (0.42, 0.84)p-valuec 0.0031

Estimated PFS (95% CI)d at:6 months 88.0% 68.4%(81.8%, 92.2%) (60.3%, 75.2%)12 months 78.7% 60.3%(71.4%, 84.4%) (51.9%, 67.6%)24 months 68.4% 53.9%(60.4%, 75.2%) (45.5%, 61.5%)36 months 65.5% 50.2%(57.1%, 72.7%) (41.6%, 58.1%)

OSe

Number of deaths (%) 29 (18) 44 (29)

Median OS, months (95% CI) NE (NE, NE) NE (NE, NE)

Hazard ratio (95% CI)b 0.54 (0.34, 0.87)p-valuec, f 0.0096

CR Rateg% (95% CI) 71% (63.3%, 77.8%) 53% (45.0%, 61.3%)p-valuef, h 0.0004

ORRg% (95% CI) 88% (81.6%, 92.3%) 71% (62.9%, 77.8%)p-valuef, h < 0.0001

CR = complete remission; IRF = Independent Review Facility; NE: Not estimable; ORR = objective response rate;

PFS = progression-free survival.a PFS per IRF is calculated using patients with centrally-confirmed sALCL, with n = 163 patients in A+CHP arm andn = 151 in CHOP arm. OS, CR, and ORR are calculated using patients with locally-diagnosed sALCLb Hazard ratio (A+CHP/CHOP) and 95% confidence intervals are based on a stratified Cox’s proportional hazardregression model with stratification factors (ALK-positive sALCL versus all others and International Prognostic Index[IPI] score at baseline). Hazard ratio < 1 favours A+CHP arm.

c p-value is calculated using a stratified log-rank test.d PFS rate is estimated using Kaplan-Meier methods and 95% CI is calculated using the complementary log-logtransformation method.e Median OS follow-up in the A+CHP arm was 38.5 months; in the CHOP arm was 41.0 months.f p-value is not adjusted for multiplicity.g Response per 2007 International Working Group Criteria at end of treatment.h p-value is calculated using a stratified Cochran-Mantel-Haenszel test.

Figure 6: Progression-free survival per IRF in the sALCL population (ADCETRIS + CHP vs.

CHOP) (primary analysis)

Figure 7: Overall survival in the sALCL population (ADCETRIS + CHP vs. CHOP) (primaryanalysis)

*p-value for overall survival is not adjusted for multiplicity.

As of study closure more than 7 years after enrollment of the first patient, PFS per investigator resultsin the ITT population indicated a 30% reduction in the risk of a PFS event in the ADCETRIS+CHParm compared with patients treated with CHOP (HR = 0.70 [95% CI (0.53, 0.91)]). PFS perinvestigator results in the sALCL population indicated a 45% reduction in the risk of a PFS event inthe ADCETRIS+CHP arm compared with patients treated with CHOP (HR = 0.55 [95% CI (0.39,0.79)]).

As of study closure, overall survival results continued to show a benefit and were consistent with thosereported at the time of the primary analysis. Overall survival results in the ITT population indicated a28% reduction in the risk of death in the ADCETRIS+CHP arm compared with patients treated with

CHOP (HR = 0.72 [95% CI (0.53 to 0.99)]). Overall survival results in the sALCL populationindicated a 34% reduction in the risk of death in the ADCETRIS+CHP arm compared with patientstreated with CHOP (HR = 0.66 [95% CI (0.43, 1.01)]), see Figure 8.

Figure 8: Overall survival in the sALCL population (ADCETRIS + CHP vs. CHOP) (studyclosure)100 Median

N Events (Months) HR (95% CI)90 A+CHP: 162 39 - 0.66 (0.43, 1.01)

CHOP: 154 49 -0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

Time (Months)

N at Risk (Events)

A+CHP: 162(0) 151(8) 143(14) 137(18) 131(24) 122(29) 119(31) 116(34) 109(35) 88(37) 76(37) 56(38) 32(39) 12(39) 3(39) 0(39)

CHOP: 154(0) 127(22) 119(30) 112(36) 109(39) 107(41) 107(41) 104(42) 97(43) 79(44) 68(46) 50(48) 31(48) 17(49) 4(49) 0(49)

The efficacy and safety of ADCETRIS as a single agent was evaluated in an open-label, single-arm,multicenter study in 58 patients with relapsed or refractory sALCL. See Table 15 below for asummary of baseline patient and disease characteristics.

Percentage of Surviving Patients

Table 15: Summary of baseline patient and disease characteristics in the phase 2 relapsed orrefractory sALCL study

Patient characteristics n = 58

Median age, years (range) 52 years (14-76)

Gender 33M (57%)/25F (43%)

ECOG statusa0 19 (33%)1 38 (66%)

Prior ASCT 15 (26%)

Prior chemotherapy Regimens (range) 2 (1-6)

Histologically confirmed CD30-expressing disease 57 (98%)

Anaplastic lymphoma kinase (ALK)-negative disease 42 (72%)

Disease characteristics

Primary Refractory to frontline therapyb 36 (62%)

Refractory to most recent therapy 29 (50%)

Relapsed to most recent therapy 29 (50%)

Baseline B symptoms 17 (29%)

Stage III at initial diagnosis 8 (14%)

Stage IV at initial diagnosis 21 (36%)

a. One patient had a baseline ECOG status of 2, which was prohibited by protocol and is captured as Inclusion Criteria Not

Met.

b. Primary refractory sALCL is defined as a failure to achieve a complete remission to, or progressed within 3 months ofcompleting frontline therapy.

The median time from initial sALCL diagnosis to first dose with ADCETRIS was 16.8 months.

Ten (10) patients (17%) received 16 cycles of ADCETRIS; the median number of cycles received was7 (range, 1 to 16).

Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the

Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response wasassessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Responseassessments were performed at cycles 2, 4, 7, 10, 13 and 16 with PET at cycles 4 and 7.

The ORR per IRF assessment was 86% (50 of 58 patients in the ITT set). CR was 59% (34 of58 patients in the ITT set) and tumour reduction (of any degree) was achieved in 97% of patients. Theestimated overall survival at 5 years was 60% (95% CI [47%,73%]). The median observation time(time to death or last contact) from first dose was 71.4 months. The investigator assessments weregenerally consistent with the independent review of the scans. Of the patients treated, 9 respondingpatients went on to receive an allogeneic stem cell transplant (SCT) and 9 responding patients went onto autologous SCT. For further efficacy results, see Table 16 and Figure 9.

Table 16: Efficacy results in relapsed or refractory sALCL patients treated with 1.8 mg/kg of

ADCETRIS every 3 weeks

Best clinical response (n = 58 ) IRF n (%) 95% CI

Objective response rate (CR + PR) 50 (86) 74.6, 93.9

Complete remission (CR) 34 (59) 44.9, 71.4

Partial remission (PR) 16 (28) NA

Disease control rate (CR + PR + SD) 52 (90) 78.8, 96.1

Duration of response Median per IRF 95% CI

Objective response (CR + PR)a 13.2 5.7, 26.3

Complete remission (CR) 26.3 13.2, NEb

Progression Free Survival Median per IRF 95% CI

Median 14.6 6.9, 20.6

Overall survival Median 95% CI

Median Not reached 21.3, NEb

a. The range of DOR was 0.1 months to 39.1+ months and the median follow-up time from first dose for patients whoachieved objective response (OR) per IRF was 15.5 months.

b. Not estimable.

Figure 9: Kaplan-Meier Plot of OS

An exploratory intra-patient analysis showed that approximately 69% of the sALCL patients treatedwith ADCETRIS as part of the SG035-0004 clinical study experienced an improvement in clinicalbenefit as measured by longer progression free survival (PFS) compared with their most recent priorline of therapy.

Of the 17 patients (29%) who had B symptoms at baseline, 14 patients (82%) experienced resolutionof all B symptoms in a median time from initiation of ADCETRIS of 0.7 months.

The efficacy and safety of ADCETRIS as a single agent were also evaluated in a phase 4 open-label,single-arm multicenter study in 50 patients with relapsed or refractory sALCL. The ORR per IRFassessment was 64% (32 of 50 patients in the ITT set). The median DOR per IRF was not reached(95% CI 19.71 months, NE). The CR rate was 30% (15 of 50 patients in the ITT set), and tumourreduction (of any degree) was achieved in 93% of evaluable patients. The median DOCR per IRF wasnot reached (95% CI 10.61 months, NE). Response assessments were generally consistent between

IRF and investigator. Of the patients treated, 13 patients went on to receive a haematopoietic stem celltransplant.

Pooled data from studies C25006 and SG035-0004 (N=108) show an ORR per IRF of 76% (82 of108 patients in the ITT set). The median DOR per IRF was 17.0 months (95% CI 12.62, 32.46). CRwas 45% (49 of 108 patients in the ITT set) and tumour reduction (of any degree) was achieved in96% of evaluable patients. The median DOCR per IRF was 26.3 months (95% CI 16.16, NE).

Response assessments per IRF and investigator were generally consistent.

The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with

ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Seven patients with relapsedsALCL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of

ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycleswas 8.5 (range, 2 to 30 cycles). Of the 8 sALCL patients, 3 were retreated twice for a total of11 retreatment experiences. Retreatment with ADCETRIS resulted in 6 CRs (55%) and 4 PRs (36%),for an ORR of 91%. The median duration of response was 8.8 and 12.3 months in patients whoachieved OR (CR+PR) and CR, respectively.

The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal phase 3,open-label, randomised, multicentre study in 128 patients with histologically confirmed CD30+

CTCL. CD30 positivity was defined as ≥ 10% target lymphoid cells demonstrating membrane,cytoplasmic, and/or Golgi staining pattern based on an immunohistochemistry assay (Ventanaanti-CD30 [Ber-H2]). Patients with a diagnosis of mycosis fungoides [MF] or primary cutaneousanaplastic large cell lymphoma [pcALCL] were considered eligible for the study. Patients werestratified by these disease types and randomised 1:1 to receive either ADCETRIS or the physician’schoice of either methotrexate or bexarotene. Patients with pcALCL received either prior radiationtherapy or at least 1 prior systemic therapy and patients with MF received at least 1 prior systemictherapy. Patients with a concurrent diagnosis of systemic ALCL, Sezary syndrome and othernon-Hodgkin lymphoma (except for lymphomatoid papulosis [LyP]) were excluded from this study.

Patients were treated with 1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks forup to 16 cycles or physician’s choice for up to 48 weeks. The median number of cycles wasapproximately 12 cycles in the ADCETRIS arm. In the physician’s choice arm, the median duration oftreatment (number of cycles) for patients receiving bexarotene was approximately 16 weeks(5.5 cycles) and 11 weeks (3 cycles) for patients receiving methotrexate. Table 17 provides a summaryof the baseline patient and disease characteristics.

Table 17: Summary of baseline patient and disease characteristics in the phase 3 CTCL Study(ITT Population)

Patient characteristics ADCETRIS Physician’s Choicen = 64 (Methotrexate or

Bexarotene)n = 64

Median age (range) 62 years (22-83) 58.5 years (22-83)

Patients ≥ 65 years old n (%) 28 (44%) 24 (38%)

Gender n (%) 33M (52%)/31F (48%) 37M (58%)/27F (42%)

ECOG status n (%)0 43 (67) 46 (72)1 18 (28) 16 (25)2 3 (5) 2 (3)

Disease characteristics

Median number of prior therapies 4 (0-13) 3.5 (1-15)(range)

Median number of skin-directed 1 (0-6) 1 (0-9)therapies (range)

Median number of systemic 2 (0-11) 2 (1-8)therapies (range)

MF, n (%) 48 (75) 49 (77)

Early (IA-IIA) 15 (31) 18 (37)

Advanced (IIB-IVBa) 32 (67) 30 (61)pcALCL, n (%) 16 (25) 15 (23)

Skin only 9 (56) 11 (73)

Extracutaneous disease 7 (44) 4 (27)a One patient in each arm had incomplete staging data and are not included in the table.

The most common prior skin directed therapies in the ITT population were radiotherapy (64%),phototherapy (48%) and topical steroids (17%). The most common prior systemic therapies in the ITTpopulation were chemotherapy (71%), immunotherapy (43%) and bexarotene (38%).

The primary endpoint was objective response rate that lasts at least 4 months (ORR4) (duration fromfirst response to last response ≥ 4 months), as determined by an independent review of the Global

Response Score (GRS) consisting of skin evaluations (modified severity weighted assessment tool[mSWAT] as assessed per investigator), nodal and visceral radiographic assessment, and detection ofcirculating Sézary cells (Olsen 2011). Table 18 includes the results for ORR4 and other key secondaryendpoints.

Table 18: Efficacy results in CTCL patients treated with 1.8 mg/kg of ADCETRIS every 3 weeks(ITT population)

ADCETRIS Physician’s Choice(n = 64) (Methotrexate or

Bexarotene)n = 64

Objective Response Rate lasting at least 4 months (ORR4) per IRFn (%) 36 (56.3) 8 (12.5)

Percent Difference (95% CI) 43.8 (29.1, 58.4)p-value < 0.001

Complete Response (CR) per IRFn (%) 10 (15.6) 1 (1.6)

Percent Difference (95% CI) 14.1 (-4.0, 31.5)

Adjusted p-valuea 0.0046

Progression Free Survival (PFS) per IRF

Median (months) 16.7 3.5

Hazard Ratio 0.27095% CI (0.17, 0.43)

Adjusted p-valuea < 0.001a Calculated from a weighted Holm’s procedure.

Pre-specified subgroup analyses of ORR4 per IRF were performed by patients’ CTCL subtype,physicians’ choice of treatment, baseline ECOG status, age, gender, and geographic region. Theanalyses showed a consistent trend towards benefit for patients who received ADCETRIS comparedwith patients who received physician’s choice. ORR4 was 50% and 75% in the ADCETRIS armversus 10.2% and 20% in the physician’s choice arm for MF and pcALCL, respectively.

No meaningful differences in quality of life (assessed by the EuroQol five dimensions questionnaire[EQ-5D] and Functional Assessment of Cancer Therapy-General [FACT-G]) were observed betweenthe treatment arms.

The efficacy and safety of ADCETRIS were evaluated in two additional open-label studies in108 patients with relapsed CD30+ CTCL (including MF and pcALCL as well as SS, LyP and mixed

CTCL histology), regardless of CD30 expression level. Patients were treated with ADCETRIS1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles. The safety and efficacyresults in these studies were consistent with results in Study C25001. Overall response rates for MFwere 54-66%; pcALCL, 67%; SS, 50%; LyP, 92%; and mixed CTCL histology, 82-85%.

The safety and anti-tumour activity of ADCETRIS were evaluated in an open-label, multicenter trialin 59 paediatric patients (6-17 years of age) with previously untreated advanced-stage classical

CD30+ HL in combination with chemotherapy (doxorubicin [A], vinblastine [V] and dacarbazine [D][AVD]). All patients had a histologically confirmed CD30-expressing disease. Fifty-nine percent ofpatients (n = 35) had extranodal site involvement. All 59 paediatric patients were treated on days 1 and15 of each 28-day cycle with 48 mg/m2 of ADCETRIS administered as an intravenous infusion over30 minutes + doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2. The

BSA-based dose of ADCETRIS was chosen to match the observed PK exposures in adults in Study

C25003. The paediatric maximum tolerated dose (MTD) was not reached. The majority of patients(88%) achieved an objective response by IRF assessment at the EOT, with 76% achieving a CR. Nopatient died. A total of 13 patients (22%) in the safety population were reported to have receivedirradiation after Cycle 6.

The safety, pharmacokinetics and anti-tumour activity of ADCETRIS in 36 paediatric patients(7-17 years of age) with r/r HL and sALCL (children aged 7-11 years, n = 12 and adolescents aged12 to 17 years, n = 24) were evaluated in a phase 1/2 open-label, single-agent, multicentredose-escalation study (C25002). Phase 1 of the study assessed the safety profile (see section 4.8),determined the paediatric maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D),and assessed the pharmacokinetics of ADCETRIS (see section 5.2). Phase 1 included 3 r/r HL patientstreated at 1.4 mg/kg and 9 patients (7 r/r HL and 2 sALCL) treated at 1.8 mg/kg. The MTD was notreached. The RP2D was determined to be 1.8 mg/kg. Across the study, a total of 16 patients with r/r

HL and 17 patients with r/r sALCL, of whom 10 were in first relapse, were treated with 1.8 mg/kg of

ADCETRIS. The overall response rate (ORR) per independent review facility (IRF) was analysedacross both study phases at the RP2D. Of these 33 patients who received the RP2D, 32 were evaluablefor response. The ORR was 47% in response-evaluable patients with r/r HL, 53% in patients with r/rsALCL and 60% in sALCL patients in first relapse. Eight HL patients and 9 sALCL patients went onto receive SCT following treatment with ADCETRIS.

The pharmacokinetics of brentuximab vedotin were evaluated in phase 1 studies and in a populationpharmacokinetic analysis of data from 314 patients. In all clinical trials, brentuximab vedotin wasadministered as an intravenous infusion.

Maximum concentrations of brentuximab vedotin ADC were typically observed at the end of infusionor the sampling timepoint closest to the end of infusion. A multiexponential decline in ADC serumconcentrations was observed with a terminal half-life of approximately 4 to 6 days. Exposures wereapproximately dose proportional. Minimal to no accumulation of ADC was observed with multipledoses at the every 3-week schedule, consistent with the terminal half-life estimate. Typical Cmax and

AUC of ADC after a single 1.8 mg/kg in a phase 1 study was approximately 31.98 μg/ mL and79.41 μg/ mL x day respectively.

MMAE is the major metabolite of brentuximab vedotin. Median Cmax, AUC and Tmax of MMAE aftera single 1.8 mg/kg of the ADC in a phase 1 study was approximately 4.97 ng/ mL, 37.03 ng/ mL x dayand 2.09 days respectively. MMAE exposures decreased after multiple doses of brentuximab vedotinwith approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses.

MMAE is further metabolised mainly to an equally potent metabolite; however, its exposure is anorder of magnitude lower than that of MMAE. Thus, it is not likely to have any substantialcontribution to the systemic effects of MMAE.

In the first cycle, higher MMAE exposure was associated with an absolute decrease in neutrophilcount.

The pharmacokinetics of ADCETRIS in combination with AVD were evaluated in a single phase 3study in 661 patients. Population pharmacokinetic analysis indicated that the pharmacokinetics of

ADCETRIS in combination with AVD were consistent to that in monotherapy.

After multiple-dose, IV infusion of 1.2 mg/kg brentuximab vedotin every two weeks, maximal serumconcentrations of ADC were observed near the end of the infusion and elimination exhibited amulti-exponential decline with a t1/2z of approximately 4 to 5 days. Maximal plasma concentrations of

MMAE were observed approximately 2 days after the end of infusion, and exhibited amono-exponential decline with a t1/2z of approximately 3 to 4 days.

After multiple-dose, IV infusion of 1.2 mg/kg brentuximab vedotin every two weeks, steady-statetrough concentrations of ADC and MMAE were achieved by Cycle 3. Once steady-state was achieved,the PK of ADC did not appear to change with time. ADC accumulation (as assessed by AUC14Dbetween Cycle 1 and Cycle 3) was 1.27-fold. The exposure of MMAE (as assessed by AUC14Dbetween Cycle 1 and Cycle 3) appeared to decrease with time by approximately 50%.

The pharmacokinetics of ADCETRIS in combination with CHP were evaluated in a single phase3 study in 223 patients (SGN35-014). After multiple-dose IV infusion of 1.8 mg/kg ADCETRIS every3 weeks, the pharmacokinetics of ADC and MMAE were similar to those of monotherapy.

In vitro, the binding of MMAE to human serum plasma proteins ranged from 68-82%. MMAE is notlikely to displace or to be displaced by highly protein-bound medicines. In vitro, MMAE was asubstrate of P-gp and was not an inhibitor of P-gp at clinical concentrations.

In humans, the mean steady state volume of distribution was approximately 6-10 L for ADC. Based onpopulation PK estimation the typical apparent central volume of distribution of MMAE was 35.5 L.

The ADC is expected to be catabolised as a protein with component amino acids recycled oreliminated.

In vivo data in animals and humans suggest that only a small fraction of MMAE released frombrentuximab vedotin is metabolised. The levels of MMAE metabolites have not been measured inhuman plasma. At least one metabolite of MMAE has been shown to be active in vitro.

MMAE is a substrate of CYP3A4 and possibly CYP2D6. In vitro data indicate that the MMAEmetabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human livermicrosomes indicate that MMAE inhibits only CYP3A4/5 at concentrations much higher than wasachieved during clinical application. MMAE does not inhibit other isoforms.

MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes.

The ADC is eliminated by catabolism with a typical estimated CL and half-life of 1.5 L/day and4-6 days respectively.

The elimination of MMAE was limited by its rate of release from ADC, typical apparent CL andhalf-life of MMAE was 19.99 L/day and 3-4 days respectively.

An excretion study was undertaken in patients who received a dose of 1.8 mg/kg of brentuximabvedotin. Approximately 24% of the total MMAE administered as part of the ADC during abrentuximab vedotin infusion was recovered in both urine and faeces over a 1-week period. Of therecovered MMAE, approximately 72% was recovered in the faeces. A lesser amount of MMAE (28%)was excreted in the urine.

Population PK analysis showed that baseline serum albumin concentration was a significant covariateof MMAE clearance. The analysis indicated that MMAE clearance was 2-fold lower in patients withlow serum albumin concentrations < 3.0 g/dL compared with patients with serum albuminconcentrations within the normal range.

A study evaluated the PK of brentuximab vedotin and MMAE after the administration of 1.2 mg/kg of

ADCETRIS to patients with mild (Child-Pugh A; n = 1), moderate (Child-Pugh B; n = 5) and severe(Child-Pugh C; n = 1) hepatic impairment. Compared to patients with normal hepatic function,

MMAE exposure increased approximately 2.3-fold (90% CI 1.27-4.12-fold) in patients with hepaticimpairment.

A study evaluated the PK of brentuximab vedotin and MMAE after the administration of 1.2 mg/kg of

ADCETRIS to patients with mild (n = 4), moderate (n = 3) and severe (n = 3) renal impairment.

Compared to patients with normal renal function, MMAE exposure increased approximately 1.9-fold(90% CI 0.85-4.21-fold) in patients with severe renal impairment (creatinine clearance < 30 mL/min).

No effect was observed in patients with mild or moderate renal impairment.

The population pharmacokinetics of brentuximab vedotin were examined from several studies,including data from 380 patients up to 87 years old (34 patients ≥ 65-< 75 and 17 patients ≥ 75 yearsof age). Additionally, the population pharmacokinetics of brentuximab vedotin in combination with

AVD were examined, including data from 661 patients up to 82 years old (42 patients ≥ 65-< 75 and17 patients ≥ 75 years of age). The influence of age on pharmacokinetics was investigated in eachanalysis and it was not a significant covariate.

The pharmacokinetics of brentuximab vedotin ADC and MMAE following a 30-minute intravenousinfusion of BV administered at 1.4 mg/kg or 1.8 mg/kg given every 3 weeks were evaluated in a phase1/2 clinical trial of 36 paediatric patients (7-17 years of age) with r/r HL and sALCL (children aged7-11 years, n = 12 and adolescents aged 12 to 17 years, n = 24) (see section 5.1). The Cmax of ADCwas typically observed at the end of infusion or the sampling closest to the end of infusion. Amulti-exponential decline in ADC serum concentrations was observed with a terminal half-life ofapproximately 4 to 5 days. Exposures were approximately dose proportional with a trend observed forlower ADC exposures at lower ages/ body weights in the study population.

Median ADC AUC in children and adolescents from this study was approx. 14% and 3% lower than inadult patients, respectively, while MMAE exposures were 53% lower and 13% higher, respectively,than in adult patients. Median Cmax and AUC of ADC after a single 1.8 mg/kg dose were 29.8 µg/ mLand 67.9 µg*day/ mL, respectively, in patients < 12 years of age and 34.4 µg/mL and77.8 µg*day/mL, respectively, in patients ≥ 12 years of age. Median Cmax, AUC, and Tmax of MMAEafter a single 1.8 mg/kg dose were 3.73 ng/mL, 17.3 ng*day/mL, and 1.92 days, respectively, inpatients < 12 years of age and 6.33 ng/mL, 42.3 ng*day/mL, and 1.82 days, respectively, in patients≥ 12 years of age. There was a trend of increased clearance of brentuximab vedotin in paediatricpatients confirmed positive for ADAs. No patients aged < 12 years (0 of 11) and 2 patients aged≥ 12 years (2 of 23) became persistently ADA positive.

The pharmacokinetics of brentuximab vedotin ADC and MMAE following a 30-minute intravenousinfusion of BV administered at 48 mg/m2 every 2 weeks in combination with doxorubicin, vinblastine,and dacarbazine (AVD) were evaluated in a phase 1/2 clinical trial of 59 paediatric patients(6-17 years of age) with advanced-stage newly diagnosed CD30+ classical Hodgkin lymphoma(children aged 6-11 years, n = 11 and adolescents aged 12 to 17 years, n = 48). The Cmax of ADCoccurred in serum approximately at the end of infusion and declined in a multiexponential mannerwith a terminal half-life of approximately 4 days. The Cmax of MMAE occurred in plasmaapproximately 2 days following BV administration with a half-life of approximately 2 days.

Geometric mean Cmax and AUC of ADC following a single 48 mg/m2 dose were 22.5 µg/mL and46.7 µg*day/mL, respectively. Geometric mean Cmax and AUC of MMAE following a single48 mg/m2 dose were 4.9 ng/mL and 27.2 ng*day/mL, respectively. Similar ADC exposures wereachieved following body surface area-based dosing of BV at 48 mg/m2 in combination with AVDamong paediatric age groups (< 12 years, 12 - 16 years and > 16 years).

MMAE has been shown to have aneugenic properties in an in vivo rat bone marrow micronucleusstudy. These results were consistent with the pharmacological effect of MMAE on the mitoticapparatus (disruption of the microtubule network) in cells.

The effects of brentuximab vedotin on human male and female fertility have not been studied.

However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotinto impair male reproductive function and fertility. Testicular atrophy and degeneration were partiallyreversible following a 16-week treatment-free period.

Brentuximab vedotin caused embryo-foetal lethality in pregnant female rats.

In nonclinical studies, lymphoid depletion and reduced thymic weight were observed, consistent withthe pharmacologic disruption of microtubules caused by MMAE derived from brentuximab vedotin.

Citric acid monohydrate (for pH-adjustment)

Sodium citrate dihydrate (for pH-adjustment)α,α-Trehalose dihydrate

Polysorbate 80

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

4 years.

After reconstitution/dilution, from a microbiological point of view, the product should be usedimmediately. However, chemical and physical in-use stability has been demonstrated for 24 hours at2 °C-8 °C.

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

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

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

Type I glass vial with a butyl rubber stopper and an aluminium/plastic flip-off seal, containing 50 mgpowder.

Pack of 1 vial.

Procedures for proper handling and disposal of anticancer medicinal products should be considered.

Proper aseptic technique throughout the handling of this medicinal product should be followed.

Each single use vial must be reconstituted with 10.5 mL of water for injections to a final concentrationof 5 mg/ mL. Each vial contains a 10% overfill giving 55 mg of ADCETRIS per vial and a totalreconstituted volume of 11 mL.

1. Direct the stream toward the wall of the vial and not directly at the cake or powder.2. Gently swirl the vial to aid dissolution. DO NOT SHAKE.3. The reconstituted solution in the vial is a clear to slightly opalescent, colourless solution with afinal pH of 6.6.4. The reconstituted solution should be inspected visually for any foreign particulate matter and/ordiscolouration. In the event of either being observed, discard the medicinal product.

The appropriate amount of reconstituted ADCETRIS must be withdrawn from the vial(s) and added toan infusion bag containing sodium chloride 9 mg/ mL (0.9%) solution for injection in order to achievea final concentration of 0.4-1.2 mg/ mL ADCETRIS. The recommended diluent volume is 150 mL.

The already reconstituted ADCETRIS can also be diluted into 5% dextrose for injection or Lactated

Ringer's for injection.

Gently invert the bag to mix the solution containing ADCETRIS. DO NOT SHAKE.

Any portion left in the vial, after withdrawal of the volume to be diluted, must be disposed of inaccordance with local requirements.

Do not add other medicinal products to the prepared ADCETRIS infusion solution or intravenousinfusion set. The infusion line should be flushed following administration with sodium chloride9 mg/ mL (0.9%) solution for injection, 5% dextrose for injection, or Lactated Ringer's for injection.

Following dilution, infuse the ADCETRIS solution immediately at the recommended infusion rate.

Total storage time of the solution from reconstitution to infusion should not exceed 24 hours.

Calculation to determine the total ADCETRIS dose (mL) to be further diluted (see section 4.2):

ADCETRIS dose (mg/kg) x patient’s body weight (kg)

Reconstituted vial concentration (5 mg/mL) = Total ADCETRIS dose (mL) to be further diluted

Note: If patient’s weight is more than 100 kg, the dose calculation should use 100 kg. The maximalrecommended dose is 180 mg.

Total ADCETRIS dose (mL) to be administered

Total volume per vial (10 mL/vial) = Number of ADCETRIS vials needed

Table 19: Sample calculations for patients receiving the recommended dose of 1.8 mg/kg,1.2 mg/kg or 0.9 mg/kg of ADCETRIS for weights ranging from 60 kg to 120 kga, b

Recommended Patient Total dose = Total volume to be Number of vialsdose weight patient weight dilutedc = total dose needed =(kg) multiplied by divided by total volume to berecommended dose reconstituted vial diluted divided byconcentration total volume per[5 mg/mL] vial [10 mL/vial]1.8 mg/kg (up 60 kg 108 mg 21.6 mL 2.16 vialsto a maximum 80 kg 144 mg 28.8 mL 2.88 vialsof 180 mg) 100 kg 180 mg 36 mL 3.6 vials120 kgd 180 mg 36 mL 3.6 vials1.2 mg/kg (up 60 kg 72 mg 14.4 mL 1.44 vialsto a maximum 80 kg 96 mg 19.2 mL 1.92 vialsof 120 mg) 100 kg 120 mg 24 mL 2.4 vials120 kgd 120 mg 24 mL 2.4 vials0.9 mg/kg (up 60 kg 54 mg 10.8 mL 1.08 vialsto a maximum 80 kg 72 mg 14.4 mL 1.44 vialsof 90 mg) 100 kg 90 mg 18 mL 1.8 vials120 kgd 90 mg 18 mL 1.8 vials

a. This table provides sample calculations for adult patients.

b. For paediatric patients studied in clinical trials (6-17 years of age), body surface area-based dosing was calculated as48 mg/m2 every two weeks in combination with AVD in a 28-day cycle or 72 mg/m2 every three weeks as monotherapy.(See sections 5.1 and 5.2 for information on clinical studies conducted in paediatric patients.)

c. To be diluted in 150 mL of diluent and administered by intravenous infusion over 30 minutes.

d. If patient’s weight is more than 100 kg, the dose calculation should use 100 kg.

ADCETRIS is for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

Takeda Pharma A/S

Delta Park 452665 Vallensbaek Strand

DenmarkmedinfoEMEA@takeda.com

EU/1/12/794/001

Date of first authorisation: 25 October 2012

Date of latest renewal: 16 September 2021

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

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