TECENTRIQ 840mg / 14ml perfusive solution concentrate medication leaflet

Tecentriq 840 mg concentrate for solution for infusion

Tecentriq 1 200 mg concentrate for solution for infusion

Tecentriq 840 mg concentrate for solution for infusion

One 14 mL vial of concentrate contains 840 mg of atezolizumab*

Tecentriq 1 200 mg concentrate for solution for infusion

One 20 mL vial of concentrate contains 1 200 mg atezolizumab*

After dilution (see section 6.6), the final concentration of the diluted solution should be between3.2 and 16.8 mg/mL.

*Atezolizumab is an Fc-engineered, humanised IgG1 anti-programmed death-ligand 1 (PD-L1)monoclonal antibody produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear, colourless to slightly yellowish liquid. The solution has a pH of 5.5 - 6.1 and an osmolality of129 - 229 mOsm/kg.

Urothelial carcinoma (UC)

Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced ormetastatic UC:

* after prior platinum-containing chemotherapy, or

* who are considered cisplatin ineligible, and whose tumours have a PD-L1 expression ≥ 5% (seesection 5.1).

Early-stage non-small cell lung cancer (NSCLC)

Tecentriq as monotherapy is indicated as adjuvant treatment following complete resection andplatinum-based chemotherapy for adult patients with NSCLC with a high risk of recurrence whosetumours have PD-L1 expression on ≥ 50% of tumour cells (TC) and who do not have EGFR-mutant or

ALK-positive NSCLC (see section 5.1 for selection criteria).

Advanced NSCLC

Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, is indicated for the first-linetreatment of adult patients with metastatic non-squamous NSCLC. In patients with EGFR-mutant or

ALK-positive NSCLC, Tecentriq, in combination with bevacizumab, paclitaxel and carboplatin, isindicated only after failure of appropriate targeted therapies (see section 5.1).

Tecentriq, in combination with nab-paclitaxel and carboplatin, is indicated for the first-line treatmentof adult patients with metastatic non-squamous NSCLC who do not have EGFR-mutant or

ALK-positive NSCLC (see section 5.1).

Tecentriq as monotherapy is indicated for the first-line treatment of adult patients with metastatic

NSCLC whose tumours have a PD-L1 expression ≥ 50% TC or ≥ 10% tumour-infiltrating immunecells (IC) and who do not have EGFR-mutant or ALK-positive NSCLC (see section 5.1).

Tecentriq as monotherapy is indicated for the first-line treatment of adult patients with advanced

NSCLC who are ineligible for platinum-based therapy (see section 5.1 for selection criteria).

Tecentriq as monotherapy is indicated for the treatment of adult patients with locally advanced ormetastatic NSCLC after prior chemotherapy. Patients with EGFR-mutant or ALK-positive NSCLCshould also have received targeted therapies before receiving Tecentriq (see section 5.1).

Small cell lung cancer (SCLC)

Tecentriq, in combination with carboplatin and etoposide, is indicated for the first-line treatment ofadult patients with extensive-stage small cell lung cancer (ES-SCLC) (see section 5.1).

Tecentriq in combination with nab-paclitaxel is indicated for the treatment of adult patients withunresectable locally advanced or metastatic TNBC whose tumours have PD-L1 expression ≥ 1% andwho have not received prior chemotherapy for metastatic disease.

Hepatocellular carcinoma (HCC)

Tecentriq, in combination with bevacizumab, is indicated for the treatment of adult patients withadvanced or unresectable HCC who have not received prior systemic therapy (see section 5.1).

Tecentriq must be initiated and supervised by physicians experienced in the treatment of cancer.

PD-L1 testing for patients with UC or TNBC or NSCLC

Tecentriq monotherapy

If specified in the indication, patient selection for treatment with Tecentriq based on the tumourexpression of PD-L1 should be confirmed by a validated test (see sections 4.1 and 5.1).

Tecentriq in combination therapy

Patients with previously untreated TNBC should be selected for treatment based on the tumourexpression of PD-L1 confirmed by a validated test (see section 5.1).

The recommended dose of Tecentriq is either 840 mg administered intravenously every two weeks, or1 200 mg administered intravenously every three weeks, or 1 680 mg administered intravenouslyevery four weeks, as presented in Table 1.

When Tecentriq is administered in combination therapy please also refer to the full prescribinginformation for the combination products (see also section 5.1).

Table 1: Recommended dose for Tecentriq by intravenous administration

Indication Recommended dose and schedule Duration of treatment

Tecentriq monotherapy1L UC * 840 mg every 2 weeks or Until disease progression or1L metastatic NSCLC * 1 200 mg every 3 weeks or unmanageable toxicity.1L platinum-ineligible NSCLC * 1 680 mg every 4 weeks

Early-stage NSCLC * 840 mg every 2 weeks or For 1 year unless disease

* 1 200 mg every 3 weeks or recurrence or unacceptable

* 1 680 mg every 4 weeks toxicity. Treatment durationfor more than 1 year was notstudied.

2L UC * 840 mg every 2 weeks or Until loss of clinical benefit or

* 1 200 mg every 3 weeks or unmanageable toxicity.2L NSCLC * 1 680 mg every 4 weeks

Tecentriq combination therapy1L non-squamous NSCLC Induction and maintenance phases: Until disease progression orwith bevacizumab, paclitaxel, * 840 mg every 2 weeks or unmanageable toxicity.and carboplatin * 1 200 mg every 3 weeks or Atypical responses (i.e., an

* 1 680 mg every 4 weeks initial disease progressionfollowed by tumour

Tecentriq should be administered first shrinkage) have beenwhen given on the same day. observed with continued

Tecentriq treatment after

Induction phase for combination partners disease progression.(four or six cycles): Treatment beyond disease

Bevacizumab, paclitaxel, and then progression may becarboplatin are administered every three considered at the discretion ofweeks. the physician.

Maintenance phase (withoutchemotherapy): Bevacizumab every3 weeks.

1L non-squamous NSCLC Induction and maintenance phases: Until disease progression orwith nab-paclitaxel and * 840 mg every 2 weeks or unmanageable toxicity.carboplatin * 1 200 mg every 3 weeks or Atypical responses (i.e., an

* 1 680 mg every 4 weeks initial disease progressionfollowed by tumour

Tecentriq should be administered first shrinkage) have beenwhen given on the same day. observed with continued

Tecentriq treatment after

Induction phase for combination partners disease progression.(four or six cycles): Nab-paclitaxel, and Treatment beyond diseasecarboplatin are administered on day 1; in progression may beaddition, nab-paclitaxel is administered considered at the discretion ofon days 8 and 15 of each 3-weekly cycle. the physician.

Indication Recommended dose and schedule Duration of treatment1L ES-SCLC Induction and maintenance phases: Until disease progression orwith carboplatin and etoposide * 840 mg every 2 weeks or unmanageable toxicity.

* 1 200 mg every 3 weeks or Atypical responses (i.e., an

* 1 680 mg every 4 weeks initial disease progressionfollowed by tumour

Tecentriq should be administered first shrinkage) have beenwhen given on the same day. observed with continued

Tecentriq treatment after

Induction phase for combination partners disease progression.(four cycles): Carboplatin, and then Treatment beyond diseaseetoposide are administered on day 1; progression may beetoposide is also administered on days 2 considered at the discretion ofand 3 of each 3-weekly cycle. the physician.

1L unresectable locally * 840 mg every 2 weeks or Until disease progression oradvanced or metastatic TNBC * 1 200 mg every 3 weeks or unmanageable toxicity.with nab-paclitaxel * 1 680 mg every 4 weeks

Tecentriq should be administered prior tonab-paclitaxel when given on the sameday. Nab-paclitaxel should beadministered at 100 mg/m2 on days 1, 8,and 15 of each 28-day cycle.

Advanced or unresectable HCC * 840 mg every 2 weeks or Until loss of clinical benefit orwith bevacizumab * 1 200 mg every 3 weeks or unmanageable toxicity.

* 1 680 mg every 4 weeks

Tecentriq should be administered prior tobevacizumab when given on the sameday. Bevacizumab is administered at15 mg/kg body weight (bw) every 3weeks.

If a planned dose of Tecentriq is missed, it should be administered as soon as possible. The scheduleof administration must be adjusted to maintain the appropriate interval between doses.

Dose modifications during treatment

Dose reductions of Tecentriq are not recommended.

Dose delay or discontinuation (see also sections 4.4 and 4.8)

Table 2: Dose modification advice for Tecentriq

Immune-mediated Severity Treatment modificationadverse reaction

Pneumonitis Grade 2 Withhold Tecentriq

Treatment may be resumed whenthe event improves to Grade 0 or

Grade 1 within 12 weeks, andcorticosteroids have been reducedto ≤ 10 mg prednisone orequivalent per day

Grade 3 or 4 Permanently discontinue

Tecentriq

Hepatitis in patients Grade 2: Withhold Tecentriqwithout HCC (ALT or AST > 3 to 5 x upper limitof normal [ULN] Treatment may be resumed whenthe event improves to Grade 0 oror Grade 1 within 12 weeks andcorticosteroids have been reducedblood bilirubin > 1.5 to 3 x ULN) to ≤ 10 mg prednisone orequivalent per day

Grade 3 or 4: Permanently discontinue(ALT or AST > 5 x ULN Tecentriqorblood bilirubin > 3 x ULN)

Hepatitis in patients with If AST/ALT is within normal limits Withhold Tecentriq

HCC at baseline and increases to > 3 x to≤ 10x ULN Treatment may be resumed whenthe event improves to Grade 0 oror Grade 1 within 12 weeks andcorticosteroids have been reduced

If AST/ALT is > 1 to ≤ 3 x ULN at to ≤ 10 mg prednisone orbaseline and increases to > 5x to equivalent per day≤ 10x ULNor

If AST/ALT is > 3 x to ≤ 5 x ULNat baseline and increases to >8 x to≤ 10x ULN

If AST/ALT increases to > 10 x Permanently discontinue

ULN Tecentriqortotal bilirubin increases to > 3 x

ULN

Immune-mediated Severity Treatment modificationadverse reaction

Colitis Grade 2 or 3 Diarrhoea (increase of Withhold Tecentriq≥ 4 stools/day over baseline)

Treatment may be resumed whenor the event improves to Grade 0 or

Grade 1 within 12 weeks and

Symptomatic Colitis corticosteroids have been reducedto ≤ 10 mg prednisone orequivalent per day

Grade 4 Diarrhoea or Colitis (life Permanently discontinuethreatening; urgent intervention Tecentriqindicated)

Hypothyroidism or Symptomatic Withhold Tecentriqhyperthyroidism

Treatment may be resumed whensymptoms are controlled bythyroid replacement therapy and

TSH levels are decreasing

Treatment may be resumed whensymptoms are controlled by anti-thyroid medicinal product andthyroid function is improving

Adrenal insufficiency Symptomatic Withhold Tecentriq

Treatment may be resumed whenthe symptoms improve to Grade0 or Grade 1 within 12 weeks andcorticosteroids have been reducedto ≤ 10 mg prednisone orequivalent per day and patient isstable on replacement therapy

Hypophysitis Grade 2 or 3 Withhold Tecentriq

Treatment may be resumed whenthe symptoms improve to Grade0 or Grade 1 within 12 weeks andcorticosteroids have been reducedto ≤ 10 mg prednisone orequivalent per day and patient isstable on replacement therapy

Grade 4 Permanently discontinue

Tecentriq

Immune-mediated Severity Treatment modificationadverse reaction

Type 1 diabetes mellitus Grade 3 or 4 hyperglycaemia Withhold Tecentriq(fasting glucose > 250 mg/dL or13.9 mmol/L) Treatment may be resumed whenmetabolic control is achieved oninsulin replacement therapy

Rash/Severe cutaneous Grade 3 Withhold Tecentriqadverse reactionsor suspected Stevens-Johnson Treatment may be resumed whensyndrome (SJS) or toxic epidermal the symptoms improve to Gradenecrolysis (TEN)1 0 or Grade 1 within 12 weeks andcorticosteroids have been reducedto ≤ 10 mg prednisone orequivalent per day

Grade 4 Permanently discontinue

Tecentriqor confirmed Stevens-Johnsonsyndrome (SJS) or toxic epidermalnecrolysis (TEN)1

Myasthenic Facial paresis Grade 1 or 2 Withhold Tecentriqsyndrome/myastheniagravis, Guillain-Barré Treatment may be resumed if thesyndrome, event fully resolves. If the event

Meningoencephalitis and does not fully resolve while

Facial paresis withholding Tecentriq,permanently discontinue

Tecentriq

All Grades Myasthenic Permanently discontinuesyndrome/myasthenia gravis, Tecentriq

Guillain Barré syndrome and

Meningoencephalitisor Facial paresis Grade 3 or 4

Myelitis Grade 2, 3, or 4 Permanently discontinue

Tecentriq

Pancreatitis Grade 3 or 4 serum amylase or Withhold Tecentriqlipase levels increased (> 2 x ULN)or Grade 2 or 3 pancreatitis Treatment may be resumed whenserum amylase and lipase levelsimprove to Grade 0 or Grade 1within 12 weeks, or symptoms ofpancreatitis have resolved, andcorticosteroids have been reducedto ≤ 10 mg prednisone orequivalent per day

Grade 4 or any grade of recurrent Permanently discontinuepancreatitis Tecentriq

Immune-mediated Severity Treatment modificationadverse reaction

Myocarditis Grade 2 or above Permanently discontinue

Tecentriq

Nephritis Grade 2: Withhold Tecentriq(creatinine level > 1.5 to 3.0 xbaseline or > 1.5 to 3.0 x ULN) Treatment may be resumed whenthe event improves to Grade 0 or

Grade 1 within 12 weeks andcorticosteroids have been reducedto ≤ 10 mg prednisone orequivalent per day

Grade 3 or 4: Permanently discontinue(creatinine level > 3.0 x baseline or Tecentriq> 3.0 x ULN)

Myositis Grade 2 or 3 Withhold Tecentriq

Grade 4 or Grade 3 recurrent Permanently discontinuemyositis Tecentriq

Pericardial disorders Grade 1 pericarditis Withhold Tecentriq2

Grade 2 or above Permanently discontinue

Tecentriq

Haemophagocytic Suspected haemophagocytic Permanently discontinuelymphohistiocytosis lymphohistiocytosis1 Tecentriq

Other immune-mediated Grade 2 or Grade 3 Withhold until adverse reactionsadverse reactions recovers to Grade 0-1 within 12weeks, and corticosteroids havebeen reduced to ≤ 10 mgprednisone or equivalent per day

Grade 4 or recurrent Grade 3 Permanently discontinue

Tecentriq (exceptendocrinopathies controlled withreplacement hormones)

Other adverse reactions Severity Treatment modification

Infusion-related Grade 1 or 2 Reduce infusion rate or interrupt.reactions Treatment may be resumed whenthe event is resolved

Grade 3 or 4 Permanently discontinue

Tecentriq

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.

Note: Toxicity should be graded with the current version of National Cancer Institute Common

Terminology Criteria for Adverse Events (NCI CTCAE).1 Regardless of severity2 Conduct a detailed cardiac evaluation to determine the aetiology and manage appropriately

The safety and efficacy of Tecentriq in children and adolescents aged below 18 years have not beenestablished. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendationon a posology can be made.

Based on a population pharmacokinetic analysis, no dose adjustment of Tecentriq is required inpatients ≥ 65 years of age (see sections 4.8 and 5.1).

Asian patients

Due to increased haematologic toxicities observed in Asian patients in IMpower150, it isrecommended that the starting dose of paclitaxel should be 175 mg/m2 every three weeks.

Based on a population pharmacokinetic analysis, no dose adjustment is required in patients with mildor moderate renal impairment (see section 5.2). Data from patients with severe renal impairment aretoo limited to draw conclusions on this population.

Based on a population pharmacokinetic analysis, no dose adjustment is required for patients with mildor moderate hepatic impairment. Tecentriq has not been studied in patients with severe hepaticimpairment (see section 5.2).

Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2

Patients with ECOG performance status ≥ 2 were excluded from the clinical trials in TNBC, ES-

SCLC, 2nd line UC and HCC (see sections 4.4 and 5.1).

It is important to check the product labels to ensure that the correct formulation (intravenous orsubcutaneous) is being administered to the patient, as prescribed.

Tecentriq intravenous formulation is not intended for subcutaneous administration and should beadministered via an intravenous infusion only. The infusions must not be administered as anintravenous push or bolus.

Patients currently receiving intravenous Tecentriq can switch to atezolizumab solution for injection orvice versa.

The initial dose of intravenous Tecentriq must be administered over 60 minutes. If the first infusion iswell tolerated, all subsequent infusions may be administered over 30 minutes.

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

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

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

Immune-mediated adverse reactions

Most immune-mediated adverse reactions occurring during treatment with atezolizumab werereversible with interruptions of atezolizumab and initiation of corticosteroids and/or supportive care.

Immune-mediated adverse reactions affecting more than one body system have been observed.

Immune-mediated adverse reactions with atezolizumab may occur after the last dose of atezolizumab.

For suspected immune-mediated adverse reactions, thorough evaluation to confirm aetiology orexclude other causes should be performed. Based on the severity of the adverse reaction, atezolizumabshould be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroidshould be tapered over ≥ 1 month. Based on limited data from clinical trials in patients whoseimmune-mediated adverse reactions could not be controlled with systemic corticosteroid use,administration of other systemic immunosuppressants may be considered.

Atezolizumab must be permanently discontinued for any Grade 3 immune-mediated adverse reactionthat recurs and for any Grade 4 immune-mediated adverse reactions, except for endocrinopathies thatare controlled with replacement hormones (see sections 4.2 and 4.8).

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest thatthe risk of immune-mediated adverse reactions following immune checkpoint inhibitor therapy may beincreased as compared with the risk in patients without pre-existing AID. In addition, flares of theunderlying AID were frequent, but the majority were mild and manageable.

Immune-mediated pneumonitis

Cases of pneumonitis, including fatal cases, have been observed in clinical trials with atezolizumab(see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis and causesother than immune-mediated pneumonitis should be ruled out.

Treatment with atezolizumab should be withheld for Grade 2 pneumonitis, and 1 to 2 mg/kgbody weight (bw)/day prednisone or equivalent should be started. If symptoms improve to ≤ Grade 1,corticosteroids should be tapered over ≥ 1 month. Treatment with atezolizumab may be resumed if theevent improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mgprednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for

Grade 3 or 4 pneumonitis.

Immune-mediated hepatitis

Cases of hepatitis, some leading to fatal outcomes have been observed in clinical trials withatezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis.

Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin should be monitoredprior to initiation of treatment, periodically during treatment with atezolizumab and as indicated basedon clinical evaluation.

For patients without HCC, treatment with atezolizumab should be withheld if Grade 2 event (ALT or

AST > 3 to 5 x ULN or blood bilirubin > 1.5 to 3 x ULN) persists for more than 5 to 7 days, and 1 to2 mg/kg bw/day of prednisone or equivalent should be started. If the event improves to ≤ Grade 1,corticosteroids should be tapered over ≥ 1 month.

Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks andcorticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment withatezolizumab must be permanently discontinued for Grade 3 or Grade 4 events (ALT or AST> 5.0 x ULN or blood bilirubin > 3 x ULN).

For patients with HCC, treatment with atezolizumab should be withheld if ALT or AST increases to> 3 to ≤ 10 x ULN from normal limits at baseline, or > 5 to ≤ 10 x ULN from > 1 ULN to ≤ 3 x ULNat baseline, or > 8 to ≤ 10 x ULN from > 3 ULN to ≤ 5 x ULN at baseline, and persists for more than 5to 7 days, and 1 to 2 mg/kg bw/day of prednisone or equivalent should be started. If the eventimproves to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month.

Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks andcorticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment withatezolizumab must be permanently discontinued if ALT or AST increases to > 10 x ULN or totalbilirubin increases > 3 x ULN).

Immune-mediated colitis

Cases of diarrhoea or colitis have been observed in clinical trials with atezolizumab (see section 4.8).

Patients should be monitored for signs and symptoms of colitis.

Treatment with atezolizumab should be withheld for Grade 2 or 3 diarrhoea (increase of ≥ 4 stools/dayover baseline) or colitis (symptomatic). For Grade 2 diarrhoea or colitis, if symptoms persist > 5 daysor recur, treatment with 1 to 2 mg/kg bw/day prednisone or equivalent should be started. For

Grade 3 diarrhoea or colitis, treatment with intravenous corticosteroids (1 to 2 mg/kg bw/daymethylprednisolone or equivalent) should be started. Once symptoms improve, treatment with1 to 2 mg/kg bw/day of prednisone or equivalent should be started. If symptoms improve to ≤ Grade 1,corticosteroids should be tapered over ≥ 1 month. Treatment with atezolizumab may be resumed if theevent improves to ≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mgprednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for

Grade 4 (life threatening; urgent intervention indicated) diarrhoea or colitis. The potentialcomplication of gastrointestinal perforation associated with colitis should be taken into consideration.

Immune-mediated endocrinopathies

Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus,including diabetic ketoacidosis have been observed in clinical trials with atezolizumab (seesection 4.8).

Patients should be monitored for clinical signs and symptoms of endocrinopathies. Thyroid functionshould be monitored prior to and periodically during treatment with atezolizumab. Appropriatemanagement of patients with abnormal thyroid function tests at baseline should be considered.

Asymptomatic patients with abnormal thyroid function tests can receive atezolizumab. Forsymptomatic hypothyroidism, atezolizumab should be withheld and thyroid hormone replacementshould be initiated as needed. Isolated hypothyroidism may be managed with replacement therapy andwithout corticosteroids. For symptomatic hyperthyroidism, atezolizumab should be withheld and ananti-thyroid medicinal product should be initiated as needed. Treatment with atezolizumab may beresumed when symptoms are controlled and thyroid function is improving.

For symptomatic adrenal insufficiency, atezolizumab should be withheld and treatment withintravenous corticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started.

Once symptoms improve, treatment with 1 to 2 mg/kg bw/day of prednisone or equivalent shouldfollow. If symptoms improve to ≤ Grade 1, corticosteroids should be tapered over ≥ 1 month.

Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks and corticosteroidshave been reduced to ≤ 10 mg prednisone or equivalent per day and the patient is stable onreplacement therapy (if required).

For Grade 2 or Grade 3 hypophysitis, atezolizumab should be withheld and treatment with intravenouscorticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started, andhormone replacement should be initiated as needed. Once symptoms improve, treatment with1 to 2 mg/kg bw/day of prednisone or equivalent should follow. If symptoms improve to ≤ Grade 1,corticosteroids should be tapered over ≥ 1 month. Treatment may be resumed if the event improves to≤ Grade 1 within 12 weeks and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalentper day and the patient is stable on replacement therapy (if required). Treatment with atezolizumabshould be permanently discontinued for Grade 4 hypophysitis.

Treatment with insulin should be initiated for type 1 diabetes mellitus. For ≥ Grade 3 hyperglycaemia(fasting glucose > 250 mg/dL or 13.9 mmol/L), atezolizumab should be withheld. Treatment withatezolizumab may be resumed if metabolic control is achieved on insulin replacement therapy.

Immune-mediated meningoencephalitis

Meningoencephalitis has been observed in clinical trials with atezolizumab (see section 4.8). Patientsshould be monitored for clinical signs and symptoms of meningitis or encephalitis.

Treatment with atezolizumab must be permanently discontinued for any grade of meningitis orencephalitis. Treatment with intravenous corticosteroids (1 to 2 mg/kg bw/day methylprednisolone orequivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg bw/day ofprednisone or equivalent should follow.

Immune-mediated neuropathies

Myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome, which may be life threatening,and facial paresis were observed in patients receiving atezolizumab. Patients should be monitored forsymptoms of motor and sensory neuropathy.

Myelitis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should beclosely monitored for signs and symptoms that are suggestive of myelitis.

Treatment with atezolizumab must be permanently discontinued for any grade of myasthenicsyndrome/myasthenia gravis or Guillain-Barré syndrome. Initiation of systemic corticosteroids (at adose of 1 to 2 mg/kg bw/day of prednisone or equivalent) should be considered.

Treatment with atezolizumab should be withheld for Grade 1 or 2 facial paresis, and treatment withsystemic corticosteroids (1 to 2 mg/kg bw/day prednisone or equivalent) should be considered.

Treatment may be resumed only if the event fully resolves. Treatment with atezolizumab should bepermanently discontinued for Grade 3 or Grade 4 facial paresis, or any other neuropathy that does notfully resolve while withholding atezolizumab.

Treatment with atezolizumab must be permanently discontinued for Grade 2, 3 or 4 myelitis.

Immune-mediated pancreatitis

Pancreatitis, including increases in serum amylase and lipase levels, has been observed in clinicaltrials with atezolizumab (see section 4.8). Patients should be closely monitored for signs andsymptoms that are suggestive of acute pancreatitis.

Treatment with atezolizumab should be withheld for ≥ Grade 3 serum amylase or lipase levelsincreased (> 2 x ULN), or Grade 2 or 3 pancreatitis, and treatment with intravenouscorticosteroids (1 to 2 mg/kg bw/day methylprednisolone or equivalent) should be started. Oncesymptoms improve, treatment with 1 to 2 mg/kg bw/day of prednisone or equivalent should follow.

Treatment with atezolizumab may be resumed when serum amylase and lipase levels improve to≤ Grade 1 within 12 weeks, or symptoms of pancreatitis have resolved, and corticosteroids have beenreduced to ≤ 10 mg prednisone or equivalent per day. Treatment with atezolizumab should bepermanently discontinued for Grade 4, or any grade of recurrent pancreatitis.

Immune-mediated myocarditis

Cases of myocarditis, including fatal cases, have been observed with atezolizumab (see section 4.8).

Patients should be monitored for signs and symptoms of myocarditis. Myocarditis may also be aclinical manifestation of myositis and should be managed accordingly.

Patients with cardiac or cardiopulmonary symptoms should be assessed for potential myocarditis, toensure the initiation of appropriate measures at an early stage. If myocarditis is suspected, treatmentwith atezolizumab should be withheld, prompt initiation of systemic corticosteroids at a dose of 1 to2 mg/kg bw/day of prednisone or equivalent should be started, and prompt cardiology consultationwith diagnostic workup according to current clinical guidelines should be initiated. Once a diagnosisof myocarditis is established, treatment with atezolizumab must be permanently discontinued for

Grade ≥ 2 myocarditis (see section 4.2).

Immune-mediated nephritis

Nephritis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should bemonitored for changes in renal function.

Treatment with atezolizumab should be withheld for Grade 2 nephritis, and treatment with systemiccorticosteroids at a dose of 1 to 2 mg/kg bw/day of prednisone or equivalent should be started.

Treatment with atezolizumab may be resumed if the event improves to ≤ Grade 1 within 12 weeks,and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment withatezolizumab must be permanently discontinued for Grade 3 or 4 nephritis.

Immune-mediated myositis

Cases of myositis, including fatal cases, have been observed with atezolizumab (see section 4.8).

Patients should be monitored for signs and symptoms of myositis. Patients with possible myositisshould be monitored for signs of myocarditis.

If a patient develops signs and symptoms of myositis, close monitoring should be implemented, andthe patient referred to a specialist for assessment and treatment without delay. Treatment withatezolizumab should be withheld for Grade 2 or 3 myositis and corticosteroid therapy (1-2mg/kg bw/day prednisone or equivalent) should be initiated. If symptoms improve to ≤ Grade 1, tapercorticosteroids as clinically indicated. Treatment with atezolizumab may be resumed if the eventimproves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg oralprednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinuedfor Grade 4 or grade 3 recurrent myositis, or when unable to reduce the corticosteroid dose to theequivalent of ≤ 10 mg prednisone per day within 12 weeks after onset.

Immune-mediated severe cutaneous adverse reactions

Immune-mediated severe cutaneous adverse reactions (SCARs), including cases of Stevens-Johnsonsyndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receivingatezolizumab. Patients should be monitored for suspected severe skin reactions and other causesshould be excluded. For suspected SCARs, patients should be referred to a specialist for furtherdiagnosis and management.

Based on the severity of the adverse reaction, atezolizumab should be withheld for Grade 3 skinreactions and treatment with systemic corticosteroids at a dose of 1-2 mg/kg bw/day of prednisone orequivalent should be started. Treatment with atezolizumab may be resumed if the event improves to ≤

Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalentper day. Treatment with atezolizumab should be permanently discontinued for Grade 4 skin reactions,and corticosteroids should be administered.

Atezolizumab should be withheld for patients with suspected SJS or TEN. For confirmed SJS or TEN,atezolizumab should be permanently discontinued.

Caution should be used when considering the use of atezolizumab in a patient who has previouslyexperienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents.

Immune-mediated pericardial disorders

Pericardial disorders, including pericarditis, pericardial effusion and cardiac tamponade, some leadingto fatal outcomes, have been observed with atezolizumab (see section 4.8). Patients should bemonitored for clinical signs and symptoms of pericardial disorders.

For suspected Grade 1 pericarditis, treatment with atezolizumab should be withheld and promptcardiology consultation with diagnostic workup according to current clinical guidelines should beinitiated. For suspected Grade ≥ 2 pericardial disorders, treatment with atezolizumab should bewithheld, prompt treatment with systemic corticosteroids at a dose of 1 to 2 mg/kg bw/day ofprednisone or equivalent should be started and prompt cardiology consultation with diagnostic workupaccording to current clinical guidelines should be initiated. Once a diagnosis of a pericardial disorderevent is established, treatment with atezolizumab must be permanently discontinued for Grade ≥ 2pericardial disorders (see section 4.2).

Haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, has been reported in patientsreceiving atezolizumab (see section 4.8). HLH should be considered when the presentation of cytokinerelease syndrome is atypical or prolonged. Patients should be monitored for clinical signs andsymptoms of HLH. For suspected HLH, atezolizumab must be permanently discontinued and patientsshould be referred to a specialist for further diagnosis and management.

Other immune-mediated adverse reactions

Given the mechanism of action of atezolizumab, other potential immune-mediated adverse reactionsmay occur, including noninfective cystitis.

Evaluate all suspected immune-mediated adverse reactions to exclude other causes. Patients should bemonitored for signs and symptoms of immune-mediated adverse reactions and, based on the severityof the reaction, managed with treatment modifications and corticosteroids as clinically indicated (seesection 4.2 and section 4.8).

Infusion-related reactions have been observed with atezolizumab (see section 4.8).

The rate of infusion should be reduced or treatment should be interrupted in patients with Grade 1 or 2infusion-related reactions. Atezolizumab should be permanently discontinued in patients with Grade 3or 4 infusion-related reactions. Patients with Grade 1 or 2 infusion-related reactions may continue toreceive atezolizumab with close monitoring; premedication with antipyretic and antihistamines may beconsidered.

Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin in metastaticnon-squamous NSCLC

Physicians should carefully consider the combined risks of the four-drug regimen of atezolizumabbevacizumab, paclitaxel, and carboplatin before initiating treatment (see section 4.8).

Use of atezolizumab in combination with nab-paclitaxel in metastatic TNBC

Neutropenia and peripheral neuropathies occurring during treatment with atezolizumab and nab-paclitaxel may be reversible with interruptions of nab-paclitaxel. Physicians should consult the nab-paclitaxel summary of product characteristics (SmPC) for specific precautions and contraindicationsof this medicine.

Use of atezolizumab in UC for previously untreated patients who are considered cisplatin ineligible

The baseline and prognostic disease characteristics of the IMvigor210 Cohort 1 study population wereoverall comparable to patients in the clinic who would be considered cisplatin ineligible but would beeligible for a carboplatin-based combination chemotherapy. There are insufficient data for thesubgroup of patients that would be unfit for any chemotherapy; therefore, atezolizumab should be usedwith caution in these patients, after careful consideration of the potential balance of risks and benefitson an individual basis.

Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin

Patients with NSCLC that had clear tumour infiltration into the thoracic great vessels or clearcavitation of pulmonary lesions, as seen on imaging, were excluded from the pivotal clinical trial

IMpower150 after several cases of fatal pulmonary haemorrhage were observed, which is a knownrisk factor of treatment with bevacizumab.

In the absence of data, atezolizumab should be used with caution in these populations after carefulevaluation of the balance of benefits and risks for the patient.

Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin in EGFR+ patientswith NSCLC who have progressed on erlotinib+bevacizumab

In study IMpower150, there are no data on the efficacy of atezolizumab in combination withbevacizumab, paclitaxel and carboplatin in EGFR+ patients who have progressed previously onerlotinib+bevacizumab.

Use of atezolizumab in combination with bevacizumab in HCC

Data in HCC patients with Child-Pugh B liver disease treated with atezolizumab in combination withbevacizumab are very limited and there are currently no data available in HCC patients with Child-

Pugh C liver disease.

Patients treated with bevacizumab have an increased risk of haemorrhage, and cases of severegastrointestinal haemorrhage, including fatal events, were reported in patients with HCC treated withatezolizumab in combination with bevacizumab. In patients with HCC, screening for and subsequenttreatment of oesophageal varices should be performed as per clinical practice prior to startingtreatment with the combination of atezolizumab and bevacizumab. Bevacizumab should bepermanently discontinued in patients who experience Grade 3 or 4 bleeding with the combinationtreatment. Please refer to the bevacizumab Summary of Product Characteristics.

Diabetes mellitus can occur during treatment with atezolizumab in combination with bevacizumab.

Physicians should monitor blood glucose levels prior to and periodically during treatment withatezolizumab in combination with bevacizumab as clinically indicated.

Use of atezolizumab as monotherapy for first-line treatment in metastatic NSCLC

Physicians should consider the delayed onset of atezolizumab effect before initiating first-linetreatment as monotherapy in patients with NSCLC. A higher number of deaths within 2.5 months afterrandomisation followed by a long-term survival benefit was observed with atezolizumab comparedwith chemotherapy. No specific factor(s) associated with early deaths could be identified (seesection 5.1).

Patients with the following conditions were excluded from clinical trials: a history of autoimmunedisease, history of pneumonitis, active brain metastasis, ECOG PS ≥ 2 (except for patients withadvanced NSCLC ineligible for a platinum-based therapy), HIV, hepatitis B or hepatitis C infection(for non-HCC patients), significant cardiovascular disease and patients with inadequate hematologicand end-organ function. Patients who were administered a live, attenuated vaccine within 28 daysprior to enrolment; systemic immunostimulatory agents within 4 weeks or systemicimmunosuppressive medicinal products within 2 weeks prior to study entry; therapeutic oral orintravenous antibiotics within 2 weeks prior to initiation of study treatment were excluded fromclinical trials.

The prescriber must discuss the risks of Tecentriq therapy with the patient. The patient will beprovided with the patient card and instructed to carry the card at all times.

No formal pharmacokinetic interaction studies have been conducted with atezolizumab. Sinceatezolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactionsare expected.

The use of systemic corticosteroids or immunosuppressants before starting atezolizumab should beavoided because of their potential interference with the pharmacodynamic activity and efficacy ofatezolizumab. However, systemic corticosteroids or other immunosuppressants can be used to treatimmune-mediated adverse reactions after starting atezolizumab (see section 4.4).

Women of childbearing potential have to use effective contraception during and for 5 months aftertreatment with atezolizumab.

There are no data from the use of atezolizumab in pregnant women. No developmental andreproductive studies were conducted with atezolizumab. Animal studies have demonstrated thatinhibition of the PD-L1/PD-1 pathway in murine pregnancy models can lead to immune-mediatedrejection of the developing foetus resulting in foetal death (see section 5.3). These results indicate apotential risk, based on its mechanism of action, that administration of atezolizumab during pregnancycould cause foetal harm, including increased rates of abortion or stillbirth.

Human immunoglobulins G1 (IgG1) are known to cross the placental barrier and atezolizumab is an

IgG1; therefore, atezolizumab has the potential to be transmitted from the mother to the developingfoetus.

Atezolizumab should not be used during pregnancy unless the clinical condition of the womanrequires treatment with atezolizumab.

It is unknown whether atezolizumab is excreted in human milk. Atezolizumab is a monoclonalantibody and is expected to be present in the first milk and at low levels afterwards. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue Tecentriq therapy taking into account the benefit of breast-feeding for the child andthe benefit of therapy for the woman.

No clinical data are available on the possible effects of atezolizumab on fertility. No reproductive anddevelopment toxicity studies have been conducted with atezolizumab; however, based on the 26-weekrepeat dose toxicity study, atezolizumab had an effect on menstrual cycles at an estimated AUCapproximately 6 times the AUC in patients receiving the recommended dose and was reversible (seesection 5.3). There were no effects on the male reproductive organs.

Tecentriq has minor influence on the ability to drive and use machines. Patients experiencing fatigueshould be advised not to drive and use machines until symptoms abate (see section 4.8).

The safety of atezolizumab as monotherapy is based on pooled data in 5 039 patients across multipletumour types. The most common adverse reactions (> 10%) were fatigue (29.3%), decreased appetite(20.1%), rash (19.7%), nausea (18.8%), cough (18.2%), diarrhoea (18.1%), pyrexia (17.9%), dyspnoea(16.6%), arthralgia (16.2%), pruritus (13.3%), asthenia (13%), back pain (12.2%), vomiting (11.7%),urinary tract infection (11%) and headache (10.2%).

The safety of atezolizumab given in combination with other medicinal products, has been evaluated in4 535 patients across multiple tumour types. The most common adverse reactions (≥ 20%) wereanaemia (36.8%), neutropenia (36.6%), nausea (35.5%), fatigue (33.1%), alopecia (28.1%), rash(27.8%), diarrhoea (27.6%), thrombocytopenia (27.1%), constipation (25.8%), decreased appetite(24.7%) and peripheral neuropathy (24.4%).

Use of atezolizumab in the adjuvant NSCLC setting

The safety profile of atezolizumab in the adjuvant setting in the non-small cell lung cancer (NSCLC)patient population (IMpower010) was generally consistent with the overall pooled monotherapy safetyprofile in the advanced setting. Nevertheless, the incidence of immune-mediated adverse reactions ofatezolizumab in IMpower010 was 51.7% compared to 38.4% in the pooled monotherapy populationwith advanced disease. No new immune-mediated adverse reactions were identified in the adjuvantsetting.

Use of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin

In the first-line NSCLC study (IMpower150), an overall higher frequency of adverse events wasobserved in the four-drug regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatincompared to atezolizumab, paclitaxel and carboplatin, including Grade 3 and 4 events (63.6%compared to 57.5%), Grade 5 events (6.1% compared to 2.5%), adverse events of special interest toatezolizumab (52.4% compared to 48.0%), as well as adverse events leading to withdrawal of anystudy treatment (33.8% compared to 13.3%). Nausea, diarrhoea, stomatitis, fatigue, pyrexia, mucosalinflammation, decreased appetite, weight decreased, hypertension and proteinuria were reportedhigher (≥5% difference) in patients receiving atezolizumab in combination with bevacizumab,paclitaxel and carboplatin. Other clinically significant adverse events which were observed morefrequently in the atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were epistaxis,haemoptysis, cerebrovascular accident, including fatal events.

Further details on serious adverse reactions are provided in section 4.4.

The adverse reactions (ARs) are listed by MedDRA system organ class (SOC) and categories offrequency in Table 3 for atezolizumab given as monotherapy or as combination therapy. Adversereactions known to occur with atezolizumab or chemotherapies given alone may occur duringtreatment with these medicinal products in combination, even if these reactions were not reported inclinical trials with combination therapy. The following categories of frequency have been used: verycommon (≥ 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 estimated from the available data). Withineach frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Summary of adverse reactions occurring in patients treated with atezolizumab

Atezolizumab monotherapy Atezolizumab in combination therapy

Very common urinary tract infectiona lung infectionb

Common sepsisaj

Very common anaemia, thrombocytopeniad,neutropeniae, leukopeniaf

Common thrombocytopeniad lymphopeniag

Rare haemophagocytic lymphohistiocytosis haemophagocytic lymphohistiocytosis

Common infusion-related reactionh infusion-related reactionh

Very common hypothyroidismi

Common hypothyroidismi, hyperthyroidismj hyperthyroidismj

Uncommon diabetes mellitusk, adrenal hypophysitisminsufficiencyl, hypophysitism

Very common decreased appetite decreased appetite

Common hypokalaemiaae, hyponatraemiaaf, hypokalaemiaae, hyponatraemiaaf,hyperglycaemia hypomagnesaemian

Very common headache peripheral neuropathyo, headache

Common peripheral neuropathyo syncope, dizziness

Atezolizumab monotherapy Atezolizumab in combination therapy

Uncommon Guillain-Barré syndromep,meningoencephalitisq

Rare myasthenic syndromer, facial paresis, facial paresismyelitis

Rare uveitis

Common pericardial disordersao

Uncommon pericardial disordersao

Rare myocarditiss

Very common hypertensionai

Common hypotension

Respiratory, thoracic, and mediastinal disorders

Very common dyspnoea, cough dyspnoea, cough, nasopharyngitisam

Common pneumonitist, hypoxiaag, dysphonianasopharyngitisam

Very common nausea, vomiting, diarrhoeau nausea, vomiting, diarrhoeau,constipation

Common colitisv, abdominal pain, dysphagia, stomatitis, dysgeusia, colitisvoropharyngeal painw, dry mouth

Uncommon pancreatitisx

Rare Coeliac disease Coeliac disease

Common AST increased, ALT increased, AST increased, ALT increasedhepatitisy

Very common rashz, pruritus rashz, pruritus, alopeciaah

Common dry skinap

Uncommon severe cutaneous adverse reactionsak, severe cutaneous adverse reactionsak,psoriasisan, lichen disordersaq psoriasisan

Rare pemphigoid pemphigoid, lichen disordersaq

Very common arthralgia, back pain arthralgia, musculoskeletal painaa, backpain

Common musculoskeletal painaa

Uncommon myositisab

Atezolizumab monotherapy Atezolizumab in combination therapy

Common blood creatinine increasedc proteinuriaac, blood creatinine increasedc

Uncommon nephritisad

Not known cystitis noninfectiveal

Very common pyrexia, fatigue, asthenia pyrexia, fatigue, asthenia, oedemaperipheral

Common influenza like illness, chills

Common blood alkaline phosphatase increased

Uncommon blood creatine phosphokinaseincreaseda Includes reports of urinary tract infection, cystitis, pyelonephritis, escherichia urinary tract infection,urinary tract infection bacterial, kidney infection, pyelonephritis acute, pyelonephritis chronic, pyelitis,renal abscess, streptococcal urinary tract infection, urethritis, urinary tract infection fungal, urinarytract infection pseudomonal.b Includes reports of pneumonia, bronchitis, lower respiratory tract infection, infectious pleuraleffusion, tracheobronchitis, atypical pneumonia, lung abscess, infective exacerbation of chronicobstructive airways disease, paracancerous pneumonia, pyopneumothorax, pleural infection, postprocedural pneumonia.c Includes reports of blood creatinine increased, hypercreatininaemia.d Includes reports of immune thrombocytopenia, thrombocytopenia, platelet count decreased.e Includes reports of neutropenia, neutrophil count decreased, febrile neutropenia, neutropenic sepsis,granulocytopenia.f Includes reports of white blood cell count decreased, leukopenia.g Includes reports of lymphopenia, lymphocyte count decreased.h Includes reports of infusion-related reaction, cytokine release syndrome, hypersensitivity,anaphylaxis.i Includes reports of anti-thyroid antibody positive, autoimmune hypothyroidism, autoimmunethyroiditis, blood thyroid stimulating hormone decreased, blood thyroid stimulating hormoneincreased, euthyroid sick syndrome, goitre, hypothyroidism, immune-mediated hypothyroidism,immune-mediated thyroiditis, myxoedema, primary hypothyroidism, thyroid disorder, thyroidhormones decreased, thyroid function test abnormal, thyroiditis, thyroiditis acute, thyroxine decreased,thyroxine free decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine decreased,tri-iodothyronine increased, tri-iodothyronine free abnormal, tri-iodothyronine free decreased, tri-iodothyronine free increased, silent thyroiditis.j Includes reports of hyperthyroidism, Basedow’s disease, endocrine ophthalmopathy, exophthalmos.k Includes reports of diabetes mellitus, type 1 diabetes mellitus, diabetic ketoacidosis, ketoacidosis.l Includes reports of adrenal insufficiency, blood corticotropin decreased, glucocorticoid deficiency,primary adrenal insufficiency, secondary adrenocortical insufficiency.m Includes reports of hypophysitis, hypopituitarism, secondary adrenocortical insufficiency,temperature regulation disorder.n Includes reports of hypomagnesaemia, blood magnesium decreased.o Includes reports of neuropathy peripheral, autoimmune neuropathy, peripheral sensory neuropathy,polyneuropathy, herpes zoster, peripheral motor neuropathy, neuralgic amyotrophy, peripheralsensorimotor neuropathy, toxic neuropathy, axonal neuropathy, lumbosacral plexopathy, neuropathicarthropathy, peripheral nerve infection, neuritis, immune-mediated neuropathy.p Includes reports of Guillain-Barré syndrome, ascending flaccid paralysis, demyelinatingpolyneuropathy.

q Includes reports of encephalitis, encephalitis autoimmune, meningitis, meningitis aseptic,photophobia.r Includes reports of myasthenia gravis.s Includes reports of myocarditis, autoimmune myocarditis, and immune-mediated myocarditis.t Includes reports of pneumonitis, lung infiltration, bronchiolitis, immune-mediated lung disease,immune-mediated pneumonitis, interstitial lung disease, alveolitis, lung opacity, pulmonary fibrosis,pulmonary toxicity, radiation pneumonitis.u Includes reports of diarrhoea, defaecation urgency, frequent bowel movements, gastrointestinalhypermotility.v Includes reports of colitis, autoimmune colitis, colitis ischaemic, colitis microscopic, colitisulcerative, diversion colitis, eosinophilic colitis, immune-mediated enterocolitis.w Includes reports of oropharyngeal pain, oropharyngeal discomfort, throat irritation.x Includes reports of autoimmune pancreatitis, pancreatitis, pancreatitis acute, lipase increased,amylase increased.y Includes reports of ascites, autoimmune hepatitis, hepatic cytolysis, hepatitis, hepatitis acute,hepatitis toxic, hepatotoxicity, immune-mediated hepatitis, liver disorder, drug-induced liver injury,hepatic failure, hepatic steatosis, hepatic lesion, liver injury, oesophageal varices haemorrhage, varicesoesophageal, spontaneous bacterial peritonitis.z Includes reports of acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, drug eruption,eczema, eczema infected, erythema, erythema of eyelid, eyelid rash, fixed eruption, folliculitis,furuncle, hand dermatitis, immune-mediated dermatitis, lip blister, oral blood blister, palmar-plantarerythrodysaesthesia syndrome, pemphigoid, rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash papulosquamous, rash pruritic, rash pustular, rashvesicular, scrotal dermatitis, seborrhoeic dermatitis, skin exfoliation, skin toxicity, skin ulcer, vascularaccess site rash.aa Includes reports of musculoskeletal pain, myalgia, bone pain.ab Includes reports of myositis, rhabdomyolysis, polymyalgia rheumatica, dermatomyositis, muscleabscess, myoglobin urine present, myopathy, polymyositis.ac Includes reports of proteinuria, protein urine present, haemoglobinurea, urine abnormality, nephroticsyndrome, albuminuria.ad Includes reports of nephritis, autoimmune nephritis, Henoch-Schonlein purpura nephritis,paraneoplastic glomerulonephritis, tubulointerstitial nephritis.ae Includes reports of hypokalaemia, blood potassium decreased.af Includes reports of hyponatraemia, blood sodium decreased.ag Includes reports of hypoxia, oxygen saturation decreased, pO2 decreased.ah Includes reports of alopecia, madarosis, alopecia areata, alopecia totalis, hypotrichosis.ai Includes reports of hypertension, blood pressure increased, hypertensive crisis, blood pressuresystolic increased, diastolic hypertension, blood pressure inadequately controlled, retinopathyhypertensive, hypertensive nephropathy, essential hypertension, orthostatic hypertension.aj Includes reports of sepsis, septic shock, urosepsis, neutropenic sepsis, pulmonary sepsis, bacterialsepsis, klebsiella sepsis, abdominal sepsis, candida sepsis, escherichia sepsis, pseudomonal sepsis,staphylococcal sepsis.ak Includes reports of dermatitis bullous, exfoliative rash, erythema multiforme, dermatitis exfoliative,dermatitis exfoliative generalised, toxic skin eruption, Stevens-Johnson syndrome, drug reaction witheosinophilia and systemic symptoms, toxic epidermal necrolysis, cutaneous vasculitis.al Includes reports of cystitis noninfective and immune-mediated cystitis.am Includes reports of nasopharyngitis, nasal congestion and rhinorrhoea.an Includes reports of psoriasis, dermatitis psoriasiform.ao Includes reports of pericarditis, pericardial effusion, cardiac tamponade and pericarditis constrictive.ap Includes reports of dry skin, xerosis.aq Includes reports of lichenoid keratosis, lichen sclerosus and lichen planus.

The data below reflect information for significant adverse reactions for atezolizumab as monotherapyin clinical trials (see section 5.1). Details for the significant adverse reactions for atezolizumab whengiven in combination are presented if clinically relevant differences were noted in comparison toatezolizumab monotherapy. The management guidelines for these adverse reactions are described insections 4.2 and 4.4.

Immune-mediated pneumonitis

Pneumonitis occurred in 3.0% (151/5 039) of patients who received atezolizumab monotherapy. Ofthese patients, three experienced fatal events. The median time to onset was 3.7 months (range: 3 daysto 29.8 months). The median duration was 1.7 months (range: 0 days to 27.8+ months; + denotes acensored value). Pneumonitis led to discontinuation of atezolizumab in 41 (0.8%) patients.

Pneumonitis requiring the use of corticosteroids occurred in 1.8% (92/5 039) of patients receivingatezolizumab monotherapy.

Immune-mediated hepatitis

Hepatitis occurred in 1.7% (88/5 039) of patients who received atezolizumab monotherapy. Of the88 patients, three experienced fatal events. The median time to onset was 1.4 months (range: 0 days to26.3 months). The median duration was 1 month (range: 0 day to 52.1+ months; + denotes a censoredvalue). Hepatitis led to discontinuation of atezolizumab in 46 (0.9%) patients. Hepatitis requiring theuse of corticosteroids occurred in 2.6% (130/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated colitis

Colitis occurred in 1.2% (62/5 039) of patients who received atezolizumab monotherapy. The mediantime to onset was 4.5 months (range: 15 days to 36.4 months). The median duration was 1.4 months(range: 3 days to 50.2+ months; + denotes a censored value). Colitis led to discontinuation ofatezolizumab in 24 (0.5%) patients. Colitis requiring the use of corticosteroids occurred in 0.6%(30/5 039) of patients receiving atezolizumab monotherapy.

Immune-mediated endocrinopathies

Thyroid disorders

Hypothyroidism occurred in 8.5% (427/5 039) of patients who received atezolizumab monotherapy.

The median time to onset was 4.2 months (range: 0 days to 38.5 months). Hypothyroidism occurred in17.4% (86/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting.

The median time to onset was 4.0 months (range: 22 days to 11.8 months).

Hyperthyroidism occurred in 2.4% (121/5 039) of patients who received atezolizumab monotherapy.

The median time to onset was 2.7 months (range: 0 days to 24.3 months). Hyperthyroidism occurredin 6.5% (32/495) of patients who received atezolizumab monotherapy in the adjuvant NSCLC setting.

The median time to onset was 2.8 months (range: 1 day to 9.9 months).

Adrenal insufficiency occurred in 0.5% (25/5 039) of patients who received atezolizumabmonotherapy. The median time to onset was 6.2 months (range: 3 days to 21.4 months). Adrenalinsufficiency led to discontinuation of atezolizumab in 5 (0.1%) patients. Adrenal insufficiencyrequiring the use of corticosteroids occurred in 0.4% (20/5 039) of patients receiving atezolizumabmonotherapy.

Hypophysitis

Hypophysitis occurred in 0.2% (9/5 039) of patients who received atezolizumab monotherapy. Themedian time to onset was 5.3 months (range: 21 days to 13.7 months). Six (0.1%) patients required theuse of corticosteroids and treatment with atezolizumab was discontinued in 1 (< 0.1%) patient.

Hypophysitis occurred in 1.4% (15/1 093) of patients who received atezolizumab in combination withpaclitaxel followed by atezolizumab, dose-dense doxorubicin or epirubicin, and cyclophosphamide.

The median time to onset was 3.8 months (range: 2.4 to 10.7 months). Eleven patients (1.0%) requiredthe use of corticosteroids. Treatment with atezolizumab was discontinued in 7 (0.6%) patients.

Hypophysitis occurred in 0.8% (3/393) of patients who received atezolizumab with bevacizumab,paclitaxel, and carboplatin. The median time to onset was 7.7 months (range: 5.0 to 8.8 months). Twopatients required the use of corticosteroids.

Hypophysitis occurred in 0.4% (2/473) of patients who received atezolizumab in combination withnab-paclitaxel and carboplatin. The median time to onset was 5.2 months (range: 5.1 to 5.3 months).

Both patients required the use of corticosteroids.

Diabetes mellitus

Diabetes mellitus occurred in 0.6% (30/5 039) of patients who received atezolizumab monotherapy.

The median time to onset was 5.5 months (range: 3 days to 29.0 months). Diabetes mellitus led to thediscontinuation of atezolizumab in < 0.1% (3/5 039) patients. Four (< 0.1%) patients required the useof corticosteroids.

Diabetes mellitus occurred in 2.0% (10/493) of HCC patients who received atezolizumab incombination with bevacizumab. The median time to onset was 4.4 months (range: 1.2 months -8.3 months). No events of diabetes mellitus led to atezolizumab withdrawal.

Immune-mediated meningoencephalitis

Meningoencephalitis occurred in 0.4% (22/5 039) of patients who received atezolizumabmonotherapy. The median time to onset was 15 days (range: 0 days to 12.5 months). The medianduration was 24 days (range: 6 days to 14.5+ months; + denotes a censored value).

Meningoencephalitis requiring the use of corticosteroids occurred in 0.2% (12/5 039) of patientsreceiving atezolizumab and eight patients (0.2%) discontinued atezolizumab.

Immune-mediated neuropathies

Guillain-Barré syndrome and demyelinating polyneuropathy

Guillain-Barré syndrome and demyelinating polyneuropathy occurred in 0.1% (6/5 039) of patientswho received atezolizumab monotherapy. The median time to onset was 4.1 months (range: 18 days to8.1 months). The median duration was 8.0 months (range: 18 days to 24.5+ months; + denotes acensored value). Guillain-Barré syndrome led to discontinuation of atezolizumab in 1 patient (< 0.1%).

Guillain-Barré syndrome requiring the use of corticosteroids occurred in < 0.1% (3/5 039) of patientsreceiving atezolizumab monotherapy.

Immune-mediated facial paresis

Facial paresis occurred in < 0.1% (1/5 039) of patients who received atezolizumab monotherapy. Thetime to onset was 29 days. The duration was 1.1 months. The event did not require the use ofcorticosteroids and the event did not lead to discontinuation of atezolizumab.

Immune-mediated myelitis

Myelitis occurred in < 0.1% (1/5 039) of patients who received atezolizumab monotherapy. The timeto onset was 3 days. The event required the use of corticosteroids but did not lead to discontinuation ofatezolizumab.

Myasthenic syndrome

Myasthenia gravis occurred in < 0.1% (2/5 039) of patients (including 1 fatal case) who receivedatezolizumab monotherapy. The median time to onset was 2.6 months (range: 1.2 months to4 months).

Immune-mediated pancreatitis

Pancreatitis, including amylase increased and lipase increased, occurred in 0.8% (40/5 039) of patientswho received atezolizumab monotherapy. The median time to onset was 5 months (range: 0 days to24.8 months). The median duration was 24 days (range: 3 days to 40.4+ months; + denotes a censoredvalue). Pancreatitis led to the discontinuation of atezolizumab in 3 (< 0.1%) patients. Pancreatitisrequiring the use of corticosteroids occurred in 0.2% (8/5 039) of patients receiving atezolizumabmonotherapy.

Immune-mediated myocarditis

Myocarditis occurred in < 0.1% (5/5 039) of patients who received atezolizumab monotherapy. Of the5 patients, one experienced a fatal event in the adjuvant NSCLC setting. The median time to onset was3.7 months (range: 1.5 to 4.9 months). The median duration was 14 days (range: 12 days to2.8 months). Myocarditis led to the discontinuation of atezolizumab in 3 (< 0.1%) patients. Three(<0.1%) patients required the use of corticosteroids.

Immune-mediated nephritis

Nephritis occurred in 0.2% (11/5 039) of patients who received atezolizumab. The median time toonset was 5.1 months (range: 3 days to 17.5 months). Nephritis led to discontinuation of atezolizumabin 5 (≤ 0.1%) patients. Five (0.1%) patients required the use of corticosteroids.

Immune-mediated myositis

Myositis occurred in 0.6% (32/5 039) of patients who received atezolizumab monotherapy. Themedian time to onset was 3.5 months (range: 12 days to 11.5 months). The median duration was3.2 months (range: 9 days to 51.1+ months; + denotes a censored value). Myositis led todiscontinuation of atezolizumab in 6 (0.1%) patients. Ten (0.2%) patients required the use ofcorticosteroids.

Immune-mediated severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) occurred in 0.6% (30/5 039) of patients who receivedatezolizumab monotherapy. Of the 30 patients, one experienced a fatal event. The median time toonset was 4.8 months (range: 3 days to 15.5 months). The median duration was 2.4 months (range:1 day to 37.5+ months; + denotes a censored value). SCARs led to discontinuation of atezolizumab in3 (< 0.1%) patients. SCARs requiring the use of systemic corticosteroids occurred in 0.2% (9/5 039)of patients receiving atezolizumab monotherapy.

Immune-mediated pericardial disorders

Pericardial disorders occurred in 1% (49/5 039) of patients who received atezolizumab monotherapy.

The median time to onset was 1.4 months (range: 6 days to 17.5 months). The median duration was2.5 months (range: 0 to 51.5+ months; + denotes a censored value). Pericardial disorders led todiscontinuation of Tecentriq in 3 (< 0.1%) patients. Pericardial disorders requiring the use ofcorticosteroids occurred in 0.2% (7/5 039) of patients.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reaction(s) reported during treatment with otherimmune checkpoint inhibitors which might also occur during treatment with atezolizumab:pancreatic exocrine insufficiency.

Across multiple phase II and III studies, 13.1% to 54.1% of patients developed treatment-emergentanti-drug antibodies (ADAs). Patients who developed treatment-emergent ADAs tended to haveoverall poorer health and disease characteristics at baseline. Those imbalances in health and diseasecharacteristics at baseline can confound the interpretation of pharmacokinetic (PK), efficacy and safetyanalyses. Exploratory analyses adjusting for imbalances in baseline health and disease characteristicswere conducted to assess the effect of ADA on efficacy. These analyses did not exclude possibleattenuation of efficacy benefit in patients who developed ADA compared to patients who did notdevelop ADA. The median time to ADA onset ranged from 3 weeks to 5 weeks.

Across pooled datasets for patients treated with atezolizumab monotherapy (N=3 460) and withcombination therapies (N= 2 285), the following rates of adverse events (AEs) have been observed forthe ADA-positive population compared to the ADA-negative population, respectively: Grade 3-4 AEs46.2% vs. 39.4%, Serious Adverse Events (SAEs) 39.6% vs. 33.3%, AEs leading to treatmentwithdrawal 8.5% vs 7.8% (for monotherapy); Grade 3-4 AEs 63.9% vs. 60.9%, SAEs 43.9% vs.35.6%, AEs leading to treatment withdrawal 22.8% vs 18.4% (for combination therapy). However,available data do not allow firm conclusions to be drawn on possible patterns of adverse reactions.

The safety of atezolizumab in children and adolescents has not been established. No new safety signalswere observed in a clinical trial with 69 paediatric patients (< 18 years) and the safety profile wascomparable to adults.

No overall differences in safety were observed between patients < 65, 65-74, and 75-84 years of agereceiving atezolizumab monotherapy. The data for patients ≥ 85 years of age are too limited to drawmeaningful conclusions about this population.

In study IMpower150, age ≥ 65 was associated with an increased risk of developing adverse events inpatients receiving atezolizumab in combination with bevacizumab, carboplatin and paclitaxel. Instudies IMpower150, IMpower133 and IMpower110, data for patients ≥ 75 years of age were toolimited to draw conclusions. In the IPSOS study in 1L platinum-ineligible NSCLC patients, there wereno overall differences in the safety profile for 1L atezolizumab monotherapy between the patient agesubgroups.

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 information on overdose with atezolizumab.

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

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drugconjugates, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code:

L01FF05.

Programmed death-ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltratingimmune cells, and can contribute to the inhibition of the antitumour immune response in the tumourmicroenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigenpresenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.

Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody thatdirectly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing

PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumourimmune response without inducing antibody-dependent cellular cytotoxicity. Atezolizumab spares the

PD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.

IMvigor211 (GO29294): Randomised trial in locally advanced or metastatic UC patients previouslytreated with chemotherapy

A phase III, open-label, multi-centre, international, randomised study, (IMvigor211), was conducted toevaluate the efficacy and safety of atezolizumab compared with chemotherapy (investigator’s choiceof vinflunine, docetaxel, or paclitaxel) in patients with locally advanced or metastatic UC whoprogressed during or following a platinum-containing regimen. This study excluded patients who hada history of autoimmune disease; active or corticosteroid-dependent brain metastases; administrationof a live, attenuated vaccine within 28 days prior to enrolment; and administration of systemicimmunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal product within2 weeks prior to enrolment. Tumour assessments were conducted every 9 weeks for the first 54 weeks,and every 12 weeks thereafter. Tumour specimens were evaluated prospectively for PD-L1 expressionon tumour-infiltrating immune cells (IC) and the results were used to define the PD-L1 expressionsubgroups for the analyses described below.

A total of 931 patients were enrolled. Patients were randomised (1:1) to receive either atezolizumab orchemotherapy. Randomisation was stratified by chemotherapy (vinflunine vs. taxane), PD-L1expression status on IC (< 5% vs. ≥ 5%), number of prognostic risk factors (0 vs. 1-3), and livermetastases (yes vs. no). Prognostic risk factors included time from prior chemotherapy of < 3 months,

ECOG performance status > 0 and haemoglobin < 10 g/dL.

Atezolizumab was administered as a fixed dose of 1 200 mg by intravenous infusion every 3 weeks.

No dose reduction of atezolizumab was allowed. Patients were treated until loss of clinical benefit asassessed by the investigator or unacceptable toxicity. Vinflunine was administered 320 mg/m2 byintravenous infusion on day 1 of each 3-week cycle until disease progression or unacceptable toxicity.

Paclitaxel was administered 175 mg/m2 by intravenous infusion over 3 hours on day 1 of each 3-weekcycle until disease progression or unacceptable toxicity. Docetaxel was administered 75 mg/m2 byintravenous infusion on day 1 of each 3-week cycle until disease progression or unacceptable toxicity.

For all treated patients, the median duration of treatment was 2.8 months for the atezolizumab arm,2.1 months for the vinflunine and paclitaxel arms and 1.6 months for the docetaxel arm.

The demographic and baseline disease characteristics of the primary analysis population were wellbalanced between the treatment arms. The median age was 67 years (range: 31 to 88), and 77.1% ofpatients were male. The majority of patients were white (72.1%), 53.9% of patients within thechemotherapy arm received vinflunine, 71.4% of patients had at least one poor prognostic risk factorand 28.8% had liver metastases at baseline. Baseline ECOG performance status was 0 (45.6%) or 1(54.4%). Bladder was the primary tumour site for 71.1% of patients and 25.4% of patients had uppertract UC. There were 24.2% of patients who received only prior platinum-containing adjuvant orneoadjuvant therapy and progressed within 12 months.

The primary efficacy endpoint for IMvigor211 is overall survival (OS). Secondary efficacy endpointsevaluated per investigator-assessed Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 areobjective response rate (ORR), progression-free survival (PFS), and duration of response (DOR).

Comparisons with respect to OS between the treatment arm and control arm within the IC2/3, IC1/2/3,and ITT (Intention-to-treat, i.e. all comers) populations were tested using a hierarchical fixed-sequenceprocedure based on a stratified log-rank test at two-sided level of 5% as follows: step 1) IC2/3population; step 2) IC1/2/3 population; step 3) all comers population. OS results for each of steps 2and 3 could be formally tested for statistical significance only if the result in the preceding step wasstatistically significant.

The median survival follow-up is 17 months. The primary analysis of study IMvigor211 did not meetits primary endpoint of OS. Atezolizumab did not demonstrate a statistically significant survivalbenefit compared to chemotherapy in patients with previously treated, locally advanced or metastatic

UC. Per the pre-specified hierarchical testing order, the IC2/3 population was tested first, with an OS

HR of 0.87 (95% CI: 0.63, 1.21; median OS of 11.1 vs. 10.6 months for atezolizumab andchemotherapy respectively). The stratified log-rank p-value was 0.41 and therefore the results areconsidered not statistically significant in this population. As a consequence, no formal tests ofstatistical significance could be performed for OS in the IC1/2/3 or all comer populations, and resultsof those analyses would be considered exploratory. The key results in the all comer population aresummarised in Table 4. The Kaplan-Meier curve for OS in the all comer population is presented in

Figure 1.

An exploratory updated survival analysis was performed with a median duration of survival follow upof 34 months in the ITT population. The median OS was 8.6 months (95% CI: 7.8, 9.6) in theatezolizumab arm and 8.0 months (95% CI: 7.2, 8.6) in the chemotherapy arm with a hazard ratio of0.82 (95% CI: 0.71, 0.94). Consistent with the trend observed at primary analysis for 12-month OSrates, numerically higher 24-month and 30-month OS rates were observed for patients in theatezolizumab arm compared with the chemotherapy arm in the ITT population. The percentage ofpatients alive at 24 months (KM estimate) was 12.7% in the chemotherapy arm and 22.5% in theatezolizumab arm; and at 30 months (KM estimate) was 9.8% in the chemotherapy arm and 18.1% inthe atezolizumab arm.

Table 4: Summary of efficacy in all comers (IMvigor211)

Atezolizumab Chemotherapy

Efficacy endpoint(n = 467) (n = 464)

Primary efficacy endpoint

OS*

No. of deaths (%) 324 (69.4%) 350 (75.4%)

Median time to events (months) 8.6 8.095% CI 7.8, 9.6 7.2, 8.6

Stratifiedǂ hazard ratio (95% CI) 0.85 (0.73, 0.99)12-month OS (%)** 39.2% 32.4%

Secondary and exploratory endpoints

Investigator-assessed PFS (RECIST v1.1)

No. of events (%) 407 (87.2%) 410 (88.4%)

Median duration of PFS (months) 2.1 4.095% CI 2.1, 2.2 3.4, 4.2

Stratified hazard ratio (95% CI) 1.10 (0.95, 1.26)

Investigator-assessed ORR (RECIST n = 462 n = 461v1.1)

No. of confirmed responders (%) 62 (13.4%) 62 (13.4%)95% CI 10.45, 16.87 10.47, 16.91

No. of complete response (%) 16 (3.5%) 16 (3.5%)

No. of partial response (%) 46 (10.0%) 46 (10.0%)

No. of stable disease (%) 92 (19.9%) 162 (35.1%)

Investigator-assessed DOR (RECIST n = 62 n = 62v1.1)

Median in months *** 21.7 7.495% CI 13.0, 21.7 6.1, 10.3

CI = confidence interval; DOR = duration of response; ORR = objective response rate; OS = overallsurvival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumoursv1.1.

* An analysis of OS in the all comer population was performed based on the stratified log-rank testand the result is provided for descriptive purposes only (p = 0.0378); according to the pre-specifiedanalysis hierarchy, the p-value for the OS analysis in the all comer population cannot be consideredstatistically significant.ǂ Stratified by chemotherapy (vinflunine vs. taxane), status on IC (< 5% vs. ≥ 5%), number ofprognostic risk factors (0 vs. 1-3), and liver metastases (yes vs. no).

** Based on Kaplan-Meier estimate

*** Responses were ongoing in 63% of responders in the atezolizumab arm and in 21% of respondersin the chemotherapy arm.

Figure 1: Kaplan-Meier curve for overall survival (IMvigor211)

IMvigor210 (GO29293): Single-arm trial in previously untreated urothelial carcinoma patients whoare ineligible for cisplatin therapy and in urothelial carcinoma patients previously treated withchemotherapy

A phase II, multi-centre, international, two-cohort, single-arm clinical trial, IMvigor210, wasconducted in patients with locally advanced or metastatic UC (also known as urothelial bladdercancer).

The study enrolled a total of 438 patients and had two patient cohorts. Cohort 1 included previouslyuntreated patients with locally advanced or metastatic UC who were ineligible or unfit forcisplatin-based chemotherapy or had disease progression at least 12 months after treatment with aplatinum-containing neoadjuvant or adjuvant chemotherapy regimen. Cohort 2 included patients whoreceived at least one platinum-based chemotherapy regimen for locally advanced or metastatic UC orhad disease progression within 12 months of treatment with a platinum-containing neoadjuvant oradjuvant chemotherapy regimen.

In Cohort 1, 119 patients were treated with atezolizumab 1 200 mg by intravenous infusion every3 weeks until disease progression. The median age was 73 years. Most patients were male (81%), andthe majority of patients were White (91%).

Cohort 1 included 45 patients (38%) with ECOG performance status of 0, 50 patients (42%) with

ECOG performance status of 1 and 24 patients (20%) with ECOG performance status of 2, 35 patients(29%) with no Bajorin risk factors (ECOG performance status ≥ 2 and visceral metastasis), 66 patients(56%) with one Bajorin risk factor and 18 patients (15 %) with two Bajorin risk factors, 84 patients(71%) with impaired renal function (glomerular filtration rate [GFR] < 60 mL/min), and 25 patients(21%) with liver metastasis.

The primary efficacy endpoint for Cohort 1 was confirmed objective response rate (ORR) as assessedby an independent review facility (IRF) using RECIST v1.1.

The primary analysis was performed when all patients had at least 24 weeks of follow-up. Medianduration of treatment was 15.0 weeks and median duration of survival follow-up was 8.5 months in allcomers. Clinically relevant IRF-assessed ORRs per RECIST v1.1 were shown; however, whencompared to a pre-specified historical control response rate of 10%, statistical significance was notreached for the primary endpoint. The confirmed ORRs per IRF-RECIST v1.1 were 21.9% (95% CI:

9.3, 40.0) in patients with PD-L1 expression ≥ 5%, 18.8% (95% CI: 10.9, 29.0) in patients with PD-L1expression ≥ 1%, and 19.3% (95% CI: 12.7, 27.6) in all comers. The median duration of response(DOR) was not reached in any PD-L1 expression subgroup or in all comers. OS was not mature withan event patient ratio of approximately 40%. Median OS for all patient subgroups (PD-L1 expression≥ 5 % and ≥ 1 %) and in all comers was 10.6 months.

An updated analysis was performed with a median duration of survival follow-up of 17.2 months for

Cohort 1 and is summarised in Table 5. The median DOR was not reached in any PD-L1 expressionsubgroup or in all comers.

Table 5: Summary of updated efficacy (IMvigor210 Cohort 1)

PD-L1 PD-L1

Efficacy endpoint expression of expression of All Comers≥ 5% in IC ≥ 1% in IC

ORR (IRF-assessed; RECIST v1.1) n = 32 n = 80 n = 119

No. of Responders (%) 9 (28.1%) 19 (23.8%) 27 (22.7%)95% CI 13.8, 46.8 15.0, 34.6 15.5, 31.3

No. of complete response (%) 4 (12.5%) 8 (10.0%) 11 (9.2%)95% CI (3.5, 29.0) (4.4, 18.8) (4.7, 15.9)

No. of partial response (%) 5 (15.6%) 11 (13.8%) 16 (13.4%)95% CI (5.3, 32.8) (7.1, 23.3) (7.9, 20.9)

DOR (IRF-assessed; RECIST v1.1) n = 9 n = 19 n = 27

Patients with event (%) 3 (33.3%) 5 (26.3%) 8 (29.6%)

Median (months) (95% CI) NE (11.1, NE) NE (NE) NE (14.1, NE)

PFS (IRF-assessed; RECIST v1.1) n = 32 n = 80 n = 119

Patients with event (%) 24 (75.0%) 59 (73.8%) 88 (73.9%)

Median (months) (95% CI) 4.1 (2.3, 11.8) 2.9 (2.1, 5.4) 2.7 (2.1, 4.2)

OS n = 32 n = 80 n = 119

Patients with event (%) 18 (56.3%) 42 (52.5%) 59 (49.6%)

Median (months) (95% CI) 12.3 (6.0, NE) 14.1 (9.2, NE) 15.9 (10.4, NE)1-year OS rate (%) 52.4% 54.8% 57.2%

CI = confidence interval; DOR=duration of response; IC = tumour-infiltrating immune cells;

IRF = independent review facility; NE = not estimable; ORR = objective response rate; OS = overallsurvival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumoursv1.1.

At the time of the final analysis for Cohort 1, patients had a median survival follow-up time of 96.4months. Median OS was 12.3 months (95% CI: 6.0, 49.8) in patients with PD-L1 expression ≥ 5%(patients who are included in the therapeutic indication).

In Cohort 2, the co-primary efficacy endpoints were confirmed ORR as assessed by an IRF using

RECIST v1.1 and investigator-assessed ORR according to Modified RECIST (mRECIST) criteria.

There were 310 patients treated with atezolizumab 1 200 mg by intravenous infusion every 3 weeksuntil loss of clinical benefit. The primary analysis of Cohort 2 was performed when all patients had atleast 24 weeks of follow-up. The study met its co-primary endpoints in Cohort 2, demonstratingstatistically significant ORRs per IRF-assessed RECIST v1.1 and investigator-assessed mRECISTcompared to a pre-specified historical control response rate of 10%.

An analysis was also performed with a median duration of survival follow-up of 21.1 months for

Cohort 2. The confirmed ORRs per IRF-RECIST v1.1 were 28.0% (95% CI: 19.5, 37.9) in patientswith PD-L1 expression ≥ 5%, 19.3% (95% CI: 14.2, 25.4) in patients with PD-L1 expression ≥ 1%,and 15.8% (95% CI: 11.9, 20.4) in all comers. The confirmed ORR per investigator-assessedmRECIST was 29.0% (95% CI: 20.4, 38.9) in patients with PD-L1 expression ≥ 5%, 23.7% (95% CI:18.1, 30.1) in patients with PD-L1 expression ≥ 1%, and 19.7% (95% CI: 15.4, 24.6) in all comers.

The rate of complete response per IRF-RECIST v1.1 in the all comer population was 6.1% (95% CI:3.7, 9.4). For Cohort 2, median DOR was not reached in any PD-L1 expression subgroup or in allcomers, however was reached in patients with PD-L1 expression < 1% (13.3 months; 95% CI 4.2,

NE). The OS rate at 12 months was 37% in all comers.

At the time of the final analysis for Cohort 2, patients had a median survival follow-up time of46.2 months. Median OS was 11.9 months (95% CI: 9.0, 22.8) in patients with PD-L1 expression≥ 5%, 9.0 months (95% CI: 7.1, 11.1) in patients with PD-L1 expression ≥ 1%, and 7.9 months (95%

CI: 6.7, 9.3) in all comers.

IMvigor130 (WO30070): Phase III study of atezolizumab monotherapy and in combination withplatinum-based chemotherapy in patients with untreated locally advanced or metastatic urothelialcarcinoma

A phase III, multi-centre, randomised, placebo-controlled, partially blinded (Arms A and C only)study, IMvigor130, was conducted to evaluate the efficacy and safety of atezolizumab + platinum-based combination chemotherapy (i.e., either cisplatin or carboplatin with gemcitabine), Arm A, oratezolizumab monotherapy (Arm B, open-label arm) versus placebo + platinum-based combinationchemotherapy (Arm C) in patients with locally advanced or metastatic UC who had not received priorsystemic therapy in the metastatic setting. The co-primary efficacy outcomes were investigator-assessed progression-free survival (PFS) in Arm A versus Arm C and overall survival (OS) in Arm Aversus C and then Arm B versus C, analyzed in a hierarchical fashion. Overall survival was notstatistically significant for the comparison of Arm A versus Arm C, and thus no further formal testingcould be conducted per the pre-defined hierarchical testing order.

Based on an independent Data Monitoring Committee (iDMC) recommendation following an earlyreview of survival data, accrual of patients on the atezolizumab monotherapy treatment arm whosetumours had a low PD-L1 expression (less than 5% of immune cells staining positive for PD-L1 byimmunohistochemistry using VENTANA PD-L1 [SP142] assay) was stopped after observingdecreased overall survival for this subgroup at an unplanned early analysis, however, this occurredafter the vast majority of patients had already been enrolled.

Out of 719 patients enrolled in the atezolizumab monotherapy (n=360) and chemotherapy alone(n=359) arms, 50 and 43 patients, respectively, were cisplatin-ineligible by Galsky criteria and hadtumours with high PD-L1 expression (≥ 5% of immune cells staining positive for PD-L1 byimmunohistochemistry using VENTANA PD-L1 [SP142] assay). In an exploratory analysis in thissubgroup of patients, the unstratified HR for OS was 0.56 (95% CI: 0.34, 0.91). The median OS was18.6 months (95% CI: 14.0, 49.4) in the atezolizumab monotherapy arm vs. 10.0 months (95% CI: 7.4,18.1) in the chemotherapy alone arm (see Figure 2).

Figure 2 Kaplan-Meier Plot of Overall Survival in Cisplatin-ineligible patients whose tumours are

PD-L1 high (Arm B vs. Arm C)

Adjuvant treatment of early-stage NSCLC

IMpower010 (GO29527): Randomised phase III trial in patients with resected NSCLC after cisplatin-based chemotherapy

A phase III, open label, multi-centre, randomised study, GO29527 (IMpower010), was conducted toevaluate the efficacy and safety of atezolizumab for the adjuvant treatment of patients with stage IB(tumours ≥ 4 cm) - IIIA NSCLC (per the Union for International Cancer Control/American Joint

Committee on Cancer staging system, 7th edition).

The following selection criteria define patients with high risk of recurrence who are included in thetherapeutic indication and are reflective of the patient population with stage II - IIIA according to the7th edition staging system:

Tumour size ≥ 5 cm; or tumours of any size that are either accompanied by N1 or N2 status; ortumours that are invasive of thoracic structures (directly invade the parietal pleura, chest wall,diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, mediastinum, heart, great vessels,trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina); or tumours that involve themain bronchus < 2 cm distal to the carina but without involvement of the carina; or tumours that areassociated with atelectasis or obstructive pneumonitis of the entire lung; or tumours with separatenodule(s) in the same lobe or different ipsilateral lobe as the primary.

The study did not include patients who had N2 status with tumours invading the mediastinum, heart,great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina, or with separatetumour nodule(s) in a different ipsilateral lobe.

A total of 1 280 enrolled patients had complete tumour resection and were eligible to receive up to4 cycles of cisplatin-based chemotherapy. The cisplatin-based chemotherapy regimens are described in

Table 6.

Table 6: Adjuvant chemotherapy regimens (IMpower010)

Adjuvant cisplatin-based Vinorelbine 30 mg/m intravenous, Days 1 and 8chemotherapy: Docetaxel 75 mg/m2 intravenous, Day 1

Cisplatin 75 mg/m2 intravenous on

Day 1 of each 21 day cycle with one Gemcitabine 1 250 mg/m2 intravenous, Days 1 and 8of the following treatment regimens Pemetrexed 500 mg/m2 intravenous, Day 1(non-squamous)

After completion of cisplatin-based chemotherapy (up to four cycles), a total of 1 005 patients wererandomised in a 1:1 ratio to receive atezolizumab (Arm A) or best supportive care (BSC) (Arm B).

Atezolizumab was administered as a fixed dose of 1 200 mg by IV infusion every 3 weeks for16 cycles unless there was disease recurrence or unacceptable toxicity. Randomisation was stratifiedby sex, stage of disease, histology, and PD-L1 expression.

Patients were excluded if they had a history of autoimmune disease; administration of a live,attenuated vaccine within 28 days prior to randomisation; administration of systemicimmunostimulatory agents within 4 weeks or systemic immunosuppressive medications within2 weeks prior to randomisation. Tumour assessments were conducted at baseline of the randomisationphase and every 4 months for the first year following Cycle 1, Day 1 and then every 6 months untilyear five, then annually thereafter.

The demographics and baseline disease characteristics in the ITT population were well balancedbetween the treatment arms. The median age was 62 years (range: 26 to 84), and 67% of patients weremale. The majority of patients were White (73%), and 24% were Asian. Most patients were current orprevious smokers (78%) and baseline ECOG performance status in patients was 0 (55%) or 1 (44%).

Overall, 12% of patients had stage IB, 47% had stage II and 41% had stage IIIA disease. Thepercentage of patients who had tumours with PD-L1 expression ≥ 1% and ≥ 50% on TC as measuredby the VENTANA PD-L1 (SP263) Assay was 55% and 26%, respectively.

The primary efficacy outcome measure was disease-free survival (DFS) as assessed by theinvestigator. DFS was defined as the time from the date of randomisation to the date of occurrence ofany of the following: first documented recurrence of disease, new primary NSCLC, or death due toany cause, whichever occurred first. The primary efficacy objective was to evaluate DFS in the PD-L1≥ 1% TC stage II - IIIA patient population. Key secondary efficacy objectives were to evaluate DFSin the PD-L1 ≥ 50% TC stage II - IIIA patient population and overall survival (OS) in the ITTpopulation.

At the time of the interim DFS analysis, the study met its primary endpoint. In the analysis of patientswith PD-L1 ≥ 50% TC stage II - IIIA without EGFR mutations or ALK rearrangements (n = 209), animprovement in DFS in the atezolizumab arm was observed compared to the BSC arm. Results wereconsistent at the time of the final DFS analysis, with median follow up time of 65 months.

The key efficacy results for DFS and OS in the PD-L1 ≥ 50% TC stage II - IIIA patient population,without EGFR mutations and ALK rearrangements, are summarised in Table 7. The Kaplan-Meiercurve for DFS is presented in Figure 3.

Table 7: Summary of efficacy in the PD-L1 expression ≥ 50% TC stage II - IIIA patientpopulation without EGFR mutations or ALK rearrangements (IMpower010)

Efficacy endpoint Arm A Arm B(Atezolizumab) (Best supportive care)

Investigator-assessed DFS* n = 106 n = 103

No. of events (%) 34 (32 .1%) 55 (53 .4%)

Median duration of DFS (months) NE 42 .99 5% CI (NE) (32.0, NE)

Stratifiedǂ hazard ratio (95% CI) 0.52 (0.33, 0.80)

OS* n=106 n=103

No. of events (%) 22 (20.8%) 41 (39.8%)

Median OS (months) NE 87.19 5% CI (NE) (72.0, NE)

Stratifiedǂ hazard ratio (95% CI) 0.47 (0.28, 0.80)

DFS = Disease-free survival; CI = confidence interval; NE = not estimable

* Updated DFS and OS analysis at clinical cut-off 26 January 2024ǂ Stratified by stage, sex, and histology.

Figure 3: Kaplan-Meier curve for disease-free survival in the PD-L1 expression ≥ 50% TCstage II - IIIA patient population without EGFR mutations or ALK rearrangements(IMpower010)

The observed DFS improvement in the atezolizumab arm compared with the BSC arm wasconsistently shown across the majority of pre-specified subgroups in the PD-L1 ≥ 50% TCstage II - IIIA patient population without EGFR mutations or ALK rearrangements, including bothnon-squamous NSCLC patients (unstratified HR of 0.40, 95% CI: 0.23, 0.70; median DFS NE vs.36.8 months) and squamous NSCLC patients (unstratified HR of 0.67, 95% CI: 0.34, 1.32; median

DFS could not be estimated).

First-line treatment of advanced NSCLC

IMpower150 (GO29436): Randomised phase III trial in chemotherapy-naïve patients with metastaticnon-squamous NSCLC, in combination with paclitaxel and carboplatin with or without bevacizumab

A phase III, open-label, multi-centre, international, randomised study, IMpower150, was conducted toevaluate the efficacy and safety of atezolizumab in combination with paclitaxel and carboplatin, withor without bevacizumab, in chemotherapy-naïve patients with metastatic non-squamous NSCLC.

Patients were excluded if they had history of autoimmune disease, administration of a live, attenuatedvaccine within 28 days prior to randomisation, administration of systemic immunostimulatory agentswithin 4 weeks or systemic immunosuppressive medicinal product within 2 weeks prior torandomisation, active or untreated CNS metastases, clear tumour infiltration into the thoracic greatvessels or clear cavitation of pulmonary lesions, as seen on imaging. Tumour assessments wereconducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeksthereafter. Tumour specimens were evaluated for PD-L1 expression on tumour cells (TC) andtumour-infiltrating immune cells (IC) and the results were used to define the PD-L1 expressionsubgroups for the analyses described below.

A total of 1 202 patients were enrolled and were randomised (1:1:1) to receive one of the treatmentregimens described in Table 8. Randomisation was stratified by sex, presence of liver metastases and

PD-L1 tumour expression on TC and IC.

Table 8: Intravenous treatment regimens (IMpower150)

Treatment Induction Maintenanceregimen (Four or Six 21-day cycles) (21-day cycles)

A Atezolizumaba (1 200 mg) + paclitaxel Atezolizumaba (1 200 mg)(200 mg/m2)b,c + carboplatinc (AUC 6)

B Atezolizumaba (1 200 mg) + bevacizumabd Atezolizumaba (1 200 mg)(15 mg/kg bw) + paclitaxel (200 mg/m2)b,c + + bevacizumabd (15carboplatinc (AUC 6) mg/kg bw)

C Bevacizumabd (15 mg/kg bw) + paclitaxel Bevacizumabd (15(200 mg/m2)b,c + carboplatinc (AUC 6) mg/kg bw)a Atezolizumab is administered until loss of clinical benefit as assessed by the investigatorb The paclitaxel starting dose for patients of Asian race/ethnicity was 175 mg/m2 due to higher overalllevel of haematologic toxicities in patients from Asian countries compared with those from non-Asiancountriesc Paclitaxel and carboplatin are administered until completion of 4 or 6 cycles, or progressive disease,or unacceptable toxicity whichever occurs first

d. Bevacizumab is administered until progressive disease or unacceptable toxicity

The demographics and baseline disease characteristics of the study population were well balancedbetween the treatment arms. The median age was 63 years (range: 31 to 90), and 60% of patients weremale. The majority of patients were white (82%). Approximately 10% of patients had known EGFRmutation, 4% had known ALK rearrangements, 14% had liver metastasis at baseline, and mostpatients were current or previous smokers (80%). Baseline ECOG performance status was 0 (43%) or1 (57%). 51% of patients’ tumours had PD-L1 expression of ≥ 1% TC or ≥ 1% IC and 49% ofpatients’ tumours had PD-L1 expression of < 1% TC and < 1% IC.

At the time of the final analysis for PFS, patients had a median follow up time of 15.3 months. The

ITT population, including patients with EGFR mutations or ALK rearrangements who should havebeen previously treated with tyrosine kinase inhibitors, demonstrated clinically meaningful PFSimprovement in Arm B as compared to Arm C (HR of 0.61, 95% CI: 0.52, 0.72; median PFS 8.3 vs.6.8 months).

At the time of the interim OS analysis, patients had a median follow-up of 19.7 months. The keyresults from this analysis as well as from the updated PFS analysis in the ITT population aresummarised in Tables 9 and 10. The Kaplan-Meier curve for OS in the ITT population is presented in

Figure 4. Figure 5 summarises the results of OS in the ITT and PD-L1 subgroups. Updated PFS resultsare also presented in Figures 6 and 7.

Table 9: Summary of updated efficacy in the ITT population (IMpower150)

Efficacy endpoint Arm A Arm B Arm C(Atezolizumab + (Atezolizumab + (Bevacizumab

Paclitaxel + Bevacizumab + + Paclitaxel +

Carboplatin) Paclitaxel + Carboplatin)

Carboplatin)

Secondary Endpoints#

Investigator-assessed PFS (RECIST n = 402 n = 400 n = 400v1.1)*

No. of events (%) 330 (82.1%) 291 (72.8%) 355 (88.8%)

Median duration of PFS (months) 6.7 8.4 6.895% CI (5.7, 6.9) (8.0, 9.9) (6.0, 7.0)

Stratified hazard ratio‡^ (95% CI) 0.91 (0.78, 1.06) 0.59 (0.50, 0.69) ---p-value1,2 0.2194 < 0.000112-month PFS (%) 24 38 20

OS interim analysis* n = 402 n = 400 n = 400

No. of deaths (%) 206 (51.2%) 192 (48.0%) 230 (57.5%)

Median time to events (months) 19.5 19.8 14.995% CI (16.3, 21.3) (17.4, 24.2) (13.4, 17.1)

Stratified hazard ratio‡^ (95% CI) 0.85 (0.71, 1.03) 0.76 (0.63, 0.93) ---p-value1,2 0.0983 0.0066-month OS (%) 84 85 8112-month OS (%) 66 68 61

Investigator-assessed Overall Best n = 401 n = 397 n = 393

Response3* (RECIST 1.1)

No. of responders (%) 163 (40.6%) 224 (56.4%) 158 (40.2%)95% CI (35.8, 45.6) (51.4, 61.4) (35.3, 45.2)

No. of complete response (%) 8 (2.0%) 11 (2.8%) 3 (0.8%)

No. of partial response (%) 155 (38.7%) 213 (53.7%) 155 (39.4%)

Investigator-assessed DOR* n = 163 n = 224 n = 158(RECIST v1.1)

Median in months 8.3 11.5 6.095% CI (7.1, 11.8) (8.9, 15.7) (5.5, 6.9)# Primary efficacy endpoints were PFS and OS and they were analysed in the ITT-wild-type (WT)population, i.e. excluding patients with EGFR mutations or ALK rearrangements.1 Based on the stratified log-rank test2 For informational purposes; in the ITT population, comparisons between Arm B and Arm C as wellas between Arm A and Arm C were not formally tested yet as per the pre-specified analysishierarchy3 Overall best response for complete response and partial response‡ Stratified by sex, presence of liver metastases and PD-L1 tumour expression on TC and IC^ The Arm C is the comparison group for all hazard ratios

* Updated PFS analysis and interim OS analysis at clinical cut-off 22 January 2018

PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours v1.1.

CI = confidence interval; DOR = duration of response; OS = overall survival.

Table 10: Summary of updated efficacy for Arm A vs. Arm B in the ITT population(IMpower150)

Efficacy endpoint Arm A Arm B(Atezolizumab + (Atezolizumab +

Paclitaxel + Bevacizumab +

Carboplatin) Paclitaxel +

Carboplatin)

Investigator-assessed PFS (RECIST n = 402 n = 400v1.1)*

No. of events (%) 330 (82.1%) 291 (72.8%)

Median duration of PFS (months) 6.7 8.495% CI (5.7, 6.9) (8.0, 9.9)

Stratified hazard ratio‡^ (95% CI) 0.67 (0.57, 0.79)p-value1,2 < 0.0001

OS interim analysis* n = 402 n = 400

No. of deaths (%) 206 (51.2%) 192 (48.0%)

Median time to events (months) 19.5 19.895% CI (16.3, 21.3) (17.4, 24.2)

Stratified hazard ratio‡^ (95% CI) 0.90 (0.74, 1.10)p-value1,2 0.30001 Based on the stratified log-rank test2 For informational purposes; in the ITT population, comparisons between Arm A and Arm B werenot included in the pre-specified analysis hierarchy‡ Stratified by sex, presence of liver metastases and PD-L1 expression on TC and IC

* Updated PFS analysis and interim OS analysis at clinical cut-off 22 January 2018^ The Arm A is the comparison group for all hazard ratios

Figure 4: Kaplan-Meier curve for overall survival in the ITT population (IMpower150)

Figure 5: Forest plot of overall survival by PD-L1 expression in the ITT population, Arm B vs. C(IMpower150)

Figure 6: Kaplan-Meier curve for PFS in the ITT population (IMpower150)

Figure 7: Forest plot of progression free survival by PD-L1 expression in the ITT population,

Arm B vs. C (IMpower150)

In Arm B as compared to Arm C, pre-specified subgroup analyses from the interim OS analysisshowed an OS improvement for patients with EGFR mutations or ALK rearrangements (hazard ratio[HR] of 0.54, 95% CI: 0.29, 1.03; median OS not reached vs. 17.5 months), and liver metastases (HRof 0.52, 95% CI: 0.33, 0.82; median OS 13.3 vs. 9.4 months). PFS improvements were also shown inpatients with EGFR mutations or ALK rearrangements (HR of 0.55, 95% CI: 0.35, 0.87; median PFS10.0 vs. 6.1 months) and liver metastases (HR of 0.41, 95% CI: 0.26, 0.62; median PFS 8.2 vs. 5.4months). OS results were similar for patients aged < 65 and ≥ 65 subgroups, respectively. Data forpatients ≥ 75 years of age are too limited to draw conclusions on this population. For all subgroupanalyses, formal statistical testing was not planned.

IMpower130 (GO29537): Randomised phase III trial in chemotherapy-naïve patients with metastaticnon-squamous NSCLC, in combination with nab-paclitaxel and carboplatin

A phase III, open-label, randomised study, GO29537 (IMpower130), was conducted to evaluate theefficacy and safety of atezolizumab in combination with nab-paclitaxel and carboplatin, inchemotherapy-naïve patients with metastatic non-squamous NSCLC. Patients with EGFR mutations or

ALK rearrangements should have been previously treated with tyrosine kinase inhibitors.

Patients were staged according to the American Joint Committee on Cancer (AJCC) 7th edition.

Patients were excluded if they had a history of autoimmune disease, administration of live, attenuatedvaccine within 28 days prior to randomisation, administration of immunostimulatory agents within4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior to randomisation,and active or untreated CNS metastases. Patients who had prior treatment with CD137 agonists orimmune checkpoint blockade therapies (anti-PD-1, and anti-PD-L1 therapeutic antibodies) were noteligible. However, patients who had prior anti-CTLA-4 treatment could be enrolled, as long as the lastdose was received at least 6 weeks prior to randomisation, and there was no history of severe immune-mediated adverse events from anti-CTLA-4 (NCI CTCAE Grades 3 and 4). Tumour assessments wereconducted every 6 weeks for the first 48 weeks following Cycle 1, then every 9 weeks thereafter.

Tumour specimens were evaluated for PD-L1 expression on tumour cells (TC) and tumour infiltratingimmune cells (IC) and the results were used to define the PD-L1 expression subgroups for the analysesdescribed below.

Patients, including those with EGFR mutations or ALK rearrangements, were enrolled and wererandomised in a 2:1 ratio to receive one of the treatment regimens described in Table 11.

Randomisation was stratified by sex, presence of liver metastases and PD-L1 expression on TC and

IC. Patients receiving treatment regimen B were able to crossover and receive atezolizumabmonotherapy following disease progression.

Table 11: Intravenous treatment regimens (IMpower130)

Treatment Induction Maintenance

Regimen (Four or six 21-day cycles) (21-day cycles)

A Atezolizumab (1 200 mg)a + nab-paclitaxel Atezolizumab (1 200 mg)a(100 mg/m2)b,c + carboplatin (AUC 6)c

B Nab-paclitaxel (100 mg/m2)b,c + carboplatin Best supportive care or pemetrexed(AUC 6)ca Atezolizumab is administered until loss of clinical benefit as assessed by investigatorb Nab-paclitaxel is administered on days 1, 8, and 15 of each cyclec Nab-paclitaxel and carboplatin are administered until completion of 4-6 cycles, or progressivedisease or unacceptable toxicity whichever occurs first

The demographics and baseline disease characteristics of the study population defined as ITT-WT(n=679) were well balanced between the treatment arms. The median age was 64 years (range: 18 to86 years). The majority of the patients were male (59%) and white (90%). Fourteen point sevenpercent of patients had liver metastases at baseline, and most patients were current or previoussmokers (90%). The majority of patients had a baseline ECOG performance status of 1 (59%) and PD-

L1 expression < 1% (approximately 52%). Among 107 Arm B patients who had a response status ofstable disease, partial response, or complete response after induction therapy, 40 received pemetrexedswitch maintenance therapy.

The primary analysis was conducted in all patients, excluding those with EGFR mutations or ALKrearrangements, defined as ITT-WT population (n=679). Patients had a median survival follow uptime of 18.6 months and showed improved OS and PFS with atezolizumab, nab-paclitaxel andcarboplatin as compared to the control. The key results are summarised in Table 12 and Kaplan-Meiercurves for OS and PFS are presented in Figures 8 and 10, respectively. The exploratory results of OSand PFS by PD-L1 expression are summarised in Figures 9 and 11, respectively. Patients with livermetastases did not show improved PFS or OS with atezolizumab, nab-paclitaxel and carboplatin,compared to nab-paclitaxel and carboplatin (HR of 0.93, 95% CI: 0.59, 1.47 for PFS and HR of 1.04,95% CI: 0.63, 1.72 for OS, respectively).

Fifty-nine percent of patients in the nab-paclitaxel and carboplatin arm received any cancerimmunotherapy after disease progression, which includes atezolizumab as crossover treatment (41%of all patients), compared to 7.3% of patients in the atezolizumab, nab paclitaxel and carboplatin arm.

In an exploratory analysis with longer follow up (median: 24.1 months), the median OS for both armswas unchanged relative to the primary analysis, with HR = 0.82 (95% CI: 0.67, 1.01).

Table 12: Summary of efficacy from IMpower130 in the primary analysis (ITT-WT population)

Efficacy endpoints Arm A Arm B

Atezolizumab + Nab-paclitaxel +nab-paclitaxel + carboplatincarboplatin

Co-primary endpoints

OS n=451 n=228

No. of deaths (%) 226 (50.1%) 131 (57.5%)

Median time to events (months) 18.6 13.995% CI (16.0, 21.2) (12.0, 18.7)

Stratified hazard ratio‡ (95% CI) 0.79 (0.64, 0.98)p-value 0.03312-month OS (%) 63 56

Investigator-assessed PFS (RECIST v1.1) n=451 n=228

No. of events (%) 347 (76.9%) 198 (86.8%)

Median duration of PFS (months) 7.0 5.595% CI (6.2, 7.3) (4.4, 5.9)

Stratified hazard ratio‡ (95% CI) 0.64 (0.54, 0.77)p-value < 0.000112-month PFS (%) 29% 14%

Other endpoints

Investigator-assessed ORR (RECIST v1.1)^ n=447 n=226

No. of confirmed responders (%) 220 (49.2%) 72 (31.9%)95% CI (44.5, 54.0) (25.8, 38.4)

No. of complete response (%) 11 (2.5%) 3 (1.3%)

No. of partial response (%) 209 (46.8%) 69 (30.5%)

Investigator-assessed confirmed DOR (RECIST 1.1)^ n=220 n=72

Median in months 8.4 6.195% CI (6.9, 11.8) (5.5, 7.9)‡ Stratified by sex and PD-L1 expression on TC and IC^ Confirmed ORR and DoR are exploratory endpoints

PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1.;

CI=confidence interval; ORR=objective response rate; DOR=duration of response; OS=overallsurvival

Figure 8: Kaplan-Meier curves for overall survival (IMpower130)

Figure 9: Forest plot of overall survival by PD-L1 expression (IMpower130)

Figure 10: Kaplan-Meier curves for progression free survival (IMpower130)

Figure 11: Forest plot of progression free survival by PD-L1 expression (IMpower130)

IMpower110 (GO29431): Randomised phase III trial in chemotherapy-naïve patients with metastatic

A phase III, open-label, multi-centre, randomised study, IMpower110, was conducted to evaluate theefficacy and safety of atezolizumab in chemotherapy-naïve patients with metastatic NSCLC. Patientshad PD-L1 expression ≥ 1% TC (PD-L1 stained ≥ 1% of tumour cells) or ≥ 1% IC (PD-L1 stainedtumour-infiltrating immune cells covering ≥ 1% of the tumour area) based on the VENTANA PD-L1(SP142) Assay.

A total of 572 patients were randomised in a 1:1 ratio to receive atezolizumab (Arm A) orchemotherapy (Arm B). Atezolizumab was administered as a fixed dose of 1 200 mg by intravenousinfusion every 3 weeks until loss of clinical benefit as assessed by the investigator or unacceptabletoxicity. The chemotherapy regimens are described in Table 13. Randomisation was stratified by sex,

ECOG performance status, histology, and PD-L1 tumour expression on TC and IC.

Table 13: Chemotherapy intravenous treatment regimens (IMpower110)

Treatment Induction Maintenanceregimen (Four or Six 21-day cycles) (21-day cycles)

B (Non- Cisplatina (75 mg/m²) + pemetrexeda (500 mg/m²) OR b,dsquamous) carboplatina(AUC 6) + pemetrexeda (500 mg/m²) Pemetrexed(500 mg/m²)

B Cisplatina (75 mg/m²) + gemcitabinea,c (1 250 mg/m2) OR Best supportive(Squamous) carboplatina (AUC 5) + gemcitabinea,c (1 000 mg/m2) careda Cisplatin, carboplatin, pemetrexed and gemcitabine are administered until completion of 4 or 6cycles, or progressive disease, or unacceptable toxicityb Pemetrexed is administered as maintenance regimen every 21 days until progressive disease orunacceptable toxicityc Gemcitabine is administered on days 1 and 8 of each cycled No crossover was allowed from the control arm (platinum-based chemotherapy) to the atezolizumabarm (Arm A)

Patients were excluded if they had a history of autoimmune disease; administration of a live,attenuated vaccine within 28 days prior to randomisation, administration of systemicimmunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal products within2 weeks prior to randomisation, active or untreated CNS metastases. Tumour assessments wereconducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and then every 9 weeksthereafter.

The demographics and baseline disease characteristics in patients with PD-L1 expression ≥ 1% TC or≥ 1% IC who do not have EGFR mutations or ALK rearrangements (n=554) were well balancedbetween the treatment arms. The median age was 64.5 years (range: 30 to 87), and 70% of patientswere male. The majority of patients were white (84%) and Asian (14%). Most patients were current orprevious smokers (87%) and baseline ECOG performance status in patients was 0 (36%) or 1 (64%).

Overall, 69% of patients had non-squamous disease and 31% of patients had squamous disease. Thedemographics and baseline disease characteristics in patients with high PD-L1 expression (PD-L1≥ 50% TC or ≥ 10% IC) who do not have with EGFR mutations or ALK rearrangements (n=205) weregenerally representative of the broader study population and were balanced between the treatmentarms.

The primary endpoint was overall survival (OS). At the time of the interim OS analysis, patients withhigh PD-L1 expression excluding those with EGFR mutations or ALK rearrangements (n=205)showed statistically significant improvement in OS for the patients randomised to atezolizumab (Arm

A) as compared with chemotherapy (Arm B) (HR of 0.59, 95% CI: 0.40, 0.89; median OS of 20.2months vs 13.1 months) with a two-sided p-value of 0.0106. The median survival follow-up time inpatients with high PD-L1 expression was 15.7 months.

In an exploratory OS analysis with longer follow up (median: 31.3 months) for these patients, themedian OS for the atezolizumab arm was unchanged relative to the primary OS interim analysis (20.2months) and was 14.7 months for the chemotherapy arm (HR of 0.76, 95% CI: 0.54, 1.09). The keyresults at the exploratory analysis are summarised in Table 14. The Kaplan-Meier curves for OS and

PFS in patients with high PD-L1 expression are presented in Figures 12 and 13. A higher proportion ofpatients experienced death within the first 2.5 months in the atezolizumab arm (16/107, 15.0%) ascompared to the chemotherapy arm (10/98, 10.2%). No specific factor(s) associated with early deathscould be identified.

Table 14: Summary of efficacy in patients with high PD-L1 expression ≥ 50% TC or ≥ 10% IC(IMpower110)

Efficacy endpoints Arm A Arm B(Atezolizumab) (Chemotherapy)

Primary endpoint

Overall survival n = 107 n = 98

No. of deaths (%) 64 (59.8%) 64 (65.3%)

Median time to events (months) 20.2 14.795% CI (17.2, 27.9) (7.4, 17.7)

Stratified hazard ratio‡ (95% CI) 0.76 (0.54, 1.09)12-month OS (%) 66.1 52.3

Secondary endpoints

Investigator-assessed PFS (RECIST v1.1) n = 107 n = 98

No. of events (%) 82 (76.6%) 87 (88.8%)

Median duration of PFS (months) 8.2 5.095% CI (6.8, 11.4) (4.2, 5.7)

Stratified hazard ratio‡ (95% CI) 0.59 (0.43, 0.81)12-month PFS (%) 39.2 19.2

Investigator-assessed ORR (RECIST 1.1) n = 107 n = 98

No. of responders (%) 43 (40.2%) 28 (28.6%)95% CI (30.8, 50.1) (19.9, 38.6)

No. of complete response (%) 1 (0.9%) 2 (2.0%)

No. of partial response (%) 42 (39.3%) 26 (26.5%)

Investigator-assessed DOR (RECIST 1.1) n = 43 n = 28

Median in months 38.9 8.395% CI (16.1, NE) (5.6, 11.0)‡ Stratified by sex and ECOG performance status (0 vs. 1)

PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours v1.1; CI =confidence interval; ORR = objective response rate; DOR = duration of response; OS = overallsurvival; NE = not estimable.

Figure 12: Kaplan-Meier curve for overall survival in patients with high PD-L1 expression≥ 50% TC or ≥ 10% IC (IMpower110)

Figure 13: Kaplan-Meier curve for progression free survival in patients with high PD-L1expression ≥ 50% TC or ≥ 10% IC (IMpower110)

The observed OS improvement in the atezolizumab arm compared with the chemotherapy arm wasconsistently shown across subgroups in patients with high PD-L1 expression including both non-squamous NSCLC patients (hazard ratio [HR] of 0.62, 95% CI: 0.40, 0.96; median OS 20.2 vs. 10.5months) and squamous NSCLC patients (HR of 0.56, 95% CI: 0.23, 1.37; median OS not reached vs.15.3 months). Data for patients ≥ 75 years of age and patients who were never smokers are too limitedto draw conclusions in these subgroups.

IPSOS study (MO29872): Randomised phase III trial in patients with treatment-naïve locallyadvanced unresectable or metastatic NSCLC who are ineligible for platinum-based chemotherapy

A phase III, open label, randomised, controlled study, MO29872 (IPSOS), was conducted to evaluatethe efficacy and safety of atezolizumab compared with a single-agent chemotherapy regimen(vinorelbine or gemcitabine by investigator choice) in treatment-naïve patients with advanced orrecurrent (Stage IIIB [according to the AJCC 7th edition] not amenable to multimodality treatment) ormetastatic (Stage IV) NSCLC who were considered ineligible for platinum-based chemotherapy.

The following selection criteria define patients ineligible for platinum-based chemotherapy who areincluded in the therapeutic indication: Patients > 80 years of age, or with an ECOG performance status(PS) of 3, or patients with an ECOG PS 2 in combination with relevant comorbidities, or of older age(≥ 70 years) in combination with relevant comorbidities. Relevant comorbidities are related to cardiacdisorders, nervous system disorders, psychiatric disorders, vascular disorders, renal disorders,metabolism and nutrition disorders, or pulmonary disorders contraindicating treatment with platinum-based therapy, as assessed by the treating physician.

The study excluded patients younger than 70 years who had an ECOG PS of 0 or 1; patients withactive or untreated CNS metastases; administration of live, attenuated vaccine within 4 weeks prior torandomisation; administration of systemic immunostimulatory or systemic immunosuppressivemedicinal products within 4 weeks prior to randomisation. Patients with EGFR mutations or ALKrearrangements were also excluded from the study. Patients were eligible regardless of their tumour

PD-L1 status.

Patients were randomised in a 2:1 ratio to receive atezolizumab (Arm A) or chemotherapy (Arm B).

Atezolizumab was administered as a fixed dose of 1 200 mg by intravenous infusion every 3 weeks.

The chemotherapy regimens are described in Table 15. Treatment was administered until diseaseprogression per RECIST v1.1 or unacceptable toxicity. Randomisation was stratified by histology(squamous/non-squamous), PD-L1 expression (PD-L1 IHC status as measured by the VENTANA PD-

L1 (SP142) assay: TC3 or IC3 vs TC0/1/2 and IC0/1/2 vs unknown) and brain metastases (yes/no).

Table 15: Treatment regimens (IPSOS)

Treatment Regimen

A Atezolizumab 1 200 mg by IV infusion on Day 1 of every 21-day cycle.

B Vinorelbine: IV infusion at 25-30 mg/m2 or oral administration at 60-80 mg/m2 on

Days 1 and 8 of each 21-day cycle or on Days 1, 8 and 15 of each 28-day cycle orweekly administration or

Gemcitabine: IV infusion at 1 000-1 250 mg/m2 on Days 1 and 8 of each 21-daycycle or on Days 1, 8 and 15 of each 28-day cycle.

A total of 453 patients were enrolled in the study (ITT population). The population predominantlycomprised White (65.8%) and male (72.4%) patients. The median age of patients was 75 years and72.8% of patients were aged 70 years or older. The proportion of patients with ECOG PS of 0, 1, 2 and3 was 1.5%, 15.0%, 75.9%, and 7.5%, respectively. Overall, 13.7% of patients had stage IIIB diseasenot amenable to multimodality treatment and 86.3% had stage IV disease. The percentage of patientswho had tumours with PD-L1 expression TC< 1%, 1-49% and ≥ 50% as measured by the VENTANA

PD-L1 (SP263) assay was 46.8%, 28.7% and 16.6%, respectively, while 7.9% of patients had anunknown PD-L1 expression status.

The primary endpoint of the study was overall survival (OS). At the time of the final OS analysis, themedian follow-up was 41.0 months. Efficacy results are presented in Table 16 and Figure 14.

Table 16: Summary of efficacy for NSCLC patients ineligible for platinum-based chemotherapy(IPSOS)

Atezolizumab Chemotherapy

Efficacy endpoint(n = 302) (n = 151)

Primary endpoint

OS

No. of events (%) 249 (82.5%) 130 (86.1%)

Median time to events (months) (95% CI) 10.3 (9.4, 11.9) 9.2 (5.9, 11.2)

Stratified hazard ratio (95% CI) ǂ 0.78 (0.63, 0.97)p-value (Stratified Log-rank) p = 0.028

Secondary endpoints

Investigator-assessed PFS (RECIST 1.1)

No. of events (%) 276 (91.4%) 138 (91.4%)

Median duration of PFS (months) (95% CI) 4.2 (3.7, 5.5) 4.0 (2.9, 5.4)

Stratified hazard ratio (95% CI) ǂ 0.87 (0.70, 1.07)

ORR (RECIST 1.1)

No. of confirmed responders (%) 51 (16.9%) 12 (7.9%)

DOR (RECIST 1.1)

Median in months (95% CI) 14.0 (8.1, 20.3) 7.8 (4.8, 9.7)

CI = confidence interval; DOR = duration of response; ORR = objective response rate; OS = overallsurvival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid

Tumours v1.1.ǂ Estimated hazard ratio and 95% CI obtained from Cox model with treatment group as covariate. For thestratified analysis, histologic subtype, PD-L1 IHC status and brain metastases (yes/no) were added asstratification factors.

Figure 14: Kaplan-Meier curves for overall survival for NSCLC patients ineligible for platinum-based chemotherapy (IPSOS)

Second-line treatment of NSCLC

OAK (GO28915): Randomised phase III trial in locally advanced or metastatic NSCLC patientspreviously treated with chemotherapy

A phase III, open-label, multi-centre, international, randomised study, OAK, was conducted toevaluate the efficacy and safety of atezolizumab compared with docetaxel in patients with locallyadvanced or metastatic NSCLC who progressed during or following a platinum-containing regimen.

This study excluded patients who had a history of autoimmune disease, active orcorticosteroid-dependent brain metastases, administration of a live, attenuated vaccine within 28 daysprior to enrolment, administration of systemic immunostimulatory agents within 4 weeks or systemicimmunosuppressive medicinal product within 2 weeks prior to enrolment. Tumour assessments wereconducted every 6 weeks for the first 36 weeks, and every 9 weeks thereafter. Tumour specimens wereevaluated prospectively for PD-L1 expression on tumour cells (TC) and tumour-infiltrating immunecells (IC).

A total of 1 225 patients were enrolled and per the analysis plan the first 850 randomised patients wereincluded in the primary efficacy analysis. Randomisation was stratified by PD-L1 expression status on

IC, by the number of prior chemotherapy regimens, and by histology. Patients were randomised (1:1)to receive either atezolizumab or docetaxel.

Atezolizumab was administered as a fixed dose of 1 200 mg by intravenous infusion every 3 weeks.

No dose reduction was allowed. Patients were treated until loss of clinical benefit as assessed by theinvestigator. Docetaxel was administered 75 mg/m2 by intravenous infusion on day 1 of each 3-weekcycle until disease progression. For all treated patients, the median duration of treatment was2.1 months for the docetaxel arm and 3.4 months for the atezolizumab arm.

The demographic and baseline disease characteristics of the primary analysis population were wellbalanced between the treatment arms. The median age was 64 years (range: 33 to 85), and 61% ofpatients were male. The majority of patients were white (70%). Approximately three-quarters ofpatients had non-squamous histology (74%), 10% had known EGFR mutation, 0.2% had known ALKrearrangements, 10% had CNS metastases at baseline, and most patients were current or previoussmokers (82%). Baseline ECOG performance status was 0 (37%) or 1 (63%). Seventy-five percent ofpatients received only one prior platinum-based therapeutic regimen.

The primary efficacy endpoint was OS. The key results of this study with a median survival follow-upof 21 months are summarised in Table 17. Kaplan-Meier curves for OS in the ITT population arepresented in Figure 15. Figure 16 summarises the results of OS in the ITT and PD-L1 subgroups,demonstrating OS benefit with atezolizumab in all subgroups, including those with PD-L1expression < 1% in TC and IC.

Table 17: Summary of efficacy in the primary analysis population (all comers)* (OAK)

Atezolizumab Docetaxel

Efficacy endpoint(n = 425) (n = 425)

Primary efficacy endpoint

OS

No. of deaths (%) 271 (64%) 298 (70%)

Median time to events (months) 13.8 9.695% CI (11.8, 15.7) (8.6, 11.2)

Stratifiedǂ hazard ratio (95% CI) 0.73 (0.62, 0.87)p-value** 0.000312-month OS (%)*** 218 (55%) 151 (41%)18-month OS (%)*** 157 (40%) 98 (27%)

Secondary endpoints

Investigator-assessed PFS (RECIST v1.1)

No. of events (%) 380 (89%) 375 (88%)

Median duration of PFS (months) 2.8 4.095% CI (2.6, 3.0) (3.3, 4.2)

Stratified hazard ratio (95% CI) 0.95 (0.82, 1.10)

Investigator-assessed ORR (RECIST v1.1)

No. of responders (%) 58 (14%) 57 (13%)95% CI (10.5, 17.3) (10.3, 17.0)

Investigator-assessed DOR (RECIST n = 58 n = 57v1.1)

Median in months 16.3 6.295% CI (10.0, NE) (4.9, 7.6)

CI = confidence interval; DOR = duration of response; NE = not estimable; ORR = objective responserate; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteriain Solid Tumours v1.1.

* The primary analysis population consists of the first 850 randomised patientsǂ Stratified by PD-L1 expression in tumour infiltrating immune cells, the number of priorchemotherapy regimens, and histology

** Based on the stratified log-rank test

*** Based on Kaplan-Meier estimates

Figure 15: Kaplan-Meier curve for overall survival in the primary analysis population (allcomers) (OAK)

Figure 16: Forest plot of overall survival by PD-L1 expression in the primary analysispopulation (OAK)a Stratified HR for ITT and TC or IC ≥ 1%. Unstratified HR for other exploratory subgroups.

An improvement in OS was observed with atezolizumab compared to docetaxel in both non-squamous

NSCLC patients (hazard ratio [HR] of 0.73, 95% CI: 0.60, 0.89; median OS of 15.6 vs. 11.2 monthsfor atezolizumab and docetaxel, respectively) and squamous NSCLC patients (HR of 0.73,95% CI: 0.54, 0.98; median OS of 8.9 vs. 7.7 months for atezolizumab and docetaxel, respectively).

The observed OS improvement was consistently demonstrated across subgroups of patients includingthose with brain metastases at baseline (HR of 0.54, 95% CI: 0.31, 0.94; median OS of 20.1vs. 11.9 months for atezolizumab and docetaxel respectively) and patients who were never smokers(HR of 0.71, 95% CI: 0.47, 1.08; median OS of 16.3 vs. 12.6 months for atezolizumab and docetaxel,respectively). However, patients with EGFR mutations did not show improved OS with atezolizumabcompared to docetaxel (HR of 1.24, 95% CI: 0.71, 2.18; median OS of 10.5 vs. 16.2 months foratezolizumab and docetaxel, respectively).

Prolonged time to deterioration of patient-reported pain in chest as measured by the EORTC

QLQ-LC13 was observed with atezolizumab compared to docetaxel (HR of 0.71, 95% CI: 0.49, 1.05;median not reached in either arm). The time to deterioration in other lung cancer symptoms (i.e.cough, dyspnoea, and arm/shoulder pain) as measured by the EORTC QLQ-LC13 was similarbetween atezolizumab and docetaxel. These results should be interpreted with caution due to the open-label design of the study.

POPLAR (GO28753): Randomised phase II trial in locally advanced or metastatic NSCLC patientspreviously treated with chemotherapy

A phase II, multi-centre, international, randomised, open-label, controlled study, POPLAR, wasconducted in patients with locally advanced or metastatic NSCLC who progressed during or followinga platinum-containing regimen, regardless of PD-L1 expression. The primary efficacy outcome wasoverall survival. A total of 287 patients were randomised 1:1 to receive either atezolizumab (1 200 mgby intravenous infusion every 3 weeks until loss of clinical benefit) or docetaxel (75 mg/m2 byintravenous infusion on day 1 of each 3-week cycle until disease progression). Randomisation wasstratified by PD-L1 expression status on IC, by the number of prior chemotherapy regimens and byhistology. An updated analysis with a total of 200 deaths observed and a median survival follow-up of22 months showed a median OS of 12.6 months in patients treated with atezolizumab, vs. 9.7 monthsin patients treated with docetaxel (HR of 0.69, 95% CI: 0.52, 0.92). ORR was 15.3% vs. 14.7% andmedian DOR was 18.6 months vs. 7.2 months for atezolizumab vs. docetaxel, respectively.

Small cell lung cancer

IMpower133 (GO30081): Randomised phase I/III trial in patients with chemotherapy-naïve extensive-stage SCLC, in combination with carboplatin and etoposide

A Phase I/III, randomised, multicentre, double-blind, placebo-controlled study, IMpower133, wasconducted to evaluate the efficacy and safety of atezolizumab in combination with carboplatin andetoposide in patients with chemotherapy-naïve ES-SCLC.

Patients were excluded if they had active or untreated CNS metastases; history of autoimmune disease;administration of live, attenuated vaccine within 4 weeks prior to randomisation; administration ofsystemic immunosuppressive medicinal products within 1 week prior to randomisation. Tumourassessments were conducted every 6 weeks for the first 48 weeks following Cycle 1, Day 1 and thenevery 9 weeks thereafter. Patients who met established criteria and who agreed to be treated beyonddisease progression had tumour assessments conducted every 6 weeks until treatment discontinuation.

A total of 403 patients were enrolled and randomised (1:1) to receive one of the treatment regimensdescribed in Table 18. Randomisation was stratified by sex, ECOG performance status, and presenceof brain metastases.

Table 18: Intravenous treatment regimens (IMpower133)

Treatment Induction Maintenanceregimen (Four 21-Day Cycles) (21-Day Cycles)

A atezolizumab (1 200 mg)a + carboplatin (AUC 5)b+ etoposide (100 mg/m2)b,c atezolizumab (1 200 mg) a

B placebo + carboplatin (AUC 5)b + etoposide(100 mg/m2)b,c placeboa Atezolizumab was administered until loss of clinical benefit as assessed by investigatorb Carboplatin and etoposide were administered until completion of 4 cycles, or progressive disease orunacceptable toxicity, whichever occurs firstc Etoposide was administered on day 1, 2 and 3 of each cycle

The demographic and baseline disease characteristics of the study population were well balancedbetween the treatment arms. The median age was 64 years (range: 26 to 90 years) with 10% of patients≥ 75 years of age. The majority of patients were male (65%), white (80%), and 9% had brainmetastases and most patients were current or previous smokers (97%). Baseline ECOG performancestatus was 0 (35%) or 1 (65%).

At the time of the primary analysis, patients had a median survival follow up time of 13.9 months. Astatistically significant improvement in OS was observed with atezolizumab in combination withcarboplatin and etoposide compared to the control arm (HR of 0.70, 95% CI: 0.54, 0.91; median OS of12.3 months vs. 10.3 months). In the exploratory OS final analysis with longer follow up (median:22.9 months), the median OS for both arms was unchanged relative to the primary OS interimanalysis. The PFS, ORR and DOR results from the primary analysis as well as the exploratory OSfinal analysis results are summarised in Table 19. Kaplan-Meier curves for OS and PFS are presentedin Figures 17 and 18. Data for patients with brain metastases are too limited to draw conclusions onthis population.

Table 19: Summary of efficacy (IMpower133)

Key efficacy endpoints Arm A Arm B(Atezolizumab + (Placebo + carboplatin +carboplatin + etoposide) etoposide)

Co-primary endpoints

OS analysis* n=201 n=202

No. of deaths (%) 142 (70.6%) 160 (79.2%)

Median time to events (months) 12.3 10.395% CI (10.8, 15.8) (9.3, 11.3)

Stratified hazard ratio‡ (95% CI) 0.76 (0.60, 0.95)p-value 0.0154***12-month OS (%) 51.9 39.0

Investigator-assessed PFS (RECIST v1.1) ** n=201 n=202

No. of events (%) 171 (85.1%) 189 (93.6%)

Median duration of PFS (months) 5.2 4.395% CI (4.4, 5.6) (4.2, 4.5)

Stratified hazard ratio‡ (95% CI) 0.77 (0.62, 0.96)p-value 0.01706-month PFS (%) 30.9 22.412-month PFS (%) 12.6 5.4

Other endpoints

Investigator-assessed ORR (RECIST 1.1)** ^ n=201 n=202

No. of responders (%) 121 (60.2%) 130 (64.4%)95% CI (53.1, 67.0) (57.3, 71.0)

No. of complete response (%) 5 (2.5%) 2 (1.0%)

No. of partial response (%) 116 (57.7%) 128 (63.4%)

Investigator-assessed DOR (RECIST 1.1)** ^ n =121 n = 130

Median in months 4.2 3.995% CI (4.1, 4.5) (3.1, 4.2)

PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1.;

CI=confidence interval; ORR=objective response rate; DOR=duration of response; OS=overallsurvival‡ Stratified by sex and ECOG performance status

* Exploratory OS final analysis at clinical cut-off 24 January 2019

** PFS, ORR and DOR analyses at clinical cut-off 24 April 2018

*** For descriptive purposes only^ Confirmed ORR and DoR are exploratory endpoints

Figure 17: Kaplan-Meier curve for overall survival (IMpower133)

Figure 18: Kaplan-Meier curve for progression-free survival (IMpower133)

IMpassion130 (WO29522): Randomised phase III trial in locally advanced or metastatic TNBCpatients previously untreated for metastatic disease

A phase III, double-blind, two-arm, multi-centre, international, randomised, placebo-controlled study,

IMpassion130, was conducted to evaluate the efficacy and safety of atezolizumab in combination withnab-paclitaxel, in patients with unresectable locally advanced or metastatic TNBC who had notreceived prior chemotherapy for metastatic disease. Patients had to be eligible for taxane monotherapy(i.e. absence of rapid clinical progression, life-threatening visceral metastases, or need for rapidsymptom and/or disease control) and were excluded if they had received prior chemotherapy in theneoadjuvant or adjuvant setting within the last 12 months, a history of autoimmune disease;administration of a live, attenuated vaccine within 4 weeks prior to randomisation, administration ofsystemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinalproducts within 2 weeks prior to randomisation; untreated, symptomatic or corticosteroid-dependentbrain metastases. Tumour assessments were performed every 8 weeks (± 1 week) for the first12 months after Cycle 1, day 1 and every 12 weeks (± 1 week) thereafter.

A total of 902 patients were enrolled and stratified by presence of liver metastases, prior taxanetreatment, and by PD-L1 expression status in tumour-infiltrating immune cells (IC) (PD-L1 stainedtumour-infiltrating immune cells [IC] < 1% of tumour area vs. ≥ 1% of the tumour area) assessed bythe VENTANA PD-L1 (SP142) Assay.

Patients were randomised to receive atezolizumab 840 mg or placebo by intravenous infusions ondays 1 and 15 of every 28-day cycle, plus nab-paclitaxel (100 mg/m2) administered via intravenousinfusion on days 1, 8 and 15 of every 28-day cycle. Patients received treatment until radiographicdisease progression per RECIST v1.1, or unacceptable toxicity. Treatment with atezolizumab could becontinued when nab-paclitaxel was stopped due to unacceptable toxicity. The median number oftreatment cycles was 7 for atezolizumab and 6 for nab-paclitaxel in each treatment arm.

The demographic and baseline disease characteristics of the study population were well balancedbetween the treatment arms. Most patients were women (99.6%), 67.5% were white and 17.8% Asian.

The median age was 55 years (range: 20-86). Baseline ECOG performance status was 0 (58.4%)or 1 (41.3%). Overall, 41% of enrolled patients had PD-L1 expression ≥ 1%, 27% had liver metastasesand 7% asymptomatic brain metastases at baseline. Approximately half the patients had received ataxane (51%) or anthracycline (54%) in the (neo)adjuvant setting. Patient demographics and baselinetumour disease in patients with PD-L1 expression ≥ 1% were generally representative of the broaderstudy population.

The co-primary efficacy endpoints included investigator-assessed progression free survival (PFS) inthe ITT population and in patients with PD-L1 expression ≥ 1% per RECIST v1.1 as well as overallsurvival (OS) in the ITT population and in patients with PD-L1 expression ≥ 1%. Secondary efficacyendpoints included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1.

PFS, ORR and DOR results of IMpassion130 for patients with PD-L1 expression ≥ 1% at the time ofthe final analysis for PFS with a median survival follow up of 13 months are summarised in Table 20with Kaplan-Meier curves for PFS in Figure 19. Patients with PD-L1 expression < 1% did not showimproved PFS when atezolizumab was added to nab-paclitaxel (HR of 0.94, 95% CI 0.78, 1.13).

The final OS analysis was performed in patients with PD-L1 expression ≥ 1% with a median follow upof 19.12 months. OS results are presented in Table 20 and Kaplan-Meier curves in Figure 20. Patientswith PD-L1 expression < 1% did not show improved OS when atezolizumab was added to nab-paclitaxel (HR of 1.02, 95% CI 0.84, 1.24).

Exploratory subgroup analyses were performed in patients with PD-L1 expression ≥ 1%, exploringprior (neo)adjuvant treatment, BRCA1/2 mutation and asymptomatic brain metastases at baseline.

In patients who had received prior (neo) adjuvant treatment (n=242), the hazard ratio for primary(final) PFS was 0.79 and 0.77 for final OS while in patients who had not received prior (neo)adjuvanttreatment (n=127), the hazard ratio for primary (final) PFS was 0.44 and 0.54 for final OS.

In the IMpassion130 study, of the 614 patients tested, 89 (15%) carried pathogenic BRCA1/2mutations. From the PD-L1+/BRCA1/2 mutant subgroup, 19 patients received atezolizumab plus nab-paclitaxel and 26 placebo plus nab-paclitaxel. Based on exploratory analysis and acknowledging thesmall sample size, the presence of BRCA1/2 mutation does not seem to impact the PFS clinical benefitof atezolizumab and nab-paclitaxel.

There was no evidence of efficacy in patients with asymptomatic brain metastases at baseline,although the number of patients treated was small; the median PFS was 2.2 months in theatezolizumab plus nab-paclitaxel arm (n=15) compared to 5.6 months in the placebo plus nab-paclitaxel arm (n=11) (HR 1.40; 95% CI 0.57, 3.44).

Table 20: Summary of efficacy in patients with PD-L1 expression ≥ 1% (IMpassion130)

Key efficacy endpoints Atezolizumab + nab- Placebo + nab-paclitaxelpaclitaxel

Primary efficacy endpoints n=185 n=184

Investigator-assessed PFS (RECIST v1.1) - Primary analysis3

No. of events (%) 138 (74.6%) 157 (85.3%)

Median duration of PFS (months) 7.5 5.095% CI (6.7, 9.2) (3.8, 5.6)

Stratified hazard ratio‡ (95% CI) 0.62 (0.49, 0.78)p-value1 <0.000112-month PFS (%) 29.1 16.4

Investigator-assessed PFS (RECIST v1.1) - Updated exploratory analysis4

No. of events (%) 149 (80.5%) 163 (88.6%)

Median duration of PFS (months) 7.5 5.395% CI (6.7, 9.2) (3.8, 5.6)

Stratified hazard ratio‡ (95% CI) 0.63 (0.50-0.80)p-value1 <0.000112-month PFS (%) 30 .3 17 .3

OS 1,2,5

No. of deaths (%) 120 (64.9%) 139 (75.5%)

Median time to events (months) 25.4 17.995% CI (19.6, 30.7) (13.6, 20.3)

Stratified hazard ratio‡ (95% CI) 0.67 (0.53, 0.86)

Key efficacy endpoints Atezolizumab + nab- Placebo + nab-paclitaxelpaclitaxel

Secondary and exploratory endpoints

Investigator-assessed ORR (RECIST n=185 n=1831.1)3

No. of responders (%) 109 (58.9%) 78 (42.6%)95% CI (51.5, 66.1) (35.4, 50.1)

No. of complete response (%) 19 (10.3%) 2 (1.1%)

No. of partial response (%) 90 (48.6%) 76 (41.5%)

No. of stable disease 38 (20.5%) 49 (26.8%)

Investigator-assessed DOR3 n=109 n=78

Median in months 8.5 5.595% CI (7.3, 9.7) (3.7, 7.1)1. Based on the stratified log-rank test.2. OS comparisons between treatment arms in patients with PD-L1 expression ≥1% were not formallytested, as per the pre-specified analysis hierarchy.3. Per final analysis for PFS, ORR, DOR and first interim analysis for OS at clinical cut off 17th April4. Per exploratory PFS analysis at clinical cut off January 2nd 20195. Per final analysis for OS at clinical cut off April 14th 2020‡ Stratified by presence of liver metastases, and by prior taxane treatment.

PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1.;

CI=confidence interval; ORR=objective response rate; DOR=duration of response; OS=overall survival,

NE=not estimable

Figure 19: Kaplan-Meier curve for progression free survival in patients with PD-L1expression ≥ 1% (IMpassion130)

Figure 20: Kaplan-Meier curve for overall survival in patients with PD-L1 expression ≥ 1%(IMpassion130)

The time to deterioration (a sustained ≥ 10-point decline from baseline score) of patient-reportedglobal health status/health-related quality of life as measured by the EORTC QLQ-C30 was similar ineach treatment group indicating that all patients maintained their baseline HRQoL for a comparableduration of time.

Hepatocellular carcinoma

IMbrave150 (YO40245): Randomised phase III trial in patients with unresectable HCC who have notreceived prior systemic therapy, in combination with bevacizumab

A phase III, randomised, multi-centre, international, open-label study, IMbrave150, was conducted toevaluate the efficacy and safety of atezolizumab in combination with bevacizumab, in patients withlocally advanced or metastatic and/or unresectable HCC, who have not received prior systemictreatment. A total of 501 patients were randomised (2:1) to receive either atezolizumab (1 200 mg) and15 mg/kg bw of bevacizumab every 3 weeks administered by intravenous infusion, or sorafenib400 mg orally twice per day. Randomisation was stratified by geographic region, macrovascularinvasion and/or extrahepatic spread, baseline α-fetoprotein (AFP) and ECOG performance status.

Patients in both arms received treatment until loss of clinical benefit, or unacceptable toxicity. Patientscould discontinue either atezolizumab or bevacizumab (e.g., due to adverse events) and continue onsingle-agent therapy until loss of clinical benefit or unacceptable toxicity associated with the single-agent.

The study enrolled adults whose disease was not amenable to or progressed after surgical and/orlocoregional therapies, were Child-Pugh A, ECOG 0/1, and who had not received prior systemictreatment. Bleeding (including fatal events) is a known adverse reaction with bevacizumab and uppergastrointestinal bleeding is a common and life threatening complication in patients with HCC. Hence,patients were required to be evaluated for the presence of varices within 6 months prior to treatment,and were excluded if they had variceal bleeding within 6 months prior to treatment, untreated orincompletely treated varices with bleeding or high risk of bleeding. For patients with active hepatitis

B, HBV DNA < 500 IU/mL was required within 28 days prior to initiation of study treatment, andstandard anti-HBV treatment for a minimum of 14 days prior to study entry and for the length ofstudy.

Patients were also excluded if they had moderate or severe ascites; history of hepatic encephalopathy;known fibrolamellar HCC; sarcomatoid HCC, mixed cholangiocarcinoma and HCC; active co-infection of HBV and HCV; history of autoimmune disease; administration of a live, attenuatedvaccine within 4 weeks prior to randomization; administration of systemic immunostimulatory agentswithin 4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior torandomization; untreated or corticosteroid-dependent brain metastases. Tumour assessments wereperformed every 6 weeks for the first 54 weeks following Cycle 1, Day 1, then every 9 weeksthereafter.

The demographic and baseline disease characteristics of the study population were well balancedbetween the treatment arms. The median age was 65 years (range: 26 to 88 years) and 83% were male.

The majority of patients were Asian (57%) and white (35%). 40% were from Asia (excluding Japan),while 60% were from rest of world. Approximately 75% of patients presented with macrovascularinvasion and/or extrahepatic spread and 37% had a baseline AFP ≥ 400 ng/mL. Baseline ECOGperformance status was 0 (62%) or 1 (38%). The primary risk factors for the development of HCCwere Hepatitis B virus infection in 48% of patients, Hepatitis C virus infection in 22% of patients, andnon-viral disease in 31% of patients. HCC was categorized as Barcelona Clinic Liver Cancer (BCLC)stage C in 82% of patients, stage B in 16% of patients, and stage A in 3% of patients.

The co-primary efficacy endpoints were OS and IRF-assessed PFS according to RECIST v1.1. At thetime of the primary analysis, patients had a median survival follow up time of 8.6 months. The datademonstrated a statistically significant improvement in OS and PFS as assessed by IRF per RECISTv1.1 with atezolizumab + bevacizumab compared to sorafenib. A statistically significant improvementwas also observed in confirmed objective response rate (ORR) by IRF per RECIST v1.1 and HCCmodified RECIST (mRECIST). The key efficacy results from the primary analysis are summarized in

Table 21.

A descriptive updated efficacy analysis was performed with a median survival follow up time of 15.6months. The median OS was 19.2 months (95% CI: 17.0, 23.7) in the atezolizumab + bevacizumabarm versus 13.4 months (95% CI: 11.4, 16.9) in the sorafenib arm with a HR of 0.66 (95% CI: 0.52,0.85). The median PFS by IRF-assessment per RECIST v1.1 was 6.9 months (95% CI: 5.8, 8.6) in theatezolizumab + bevacizumab arm versus 4.3 months (95% CI: 4.0, 5.6) in the sorafenib arm with a HRof 0.65 (95% CI: 0.53, 0.81).

The IRF-assessed ORR per RECIST v1.1 was 29.8% (95% CI: 24.8, 35.0) in theatezolizumab + bevacizumab arm and 11.3% (95% CI: 6.9, 17.3) in the sorafenib arm. The medianduration of response (DOR) by IRF-assessment per RECIST v1.1 in confirmed responders was 18.1months (95% CI: 14.6, NE) in the atezolizumab + bevacizumab arm compared to 14.9 months (95%

CI: 4.9, 17.0) in the sorafenib arm.

Kaplan-Meier curves for OS (updated analysis) and PFS (primary analysis) are presented in Figures 21and 22, respectively.

Table 21: Summary of efficacy (IMbrave150 primary analysis)

Key efficacy endpoints Atezolizumab + Bevacizumab Sorafenib

OS n=336 n=165

No. of deaths (%) 96 (28.6%) 65 (39.4%)

Median time to event NE 13.2(months)95% CI (NE, NE) (10.4, NE)

Stratified hazard ratio‡ (95% 0.58 (0.42, 0.79)

CI)p-value1 0.00066-month OS (%) 84.8% 72.3%

IRF-assessed PFS, RECIST n=336 n=1651.1

No. of events (%) 197 (58.6%) 109 (66.1%)

Median duration of PFS 6.8 4.3(months)95% CI (5.8, 8.3) (4.0, 5.6)

Stratified hazard ratio‡ (95% 0.59 (0.47, 0.76)

CI)p-value1 <0.00016-month PFS 54.5% 37.2%

IRF-assessed ORR, n=326 n=159

RECIST 1.1

No. of confirmed responders 89 (27.3%) 19 (11.9%)(%)95% CI (22.5, 32.5) (7.4, 18.0)p-value2 <0.0001

No. of complete responses 18 (5.5%) 0(%)

No. of partial responses (%) 71 (21.8%) 19 (11.9%)

No. of stable disease (%) 151 (46.3%) 69 (43.4%)

IRF-assessed DOR, n=89 n=19

RECIST 1.1

Median in months NE 6.395% CI (NE, NE) (4.7, NE)

Range (months) (1.3+, 13.4+) (1.4+, 9.1+)

Key efficacy endpoints Atezolizumab + Bevacizumab Sorafenib

IRF-assessed ORR, HCC n=325 n=158mRECIST

No. of confirmed responders 108 (33.2%) 21 (13.3%)(%)95% CI (28.1, 38.6) (8.4, 19.6)p-value2 <0.0001

No. of complete responses 33 (10.2%) 3 (1.9%)(%)

No. of partial responses (%) 75 (23.1%) 18 (11.4%)

No. of stable disease (%) 127 (39.1%) 66 (41.8%)

IRF-assessed DOR, HCC n=108 n=21mRECIST

Median in months NE 6.395% CI (NE, NE) (4.9, NE)

Range (months) (1.3+, 13.4+) (1.4+, 9.1+)‡ Stratified by geographic region (Asia excluding Japan vs rest of world), macrovascular invasion and/orextrahepatic spread (presence vs. absence), and baseline AFP (<400 vs. ≥400 ng/mL)1. Based on two-sided stratified log-rank test2. Nominal p-values based on two-sided Cochran-Mantel-Haenszel test+ Denotes a censored value

PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1; HCCmRECIST = Modified RECIST Assessment for Hepatocellular Carcinoma; CI=confidence interval;

ORR=objective response rate; DOR=duration of response; OS=overall survival; NE=not estimable

Figure 21: Kaplan-Meier curve for OS in the ITT population (IMbrave150 updated analysis)

Figure 22: Kaplan-Meier curve for IRF-PFS per RECIST v1.1 in the ITT population(IMbrave150 primary analysis)

Efficacy in elderly

No overall differences in efficacy were observed between patients ≥ 65 years of age and youngerpatients receiving atezolizumab monotherapy. In study IMpower150, age ≥ 65 was associated with adiminished effect of atezolizumab in patients receiving atezolizumab in combination with carboplatinand paclitaxel.

In studies IMpower150, IMpower133 and IMpower110, data for patients ≥ 75 years of age are toolimited to draw conclusions on this population.

An early phase, multi-centre open-label study was conducted in paediatric (< 18 years, n=69) andyoung adult patients (18-30 years, n=18) with relapsed or progressive solid tumours as well as with

Hodgkin’s and non-Hodgkin’s lymphoma, to evaluate the safety and pharmacokinetics ofatezolizumab. Patients were treated with 15 mg/kg bw atezolizumab intravenously every 3 weeks (seesection 5.2).

Exposure to atezolizumab increased dose proportionally over the dose range 1 mg/kg bw to20 mg/kg bw including the fixed dose 1 200 mg administered every 3 weeks. A population analysisthat included 472 patients described atezolizumab pharmacokinetics for the dose range:1 to 20 mg/kg bw with a linear two-compartment disposition model with first-order elimination. Thepharmacokinetic properties of 840 mg intravenous atezolizumab administered every 2 weeks,1 200 mg administered every 3 weeks, and 1 680 mg administered every 4 weeks are the same;comparable total exposures are expected to be achieved with these three dosing regimens. Apopulation pharmacokinetic analysis suggests that steady-state is obtained after 6 to 9 weeks ofmultiple dosing. The systemic accumulation in area under the curve, maximum concentration andtrough concentration was 1.91, 1.46 and 2.75-fold, respectively.

Atezolizumab is administered as an intravenous infusion.

A population pharmacokinetic analysis indicates that central compartment volume of distribution is3.28 L and volume at steady-state is 6.91 L in the typical patient.

The metabolism of atezolizumab has not been directly studied. Antibodies are cleared principally bycatabolism.

A population pharmacokinetic analysis indicates that the clearance of atezolizumab is 0.200 L/day andthe typical terminal elimination half-life is 27 days.

Based on population PK and exposure-response analyses age (21-89 years), region, ethnicity, renalimpairment, mild hepatic impairment, level of PD-L1 expression, or ECOG performance status haveno effect on atezolizumab pharmacokinetics. Body weight, gender, positive ADA status, albuminlevels and tumour burden have a statistically significant, but not clinically relevant effect onatezolizumab pharmacokinetics. No dose adjustments are recommended.

No dedicated studies of atezolizumab have been conducted in elderly patients. The effect of age on thepharmacokinetics of atezolizumab was assessed in a population pharmacokinetic analysis. Age wasnot identified as a significant covariate influencing atezolizumab pharmacokinetics based on patientsof age range of 21-89 years (n=472), and median of 62 years of age. No clinically important differencewas observed in the pharmacokinetics of atezolizumab among patients < 65 years (n=274), patientsbetween 65−75 years (n=152) and patients > 75 years (n=46) (see section 4.2).

The pharmacokinetic results from one early-phase, multi-centre open-label study that was conductedin paediatric (< 18 years, n=69) and young adult patients (18-30 years, n=18), show that the clearanceand volume of distribution of atezolizumab were comparable between paediatric patients receiving15 mg/kg bw and young adult patients receiving 1 200 mg of atezolizumab every 3 weeks whennormalized by body weight, with exposure trending lower in paediatric patients as body weightdecreased. These differences were not associated with a decrease in atezolizumab concentrationsbelow the therapeutic target exposure. Data for children < 2 years is limited thus no definitiveconclusions can be made.

No dedicated studies of atezolizumab have been conducted in patients with renal impairment. In thepopulation pharmacokinetic analysis, no clinically important differences in the clearance ofatezolizumab were found in patients with mild (estimated glomerular filtration rate [eGFR] 60 to89 mL/min/1.73 m2; n=208) or, moderate (eGFR 30 to 59 mL/min/1.73 m2; n=116) renal impairmentcompared to patients with normal (eGFR greater than or equal to 90 mL/min/1.73 m2; n=140) renalfunction. Only a few patients had severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2; n=8) (seesection 4.2). The effect of severe renal impairment on the pharmacokinetics of atezolizumab isunknown.

No dedicated studies of atezolizumab have been conducted in patients with hepatic impairment. In thepopulation pharmacokinetic analysis, there were no clinically important differences in the clearance ofatezolizumab observed in patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN orbilirubin > 1.0 × to 1.5 × ULN and any AST) or moderate hepatic impairment (bilirubin > 1.5 to 3x

ULN and any AST) in comparison to patients with normal hepatic function (bilirubin ≤ ULN and

AST ≤ ULN). No data are available in patients with severe hepatic impairment (bilirubin > 3 X ULNand any AST). Hepatic impairment was defined by the National Cancer Institute-Organ Dysfunction

Working Group (NCI-ODWG) criteria of hepatic dysfunction (see section 4.2). The effect of severehepatic impairment (bilirubin > 3 × ULN and any AST) on the pharmacokinetics of atezolizumab isunknown.

Carcinogenicity studies have not been performed to establish the carcinogenic potential ofatezolizumab.

Mutagenicity studies have not been performed to establish the mutagenic potential of atezolizumab.

However, monoclonal antibodies are not expected to alter DNA or chromosomes.

No fertility studies have been conducted with atezolizumab; however, assessment of the cynomolgusmonkey male and female reproductive organs was included in the chronic toxicity study. Weeklyadministration of atezolizumab to female monkeys at an estimated AUC approximately 6 times the

AUC in patients receiving the recommended dose caused an irregular menstrual cycle pattern and alack of newly formed corpora lutea in the ovaries which were reversible. There was no effect on themale reproductive organs.

No reproductive or teratogenicity studies in animals have been conducted with atezolizumab. Animalstudies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to immune-mediatedrejection of the developing foetus resulting in foetal death. Administration of atezolizumab couldcause foetal harm, including embryo-foetal lethality.

L-histidine

Glacial acetic acid

Sucrose

Polysorbate 20

Water for injections

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

Unopened vial3 years.

Chemical and physical in-use stability has been demonstrated for up to 24 hours at ≤ 30 °C and for upto 30 days at 2 °C to 8 °C from the time of preparation.

From a microbiological point of view, the prepared solution for infusion should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of theuser and would normally not be longer than 24 hours at 2 °C to 8 °C or 8 hours at ambient temperature(≤ 25 °C) unless dilution has taken place in controlled and validated aseptic conditions.

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

Do not freeze.

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

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

Type I glass vial with a butyl rubber stopper and an aluminium seal with a plastic grey or aqua flip-offcap containing 14 mL or 20 mL of concentrate solution for infusion.

Pack of one vial.

Tecentriq does not contain any antimicrobial preservative or bacteriostatic agents and should beprepared by a healthcare professional using aseptic technique to ensure the sterility of preparedsolutions. Use a sterile needle and syringe to prepare Tecentriq.

Aseptic preparation, handling and storage

Aseptic handling must be ensured when preparing the infusion. Preparation should be:

* performed under aseptic conditions by trained personnel in accordance with good practice rulesespecially with respect to the aseptic preparation of parenteral products.

* prepared in a laminar flow hood or biological safety cabinet using standard precautions for thesafe handling of intravenous agents.

* followed by adequate storage of the prepared solution for intravenous infusion to ensuremaintenance of the aseptic conditions.

Do not shake.

For the recommended dose of 840 mg: fourteen mL of Tecentriq concentrate should be withdrawnfrom the vial and diluted into a polyvinyl chloride (PVC), polyolefin (PO), polyethylene (PE), orpolypropylene (PP) infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection.

For the recommended dose of 1 200 mg: twenty mL of Tecentriq concentrate should be withdrawnfrom the vial and diluted into a polyvinyl chloride (PVC), polyolefin (PO), polyethylene (PE) orpolypropylene (PP) infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection.

For the recommended dose of 1 680 mg: twenty-eight mL of Tecentriq concentrate should bewithdrawn from two vials of Tecentriq 840 mg and diluted into a polyvinyl chloride (PVC), polyolefin(PO), polyethylene (PE), or polypropylene (PP) infusion bag containing sodium chloride 9 mg/mL(0.9%) solution for injection.

After dilution, the final concentration of the diluted solution should be between 3.2 and 16.8 mg/mL.

The bag should be gently inverted to mix the solution in order to avoid foaming. Once the infusion isprepared it should be administered immediately (see section 6.3).

Parenteral medicinal products should be inspected visually for particulates and discolouration prior toadministration. If particulates or discoloration are observed, the solution should not be used.

No incompatibilities have been observed between Tecentriq and intravenous bags withproduct-contacting surfaces of PVC, PO, PE, or PP. In addition, no incompatibilities have beenobserved with in-line filter membranes composed of polyethersulfone or polysulfone, and infusion setsand other infusion aids composed of PVC, PE, polybutadiene, or polyetherurethane. The use of in-linefilter membranes is optional.

Do not co-administer other medicinal products through the same infusion line.

The release of Tecentriq in the environment should be minimised. Any unused medicinal product orwaste material should be disposed of in accordance with local requirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/17/1220/001

EU/1/17/1220/002

Date of first authorisation: 21 September 2017

Date of latest renewal: 25 April 2022

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

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