ZIRABEV 25mg / ml perfusive solution concentrate medication leaflet

Zirabev 25 mg/ml concentrate for solution for infusion

Each ml of concentrate contains 25 mg of bevacizumab*.

Each 4 ml vial contains 100 mg of bevacizumab.

Each 16 ml vial contains 400 mg of bevacizumab.

For dilution and other handling recommendations, see section 6.6.

*Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in

Chinese Hamster Ovary cells.

Each 4 ml vial contains 3.0 mg of sodium.

Each 16 ml vial contains 12.1 mg of sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale brown liquid.

Zirabev in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adultpatients with metastatic carcinoma of the colon or rectum.

Zirabev in combination with paclitaxel is indicated for first-line treatment of adult patients withmetastatic breast cancer. For further information as to human epidermal growth factor receptor 2(HER2) status, please refer to section 5.1.

Zirabev in combination with capecitabine is indicated for first-line treatment of adult patients withmetastatic breast cancer in whom treatment with other chemotherapy options including taxanes oranthracyclines is not considered appropriate. Patients who have received taxane andanthracycline-containing regimens in the adjuvant setting within the last 12 months should be excludedfrom treatment with Zirabev in combination with capecitabine. For further information as to HER2status, please refer to section 5.1.

Zirabev in addition to platinum-based chemotherapy is indicated for first-line treatment of adultpatients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other thanpredominantly squamous cell histology.

Zirabev in combination with erlotinib is indicated for first-line treatment of adult patients withunresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with

Epidermal Growth Factor Receptor (EGFR) activating mutations (see section 5.1).

Zirabev in combination with interferon alfa-2a is indicated for first line treatment of adult patients withadvanced and/or metastatic renal cell cancer.

Zirabev in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adultpatients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III

C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer (see section 5.1).

Zirabev in combination with carboplatin and gemcitabine or in combination with carboplatin andpaclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-sensitiveepithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapywith bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.

Zirabev in combination with paclitaxel, topotecan or pegylated liposomal doxorubicin is indicated forthe treatment of adult patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, orprimary peritoneal cancer who received no more than two prior chemotherapy regimens and who havenot received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targetedagents (see section 5.1).

Zirabev in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan inpatients who cannot receive platinum therapy, is indicated for the treatment of adult patients withpersistent, recurrent, or metastatic carcinoma of the cervix (see section 5.1).

Zirabev must be administered under the supervision of a physician experienced in the use ofantineoplastic medicinal products.

Metastatic carcinoma of the colon or rectum (mCRC)

The recommended dose of Zirabev, administered as an intravenous infusion, is either 5 mg/kg or10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight givenonce every 3 weeks.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

Metastatic breast cancer (mBC)

The recommended dose of Zirabev is 10 mg/kg of body weight given once every 2 weeks or 15 mg/kgof body weight given once every 3 weeks as an intravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

Zirabev is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatmentfollowed by Zirabev as a single agent until disease progression.

The recommended dose of Zirabev is 7.5 mg/kg or 15 mg/kg of body weight given once every3 weeks as an intravenous infusion.

Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses(see section 5.1).

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination witherlotinib

EGFR mutation testing should be performed prior to initiation of treatment with the combination of

Zirabev and erlotinib. It is important that a well-validated and robust methodology is chosen to avoidfalse negative or false positive determinations.

The recommended dose of Zirabev when used in addition to erlotinib is 15 mg/kg of body weightgiven once every 3 weeks as an intravenous infusion.

It is recommended that the treatment with Zirabev in addition to erlotinib is continued until diseaseprogression.

For the posology and method of administration of erlotinib, please refer to the full erlotinib prescribinginformation.

Advanced and/or metastatic renal cell cancer (mRCC)

The recommended dose of Zirabev is 10 mg/kg of body weight given once every 2 weeks as anintravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment: Zirabev is administered in addition to carboplatin and paclitaxel for up to6 cycles of treatment followed by continued use of Zirabev as single agent until disease progression orfor a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier.

The recommended dose of Zirabev is 15 mg/kg of body weight given once every 3 weeks as anintravenous infusion.

Treatment of platinum-sensitive recurrent disease: Zirabev is administered in combination with eithercarboplatin and gemcitabine for 6 cycles and up to 10 cycles or in combination with carboplatin andpaclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Zirabev as single agent untildisease progression. The recommended dose of Zirabev is 15 mg/kg of body weight given once every3 weeks as an intravenous infusion.

Treatment of platinum-resistant recurrent disease: Zirabev is administered in combination with one ofthe following agents - paclitaxel, topotecan (given weekly) or pegylated liposomal doxorubicin. Therecommended dose of Zirabev is 10 mg/kg of body weight given once every 2 weeks as an intravenousinfusion. When Zirabev is administered in combination with topotecan (given on days 1-5, every3 weeks), the recommended dose of Zirabev is 15 mg/kg of body weight given once every 3 weeks asan intravenous infusion. It is recommended that treatment be continued until disease progression orunacceptable toxicity (see section 5.1, study MO22224).

Cervical cancer

Zirabev is administered in combination with one of the following chemotherapy regimens: paclitaxeland cisplatin or paclitaxel and topotecan.

The recommended dose of Zirabev is 15 mg/kg of body weight given once every 3 weeks as anintravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or untilunacceptable toxicity (see section 5.1).

No dose adjustment is required in the patients ≥ 65 years of age.

The safety and efficacy have not been studied in patients with renal impairment (see section 5.2).

The safety and efficacy have not been studied in patients with hepatic impairment (see section 5.2).

The safety and efficacy of bevacizumab in children aged less than 18 years old 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.

There is no relevant use of bevacizumab in the paediatric population in the indications for treatment ofcancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney.

Zirabev is for intravenous use. The initial dose should be delivered over 90 minutes as an intravenousinfusion. If the first infusion is well tolerated, the second infusion may be administered over60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administeredover 30 minutes.

It should not be administered as an intravenous push or bolus.

Dose reduction for adverse reactions is not recommended. If indicated, therapy should either bepermanently discontinued or temporarily suspended as described in section 4.4.

For instructions on dilution of the medicinal product before administration, see section 6.6. Zirabevinfusions should not be administered or mixed with glucose solutions. This medicinal product must notbe mixed with other medicinal products except those mentioned in section 6.6.

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

- Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human orhumanised antibodies.

- Pregnancy (see section 4.6).

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

Gastrointestinal (GI) perforations and fistulae (see section 4.8)

Patients may be at an increased risk for the development of gastrointestinal perforation and gallbladder perforation when treated with bevacizumab. Intra-abdominal inflammatory process may be arisk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon orrectum, therefore, caution should be exercised when treating these patients. Prior radiation is a riskfactor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer withbevacizumab and all patients with GI perforation had a history of prior radiation. Therapy should bepermanently discontinued in patients who develop gastrointestinal perforation.

GI-vaginal fistulae in study GOG-0240

Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are atincreased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginalfistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and allpatients with GI-vaginal fistulae had a history of prior radiation. Recurrence of cancer within the fieldof prior radiation is an additional important risk factor for the development of GI-vaginal fistulae.

Non-GI fistulae (see section 4.8)

Patients may be at increased risk for the development of fistulae when treated with bevacizumab.

Permanently discontinue Zirabev in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula[US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)].

Limited information is available on the continued use of bevacizumab in patients with other fistulae.

In cases of internal fistula not arising in the gastrointestinal tract, discontinuation of Zirabev should beconsidered.

Wound healing complications (see section 4.8)

Bevacizumab may adversely affect the wound healing process. Serious wound healing complications,including anastomotic complications, with a fatal outcome have been reported. Therapy should not beinitiated for at least 28 days following major surgery or until the surgical wound is fully healed. Inpatients who experienced wound healing complications during therapy, treatment should be withhelduntil the wound is fully healed. Therapy should be withheld for elective surgery.

Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated withbevacizumab. This condition is usually secondary to wound healing complications, gastrointestinalperforation or fistula formation. Zirabev therapy should be discontinued in patients who developnecrotising fasciitis, and appropriate treatment should be promptly initiated.

Hypertension (see section 4.8)

An increased incidence of hypertension was observed in bevacizumab-treated patients. Clinical safetydata suggest that the incidence of hypertension is likely to be dose-dependent. Pre-existinghypertension should be adequately controlled before starting Zirabev treatment. There is noinformation on the effect of bevacizumab in patients with uncontrolled hypertension at the time ofinitiating therapy.

Monitoring of blood pressure is generally recommended during therapy.

In most cases hypertension was controlled adequately using standard antihypertensive treatmentappropriate for the individual situation of the affected patient. The use of diuretics to managehypertension is not advised in patients who receive a cisplatin-based chemotherapy regimen. Zirabevshould be permanently discontinued if medically significant hypertension cannot be adequatelycontrolled with antihypertensive therapy, or if the patient develops hypertensive crisis or hypertensiveencephalopathy.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote theformation of aneurysms and/or artery dissections. Before initiating Zirabev, this risk should becarefully considered in patients with risk factors such as hypertension or history of aneurysm.

Posterior reversible encephalopathy syndrome (PRES) (see section 4.8)

There have been rare reports of bevacizumab-treated patients developing signs and symptoms that areconsistent with PRES, a rare neurologic disorder, which can present with the following signs andsymptoms among others: seizures, headache, altered mental status, visual disturbance, or corticalblindness, with or without associated hypertension. A diagnosis of PRES requires confirmation bybrain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, treatmentof specific symptoms including control of hypertension is recommended along with discontinuation of

Zirabev. The safety of reinitiating bevacizumab therapy in patients previously experiencing PRES isnot known.

Proteinuria (see section 4.8)

Patients with a history of hypertension may be at increased risk for the development of proteinuriawhen treated with bevacizumab. There is evidence suggesting that all Grade (US National Cancer

Institute- Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may berelated to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to startingand during therapy. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patientstreated with bevacizumab. Therapy should be permanently discontinued in patients who developnephrotic syndrome (NCI-CTCAE v.3).

Arterial thromboembolism (see section 4.8)

In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascularaccidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher inpatients receiving bevacizumab in combination with chemotherapy compared to those who receivedchemotherapy alone.

Patients receiving bevacizumab plus chemotherapy, with a history of arterial thromboembolism,diabetes or age greater than 65 years have an increased risk of developing arterial thromboembolicreactions during therapy. Caution should be taken when treating these patients with Zirabev.

Therapy should be permanently discontinued in patients who develop arterial thromboembolicreactions.

Venous thromboembolism (see section 4.8)

Patients may be at risk of developing venous thromboembolic reactions, including pulmonaryembolism under bevacizumab treatment.

Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab incombination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events.

Zirabev should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions,including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions ≤ Grade 3need to be closely monitored (NCI-CTCAE v.3).

Patients treated with bevacizumab have an increased risk of haemorrhage, especiallytumour-associated haemorrhage. Zirabev should be discontinued permanently in patients whoexperience Grade 3 or 4 bleeding during Zirabev therapy (NCI-CTCAE v.3) (see section 4.8).

Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab,based on imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in suchpatients has not been prospectively evaluated in randomised clinical trials (see section 4.8). Patientsshould be monitored for signs and symptoms of CNS bleeding, and Zirabev treatment discontinued incases of intracranial bleeding.

There is no information on the safety profile of bevacizumab in patients with congenital bleedingdiathesis, acquired coagulopathy or in patients receiving full dose of anticoagulants for the treatmentof thromboembolism prior to starting bevacizumab treatment, as such patients were excluded fromclinical trials. Therefore, caution should be exercised before initiating therapy in these patients.

However, patients who developed venous thrombosis while receiving therapy did not appear to havean increased rate of Grade 3 or above bleeding when treated with a full dose of warfarin andbevacizumab concomitantly (NCI-CTCAE v.3).

Pulmonary haemorrhage/haemoptysis

Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and insome cases fatal, pulmonary haemorrhage/haemoptysis. Patients with recent pulmonaryhaemorrhage/haemoptysis (> 2.5 ml of red blood) should not be treated with Zirabev.

Congestive heart failure (CHF) (see section 4.8)

Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomaticdeclines in left ventricular ejection fraction to symptomatic CHF, requiring treatment orhospitalisation. Caution should be exercised when treating patients with clinically significantcardiovascular disease such as pre-existing coronary artery disease, or congestive heart failure with

Zirabev.

Most of the patients who experienced CHF had metastatic breast cancer and had received previoustreatment with anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF werepresent.

In patients in AVF3694g who received treatment with anthracyclines and who had not receivedanthracyclines before, no increased incidence of all Grade CHF was observed in theanthracycline + bevacizumab group compared to the treatment with anthracyclines only. CHF Grade 3or higher reactions were somewhat more frequent among patients receiving bevacizumab incombination with chemotherapy than in patients receiving chemotherapy alone. This is consistent withresults in patients in other studies of metastatic breast cancer who did not receive concurrentanthracycline treatment (NCI-CTCAE v.3) (see section 4.8).

Neutropenia and infections (see section 4.8)

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severeneutropenia (including some fatalities) have been observed in patients treated with some myelotoxicchemotherapy regimens plus bevacizumab in comparison to chemotherapy alone. This has mainlybeen seen in combination with platinum- or taxane-based therapies in the treatment of NSCLC, mBC,and in combination with paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer.

Hypersensitivity reactions (including anaphylactic shock)/infusion reactions (see section 4.8)

Patients may be at risk of developing infusion/hypersensitivity reactions (including anaphylacticshock). Close observation of the patient during and following the administration of bevacizumab isrecommended as expected for any infusion of a therapeutic humanised monoclonal antibody. If areaction occurs, the infusion should be discontinued and appropriate medical therapies should beadministered. A systematic premedication is not warranted.

Osteonecrosis of the jaw (ONJ) (see section 4.8)

Cases of ONJ have been reported in cancer patients treated with bevacizumab, the majority of whomhad received prior or concomitant treatment with intravenous bisphosphonates, for which ONJ is anidentified risk. Caution should be exercised when Zirabev and intravenous bisphosphonates areadministered simultaneously or sequentially.

Invasive dental procedures are also an identified risk factor. A dental examination and appropriatepreventive dentistry should be considered prior to starting the treatment with Zirabev. In patients whohave previously received or are receiving intravenous bisphosphonates invasive dental proceduresshould be avoided, if possible.

Intravitreal use

Zirabev is not formulated for intravitreal use.

Individual cases and clusters of serious ocular adverse reactions have been reported followingunapproved intravitreal use of bevacizumab compounded from vials approved for intravenousadministration in cancer patients. These reactions included infectious endophthalmitis, intraocularinflammation such as sterile endophthalmitis, uveitis and vitritis, retinal detachment, retinal pigmentepithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous haemorrhageor retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in variousdegrees of visual loss, including permanent blindness.

Systemic effects following intravitreal use

A reduction of circulating VEGF concentration has been demonstrated following intravitrealanti-VEGF therapy. Systemic adverse reactions including non-ocular haemorrhages and arterialthromboembolic reactions have been reported following intravitreal injection of VEGF inhibitors.

Ovarian failure/fertility

Bevacizumab may impair female fertility (see sections 4.6 and 4.8). Therefore fertility preservationstrategies should be discussed with women of childbearing potential prior to starting treatment with

Zirabev.

This medicinal product contains 3.0 mg sodium per 4 ml vial, equivalent to 0.15% of the WHOmaximum recommended daily intake (RDI) of 2 g sodium for an adult.

This medicinal product contains 12.1 mg sodium per 16 ml vial, equivalent to 0.61% of the WHOmaximum recommended daily intake (RDI) of 2 g sodium for an adult.

Effect of antineoplastic agents on bevacizumab pharmacokinetics

No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokineticswas observed based on the results of population pharmacokinetic analyses. There were neitherstatistically significant nor clinically relevant differences in bevacizumab clearance in patientsreceiving bevacizumab monotherapy compared to patients receiving bevacizumab in combination withinterferon alfa-2a, erlotinib or chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine,doxorubicin or cisplatin/gemcitabine).

Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents

No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics ofco-administered interferon alfa 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapiesirinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurementof free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabinepharmacokinetics cannot be drawn.

Combination of bevacizumab and sunitinib malate

In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia(MAHA) was reported in 7 of 19 patients treated with bevacizumab (10 mg/kg every two weeks) andsunitinib malate (50 mg daily) combination.

MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, andthrombocytopenia. In addition, hypertension (including hypertensive crisis), elevated creatinine, andneurological symptoms were observed in some of these patients. All of these findings were reversibleupon discontinuation of bevacizumab and sunitinib malate (see Hypertension, Proteinuria, PRES insection 4.4).

Combination with platinum- or taxane-based therapies (see sections 4.4 and 4.8)

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severeneutropenia (including some fatalities) have been observed mainly in patients treated with platinum- ortaxane-based therapies in the treatment of NSCLC and mBC.

Radiotherapy

The safety and efficacy of concomitant administration of radiotherapy and bevacizumab has not beenestablished.

EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens

No interaction studies have been performed. EGFR monoclonal antibodies should not be administeredfor the treatment of mCRC in combination with bevacizumab-containing chemotherapy. Results fromthe randomised phase III studies, PACCE and CAIRO-2, in patients with mCRC suggest that the useof anti-EGFR monoclonal antibodies panitumumab and cetuximab, respectively, in combination withbevacizumab plus chemotherapy, is associated with decreased PFS and/or OS, and with increasedtoxicity compared with bevacizumab plus chemotherapy alone.

Women of childbearing potential have to use effective contraception during (and up to 6 months after)treatment.

There are no clinical trial data on the use of bevacizumab in pregnant women. Studies in animals haveshown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross theplacenta, and bevacizumab is anticipated to inhibit angiogenesis in the foetus, and thus is suspected tocause serious birth defects when administered during pregnancy. In the post-marketing setting, casesof foetal abnormalities in women treated with bevacizumab alone or in combination with knownembryotoxic chemotherapeutics have been observed (see section 4.8). Bevacizumab is contraindicatedin pregnancy (see section 4.3).

It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milkand bevacizumab could harm infant growth and development (see section 5.3), women mustdiscontinue breast-feeding during therapy and not breast-feed for at least six months following the lastdose of bevacizumab.

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect onfemale fertility (see section 5.3). In a phase III trial in the adjuvant treatment of patients with coloncancer, a substudy with premenopausal women has shown a higher incidence of new cases of ovarianfailure in the bevacizumab group compared to the control group. After discontinuation of bevacizumabtreatment, ovarian function recovered in the majority of patients. Long term effects of the treatmentwith bevacizumab on fertility are unknown.

Bevacizumab has no or negligible influence on the ability to drive and use machines. However,somnolence and syncope have been reported with bevacizumab use (see table 1 in section 4.8). Ifpatients are experiencing symptoms that affect their vision or concentration, or their ability to react,they should be advised not to drive and use machines until symptoms abate.

The overall safety profile of bevacizumab is based on data from over 5 700 patients with variousmalignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinicaltrials.

The most serious adverse reactions were:

- Gastrointestinal perforations (see section 4.4).

- Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common innon-small cell lung cancer patients (see section 4.4).

- Arterial thromboembolism (see section 4.4).

The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumabwere hypertension, fatigue or asthenia, diarrhoea and abdominal pain.

Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria withbevacizumab therapy are likely to be dose-dependent.

The adverse reactions listed in this section fall into the following frequency categories: Very common(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to< 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination withdifferent chemotherapy regimens in multiple indications, by MedDRA system organ class.

Table 1 provides all adverse reactions by frequency that were determined to have a causal relationshipwith bevacizumab through:

- comparative incidences noted between clinical trial treatment arms (with at least a10% difference compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a2% difference compared to the control arm for NCI-CTCAE Grade 3-5 reactions,

- post-authorisation safety studies,

- spontaneous reporting,

- epidemiological studies on-interventional or observational studies,

- or through an evaluation of individual case reports.

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adversereactions with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE

Grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to beclinically significant or severe.

Post-marketing adverse reactions are included in both Tables 1 and 2, where applicable. Detailedinformation about these post-marketing reactions are provided in Table 3.

Adverse reactions are added to the appropriate frequency category in the tables below according to thehighest incidence seen in any indication.

Within each frequency category, adverse reactions are presented in the order of decreasing seriousness.

Some of the adverse reactions are reactions commonly seen with chemotherapy; however,bevacizumab may exacerbate these reactions when combined with chemotherapeutic agents. Examplesinclude palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin orcapecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, nail disorders or alopeciawith paclitaxel, and paronychia with erlotinib.

Table 1 Adverse reactions by frequency

System organ Very common Common Uncommon Rare Very rare Frequency notclass known

Infections and Sepsis, Necrotisiinfestations Abscessb,d, ng

Cellulitis, fasciitisa

Infection,

Urinarytractinfection

Blood and Febrile Anaemia,lymphatic system neutropenia, Lymphopendisorders Leucopenia, ia

Neutropeniab,

System organ Very common Common Uncommon Rare Very rare Frequency notclass known

Immune system Hypersensit Anaphyldisorders ivity, actic

Infusion shocka,dreactionsa,b,d

Metabolism and Anorexia, Dehydrationutrition Hypomagnesae ndisorders mia,

Hyponatraemia

Nervous system Peripheral Cerebrovas Posterior Hypertendisorders sensory cular reversibl siveneuropathyb, accident, e encephal

Dysarthria, Syncope, encephal opathya

Headache, Somnolenc opathy

Dysguesia e syndromea,b,d

Eye disorders Eye disorder,

Lacrimationincreased

Cardiac disorders Congestiveheartfailureb,d,

Supraventriculartachycardia

Vascular disorders Hypertensionb,d Thromboe Aneurysms, mbolism and artery

Thromboembol (arterial)b,d, dissections,ism (venous)b,d Haemorrha Renalgeb,d, Deep thromboticvein microangiopatthrombosis hya,b

Respiratory, Dyspnoea, Pulmonary Pulmonarythoracic and Rhinitis, haemorrhag hypertensiona,mediastinal Epistaxis, e/Haemopty Nasal septumdisorders Cough sisb,d, perforationa

Pulmonaryembolism,

Hypoxia,

Dysphoniaa

Gastrointestinal Rectal Gastrointest Gastrointestinadisorders haemorrhage, inal l ulcera

Stomatitis, perforationb

Constipation, ,d, Intestinal

Diarrhoea, perforation,

Nausea, Ileus,

Vomiting, Intestinal

Abdominal obstruction,pain Recto-vaginalfistulaed,e,

Gastrointestinaldisorder,

Proctalgia

Hepatobiliary Gallbladderdisorders perforationa,b

System organ Very common Common Uncommon Rare Very rare Frequency notclass known

Skin and Wound healing Palmar-subcutaneous complicationsb, plantartissue disorders d, Exfoliative erythrodysadermatitis, Dry esthesiaskin, Skin syndromediscolouration

Musculoskeletal Arthralgia, Fistulab,d, Osteonecrosisand connective Myalgia Muscular of the jawa,b,tissue disorders weakness, Non-

Back pain mandibularosteonecrosisa,f

Renal and Proteinuriab,durinary disorders

Reproductive Ovarian Pelvic painsystem and breast failureb,c,ddisorders

Congenital, Foetalfamilial, and abnormalitiesa,bgenetic disorder

General disorders Asthenia, Lethargyand Fatigue,administration Pyrexia, Pain,site conditions Mucosalinflammation

Investigations Weightdecreased

When events were noted as both all grade and grade 3-5 adverse drug reactions in clinical trials, the highestfrequency observed in patients has been reported. Data are unadjusted for the differential time on treatment.

a For further information please refer to Table 3 ‘Adverse reactions reported in post-marketing setting.’b Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA(Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve thesame underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident,myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

c Based on a substudy from NSABP C-08 with 295 patientsd For additional information refer below within section “Further information on selected serious adversereactions.”e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.f Observed in paediatric population only.

Table 2 Severe adverse reactions by frequency

System Very Common Uncommon Rare Very rare Frequencyorgan class common not known

Infections Sepsis, Necrotisingand Cellulitis, fasciitiscinfestations Abscessa,b,

Infection,

Urinary tractinfection

System Very Common Uncommon Rare Very rare Frequencyorgan class common not known

Blood and Febrile Anaemia,lymphatic neutropenia, Lymphopenisystem Leucopenia, adisorders Neutropeniaa,

Immune Hypersensiti Anaphylactisystem vity, Infusion c shockb,cdisorders reactionsa,b,c

Metabolism Dehydration,and nutrition Hyponatraemdisorders ia

Nervous Peripheral Cerebrovasc Posteriorsystem sensory ular accident, reversibledisorders neuropathya Syncope, encephalopat

Somnolence, hy syndrome

Headache a,b,c,

Hypertensiveencephalopathyc

Cardiac Congestivedisorders heartfailurea,b,

Supraventriculartachycardia

Vascular Hypertensio Thromboemb Aneurysmsdisorders na,b olism and arteryarteriala,b, dissections,

Haemorrhage Renala,b, thrombotic

Thromboemb microangiopaolism thyb,c(venous)a,b,

Deep veinthrombosis

Respiratory, Pulmonary Pulmonarythoracic and haemorrhage hypertensionc,mediastinal /Haemoptysi Nasal septumdisorders sa,b, perforationc

Pulmonaryembolism,

Epistaxis,

Dyspnoea,

Hypoxia

Gastrointesti Diarrhoea, Intestinal Gastrointestinnal disorders Nausea, perforation, al

Vomiting, Ileus, perforationa,b,

Abdominal Intestinal Gastrointestinpain obstruction, al ulcerc,

Recto- Rectalvaginal haemorrhagefistulaec,d,

Gastrointestinal disorder,

Stomatitis,

Proctalgia

Hepatobiliar Gallbladdery disorders perforationb,c

System Very Common Uncommon Rare Very rare Frequencyorgan class common not known

Skin and Woundsubcutaneou healings tissue complicationdisorders sa,b, Palmar-plantarerythrodysaesthesiasyndrome

Musculoskel Fistulaa,b, Osteonecrosisetal and Myalgia, of the jawb,cconnective Arthralgia,tissue Musculardisorders weakness,

Back pain

Renal and Proteinuriaa,burinarydisorders

Reproductiv Pelvic pain Ovariane system and failurea,bbreastdisorders

Congenital, Foetalfamilial, and abnormalitiesgenetic a,cdisorder

General Asthenia, Pain,disorders Fatigue Lethargy,and Mucosaladministratio inflammationn siteconditions

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse reactionswith at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significantor severe. These clinically significant adverse reactions were reported in clinical trials but the grade 3-5 reactionsdid not meet the threshold of at least a 2% difference compared to the control arm. Table 2 also includesclinically significant adverse reactions that were observed only in the post-marketing setting, therefore, thefrequency and NCI-CTCAE grade is not known. These clinically significant reactions have therefore beenincluded in Table 2 within the column entitled “Frequency Not Known.”a Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA(Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve thesame underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident,myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

b For additional information refer below within section “Further information on selected serious adversereactions”c For further information please refer to Table 3 ‘Adverse reactions reported in post-marketing setting.’d Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

Description of selected serious adverse reactions

Gastrointestinal (GI) perforations and fistulae (see section 4.4)

Bevacizumab has been associated with serious cases of gastrointestinal perforation.

Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% inpatients with non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breastcancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer, andup to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study

GOG-0240), GI perforations (all grade) were reported in 3.2% of patients, all of whom had a history ofprior pelvic radiation. The occurrence of those events varied in type and severity, ranging from free airseen on the plain abdominal X-ray, which resolved without treatment, to intestinal perforation withabdominal abscess and fatal outcome. In some cases underlying intra-abdominal inflammation waspresent, either from gastric ulcer disease, tumour necrosis, diverticulitis, or chemotherapy-associatedcolitis.

Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations,which represents between 0.2%-1% of all bevacizumab-treated patients.

In bevacizumab clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidenceof up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reportedless commonly in patients with other types of cancer.

GI-vaginal fistulae in study GOG-0240

In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginalfistulae was 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had ahistory of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated withbevacizumab + chemotherapy was higher in patients with recurrence within the field of prior radiation(16.7%) compared with patients with no prior radiation and/or no recurrence inside the field of priorradiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alonewere 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowelobstructions and require surgical intervention as well as diverting ostomies.

Non-GI fistulae (see section 4.4)

Bevacizumab use has been associated with serious cases of fistulae including reactions resulting indeath.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-0240),1.8% of bevacizumab-treated patients and 1.4% of control patients were reported to have hadnon-gastrointestinal vaginal, vesical, or female genital tract fistulae.

Uncommon (≥ 0.1% to < 1%) reports of fistulae that involve areas of the body other than thegastrointestinal tract (e.g. bronchopleural and biliary fistulae) were observed across variousindications. Fistulae have also been reported in post-marketing experience.

Reactions were reported at various time points during treatment ranging from one week to greater than1 year from initiation of bevacizumab, with most reactions occurring within the first 6 months oftherapy.

Wound healing (see section 4.4)

As bevacizumab may adversely impact wound healing, patients who had major surgery within the last28 days were excluded from participation in phase III clinical trials.

In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk ofpost-operative bleeding or wound healing complications observed in patients who underwent majorsurgery 28-60 days prior to starting bevacizumab. An increased incidence of post-operative bleedingor wound healing complication occurring within 60 days of major surgery was observed if the patientwas being treated with bevacizumab at the time of surgery. The incidence varied between 10% (4/40)and 20% (3/15).

Serious wound healing complications, including anastomotic complications, have been reported, someof which had a fatal outcome.

In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications wereobserved in up to 1.1% of patients receiving bevacizumab compared with up to 0.9% of patients in thecontrol arms (NCI-CTCAE v.3).

In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to1.8% of patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3).

Hypertension (see section 4.4)

In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (allgrades) ranged up to 42.1% in the bevacizumab containing arms compared with up to 14% in thecontrol arms. The overall incidence of NCI-CTC Grade 3 and 4 hypertension in patients receivingbevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to1.0% of patients treated with bevacizumab and chemotherapy compared to up to 0.2% of patientstreated with the same chemotherapy alone.

In study JO25567, all grade hypertension was observed in 77.3% of the patients who receivedbevacizumab in combination with erlotinib as first-line treatment for non-squamous NSCLC with

EGFR activating mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3hypertension was 60.0% in patients treated with bevacizumab in combination with erlotinib comparedto 11.7% in patients treated with erlotinib alone. There were no grade 4 or 5 hypertension events.

Hypertension was generally adequately controlled with oral antihypertensives such asangiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted indiscontinuation of bevacizumab treatment or hospitalisation.

Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.

The risk of bevacizumab-associated hypertension did not correlate with the patients’ baselinecharacteristics, underlying disease or concomitant therapy.

Posterior reversible encephalopathy syndrome (see section 4.4)

There have been rare reports of bevacizumab-treated patients developing signs and symptoms that areconsistent with PRES, a rare neurological disorder. Presentation may include seizures, headache,altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension.

The clinical presentation of PRES is often nonspecific, and therefore the diagnosis of PRES requiresconfirmation by brain imaging, preferably MRI.

In patients developing PRES, early recognition of symptoms with prompt treatment of specificsymptoms including control of hypertension (if associated with severe uncontrolled hypertension) isrecommended in addition to discontinuation of bevacizumab therapy. Symptoms usually resolve orimprove within days after treatment discontinuation, although some patients have experienced someneurologic sequelae. The safety of reinitiating bevacizumab therapy in patients previouslyexperiencing PRES is not known.

Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not haveradiological confirmation via MRI.

Proteinuria (see section 4.4)

In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patients receivingbevacizumab.

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephroticsyndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria wasreported in up to 10.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to1.4% of treated patients. Testing for proteinuria is recommended prior to start of Zirabev therapy. Inmost clinical trials urine protein levels of ≥ 2 g/24 hrs led to the holding of bevacizumab until recoveryto < 2 g/24 hrs.

Haemorrhage (see section 4.4)

In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleedingreactions ranged from 0.4% to 6.9% in bevacizumab-treated patients, compared with up to 4.5% ofpatients in the chemotherapy control group.

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study

GOG-0240), grade 3-5 bleeding reactions have been reported in up to 8.3% of patients treated withbevacizumab in combination with paclitaxel and topotecan compared with up to 4.6% of patientstreated with paclitaxel and topotecan.

The haemorrhagic reactions that have been observed in clinical trials were predominantlytumour-associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e.g. epistaxis).

Tumour-associated haemorrhage (see section 4.4)

Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials inpatients with non-small cell lung cancer (NSCLC). Possible risk factors include squamous cellhistology, treatment with antirheumatic/anti-inflammatory substances, treatment with anticoagulants,prior radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central tumourlocation and cavitation of tumours prior to or during therapy. The only variables that showedstatistically significant correlations with bleeding were bevacizumab therapy and squamous cellhistology. Patients with NSCLC of known squamous cell histology or mixed cell type withpredominant squamous cell histology were excluded from subsequent phase III trials, while patientswith unknown tumour histology were included.

In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seenwith a frequency of up to 9.3% when treated with bevacizumab plus chemotherapy compared with upto 5% in the patients treated with chemotherapy alone. Grade 3-5 reactions have been observed in upto 2.3% of patients treated with bevacizumab plus chemotherapy as compared with < 1% withchemotherapy alone (NCI-CTCAE v.3). Major or massive pulmonary haemorrhage/haemoptysis canoccur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fataloutcome.

Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectalcancer patients, and have been assessed as tumour-associated haemorrhages.

Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, includingcases of central nervous system (CNS) bleeding in patients with CNS metastases (see section 4.4).

The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab hasnot been prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysisof data from 13 completed randomised trials in patients with various tumour types, 3 patients out of 91(3.3%) with brain metastases experienced CNS bleeding (all Grade 4) when treated with bevacizumab,compared to 1 case (Grade 5) out of 96 patients (1%) that were not exposed to bevacizumab. In twosubsequent studies in patients with treated brain metastases (which included around 800 patients), onecase of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab (1.2%) at thetime of interim safety analysis (NCI-CTCAE v.3).

Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% ofbevacizumab-treated patients. These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis thatlasted less than 5 minutes, resolved without medical intervention and did not require any changes inthe bevacizumab treatment regimen. Clinical safety data suggest that the incidence of minormucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent.

There have also been less common reactions of minor mucocutaneous haemorrhage in other locations,such as gingival bleeding or vaginal bleeding.

Thromboembolism (see section 4.4)

Arterial thromboembolism

An increased incidence of arterial thromboembolic reactions was observed in patients treated withbevacizumab across indications, including cerebrovascular accidents, myocardial infarction, transientischaemic attacks, and other arterial thromboembolic reactions.

In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in thebevacizumab containing arms compared with up to 2.1% in the chemotherapy control arms. Fataloutcome was reported in 0.8% of patients receiving bevacizumab compared to 0.5% in patientsreceiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) werereported in up to 2.7% of patients treated with bevacizumab in combination with chemotherapycompared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction wasreported in up to 1.4% of patients treated with bevacizumab in combination with chemotherapycompared to up to 0.7% of patients treated with chemotherapy alone.

In one clinical trial evaluating bevacizumab in combination with 5-fluorouracil/folinic acid,

AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment withirinotecan were included. In this trial arterial thromboembolic reactions were observed in11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy control group.

The incidence of venous thromboembolic reactions in clinical trials was similar in patients receivingbevacizumab in combination with chemotherapy compared to those receiving the controlchemotherapy alone. Venous thromboembolic reactions include deep venous thrombosis, pulmonaryembolism and thrombophlebitis.

In clinical trials across indications, the overall incidence of venous thromboembolic reactions rangedfrom 2.8% to 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the controlarms.

Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% ofpatients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treatedwith chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervicalcancer).

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study

GOG-0240), grade 3-5 venous thromboembolic events have been reported in up to 15.6% of patientstreated with bevacizumab in combination with paclitaxel and cisplatin compared with up to 7.0% ofpatients treated with paclitaxel and cisplatin.

Patients who have experienced a venous thromboembolic reaction may be at higher risk for arecurrence if they receive bevacizumab in combination with chemotherapy versus chemotherapyalone.

Congestive heart failure (CHF)

In clinical trials with bevacizumab, congestive heart failure (CHF) was observed in all cancerindications studied to date, but occurred predominantly in patients with metastatic breast cancer. Infour phase III trials (AVF2119g, E2100, BO17708 and AVF3694g) in patients with metastatic breastcancer CHF Grade 3 (NCI-CTCAE v.3) or higher was reported in up to 3.5% of patients treated withbevacizumab in combination with chemotherapy compared with up to 0.9% in the control arms. Forpatients in study AVF3694g who received anthracyclines concomitantly with bevacizumab, theincidences of Grade 3 or higher CHF for the respective bevacizumab and control arms were similar tothose in the other studies in metastatic breast cancer: 2.9% in the anthracycline + bevacizumab armand 0% in the anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all

Grade CHF were similar between the anthracycline + bevacizumab (6.2%) and theanthracycline + placebo arms (6.0%).

Most patients who developed CHF during mBC trials showed improved symptoms and/or leftventricular function following appropriate medical therapy.

In most clinical trials of bevacizumab, patients with pre-existing CHF of NYHA (New York Heart

Association) II-IV were excluded, therefore, no information is available on the risk of CHF in thispopulation.

Prior anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors forthe development of CHF.

An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large

B-cell lymphoma when receiving bevacizumab with a cumulative doxorubicin dose greater than300 mg/m2. This phase III clinical trial comparedrituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) plus bevacizumab to

R-CHOP without bevacizumab. While the incidence of CHF was, in both arms, above that previouslyobserved for doxorubicin therapy, the rate was higher in the R-CHOP plus bevacizumab arm. Theseresults suggest that close clinical observation with appropriate cardiac assessments should beconsidered for patients exposed to cumulative doxorubicin doses greater than 300 mg/m2 whencombined with bevacizumab.

Hypersensitivity reactions (including anaphylactic shock)/infusion reactions (see section 4.4 and Post-marketing experience below)

In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently inpatients receiving bevacizumab in combination with chemotherapy than with chemotherapy alone. Theincidence of these reactions in some clinical trials of bevacizumab is common (up to 5% inbevacizumab- treated patients).

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study

GOG-0240), grade 3-5 infections have been reported in up to 24% of patients treated withbevacizumab in combination with paclitaxel and topotecan compared with up to 13% of patientstreated with paclitaxel and topotecan.

Ovarian failure/fertility (see sections 4.4 and 4.6)

In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer,the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSHlevel ≥ 30 mIU/ml and a negative serum β-HCG pregnancy test, has been evaluated in295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in themFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. Afterdiscontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluablewomen. Long term effects of the treatment with bevacizumab on fertility are unknown.

Decreased neutrophil count, decreased white blood cell count and presence of urine protein may beassociated with bevacizumab treatment.

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalitiesoccurred in patients treated with bevacizumab with at least a 2% difference compared to thecorresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia,hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR).

Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 timesbaseline level), both with and without proteinuria, are associated with the use of bevacizumab. Theobserved increase in serum creatinine was not associated with a higher incidence of clinicalmanifestations of renal impairment in patients treated with bevacizumab.

In randomised clinical trials, age > 65 years was associated with an increased risk of developingarterial thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemicattacks (TIAs) and myocardial infarctions (MIs). Other reactions with a higher frequency seen inpatients over 65 were Grade 3-4 leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all Gradeneutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged ≤ 65 years whentreated with bevacizumab (see sections 4.4 and 4.8 under Thromboembolism). In one clinical trial, theincidence of hypertension of grade ≥ 3 was two-fold higher in patients aged > 65 years than in theyounger age group (< 65 years). In a study of platinum-resistant recurrent ovarian cancer patients,alopecia, mucosal inflammation, peripheral sensory neuropathy, proteinuria and hypertension werealso reported and occurred at a rate at least 5% higher in the CT + BV arm for bevacizumab-treatedpatients ≥ 65 years of age compared with bevacizumab-treated patients aged < 65 years.

No increase in the incidence of other reactions, including gastrointestinal perforation, wound healingcomplications, congestive heart failure, and haemorrhage was observed in elderly patients (> 65 years)receiving bevacizumab as compared to those aged ≤ 65 years treated with bevacizumab.

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

In study BO25041 of bevacizumab added to post-operative radiation therapy (RT) with concomitantand adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial,cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed inother tumour types in adults treated with bevacizumab.

In study BO20924 of bevacizumab with current standard of care in rhabdomyosarcoma andnon-rhabdomyosarcoma soft tissue sarcoma, the safety profile of bevacizumab-treated children wascomparable with that observed in adults treated with bevacizumab.

Bevacizumab is not approved for use in patients under the age of 18 years. In published literaturereports, cases of non-mandibular osteonecrosis have been observed in patients under the age of18 years treated with bevacizumab.

Table 3 Adverse reactions reported in post-marketing setting

System organ class Reactions (frequency*)(SOC)

Infections and Necrotising fasciitis, usually secondary to wound healinginfestations complications, gastrointestinal perforation or fistula formation (rare)(see also section 4.4)

System organ class Reactions (frequency*)(SOC)

Immune system Hypersensitivity reactions and infusion reactions (common); with thedisorders following possible co-manifestations: dyspnoea/difficulty breathing,flushing/redness/rash, hypotension or hypertension, oxygen desaturation,chest pain, rigors and nausea/vomiting (see also section 4.4 and

Hypersensitivity reactions (including anaphylactic shock)/infusionreactions above)

Anaphylactic shock (rare) (see also section 4.4)

Nervous system Hypertensive encephalopathy (very rare) (see also section 4.4 anddisorders Hypertension in section 4.8)

Posterior Reversible Encephalopathy Syndrome (PRES), (rare) (seealso section 4.4)

Vascular disorders Renal thrombotic microangiopathy, which may be clinicallymanifested as proteinuria (not known) with or without concomitantsunitinib use. For further information on proteinuria see section 4.4and Proteinuria in section 4.8.

Respiratory, thoracic Nasal septum perforation (not known)and mediastinaldisorders Pulmonary hypertension (not known)

Dysphonia (common)

Gastrointestinal Gastrointestinal ulcer (not known)disorders

Hepatobiliary Gall bladder perforation (not known)disorders

Musculoskeletal and Cases of Osteonecrosis of the Jaw (ONJ) have been reported inconnective tissue patients treated with bevacizumab, most of which occurred in patientsdisorders who had identified risk factors for ONJ, in particular exposure tointravenous bisphosphonates and/or a history of dental diseaserequiring invasive dental procedures (see also section 4.4)

Cases of non-mandibular osteonecrosis have been observed inbevacizumab-treated paediatric patients (see section 4.8, Paediatricpopulation).

Congenital, familial, Cases of foetal abnormalities in women treated with bevacizumaband genetic disorder alone or in combination with known embryotoxic chemotherapeuticshave been observed (see section 4.6)

* If specified, the frequency has been derived from clinical trial data

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.

The highest dose tested in humans (20 mg/kg of body weight, intravenous every 2 weeks) wasassociated with severe migraine in several patients.

Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents,monoclonal antibodies and antibody drug conjugates, ATC code: L01FG01

Zirabev is a biosimilar medicinal product. Detailed information is available on the website of the

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

Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesisand angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and

KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGFregresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits theformation of new tumour vasculature, thereby inhibiting tumour growth.

Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer innude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast,pancreas and prostate. Metastatic disease progression was inhibited and microvascular permeabilitywas reduced.

Metastatic carcinoma of the colon or rectum (mCRC)

The safety and efficacy of the recommended dose (5 mg/kg of body weight every two weeks) inmetastatic carcinoma of the colon or rectum were studied in three randomised, active-controlledclinical trials in combination with fluoropyrimidine-based first-line chemotherapy. bevacizumab wascombined with two chemotherapy regimens:

- AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/folinic acid (IFL) for a total of4 weeks of each 6 week-cycle (Saltz regimen).

- AVF0780g: In combination with bolus 5-fluorouracil/folinic acid (5-FU/FA) for a total of6 weeks of each 8 week-cycle (Roswell Park regimen).

- AVF2192g: In combination with bolus 5-FU/FA for a total of 6 weeks of each 8 week-cycle(Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecantreatment.

Three additional studies with bevacizumab have been conducted in mCRC patients: first-line(NO16966), second-line with no previous bevacizumab treatment (E3200), and second-line withprevious bevacizumab treatment following disease progression in first-line (ML18147). In thesestudies, bevacizumab was administered at the following dosing regimens in combination with

FOLFOX-4 (5-FU/LV/oxaliplatin), XELOX (capecitabine/oxaliplatin), andfluoropyrimidine/irinotecan and fluoropyrimidine/oxaliplatin:

- NO16966: Bevacizumab 7.5 mg/kg of body weight every 3 weeks in combination with oralcapecitabine and intravenous oxaliplatin (XELOX) or bevacizumab 5 mg/kg every 2 weeks incombination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, withintravenous oxaliplatin (FOLFOX-4).

- E3200: Bevacizumab 10 mg/kg of body weight every 2 weeks in combination with leucovorinand 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin(FOLFOX-4) in bevacizumab-naïve patients.

- ML18147: Bevacizumab 5.0 mg/kg of body weight every 2 weeks or bevacizumab 7.5 mg/kg ofbody weight every 3 weeks in combination with fluoropyrimidine/irinotecan orfluoropyrimidine/oxaliplatin in patients with disease progression following first-line treatmentwith bevacizumab. Use of irinotecan- or oxaliplatin-containing regimen was switched dependingon first-line usage of either oxaliplatin or irinotecan.

This was a phase III randomised, double-blind, active-controlled clinical trial evaluating bevacizumabin combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum. Eighthundred and thirteen patients were randomised to receive IFL + placebo (Arm 1) or

IFL + bevacizumab (5 mg/kg every 2 weeks, Arm 2). A third group of 110 patients received bolus5-FU/FA + bevacizumab (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once safetyof bevacizumab with the IFL regimen was established and considered acceptable. All treatments werecontinued until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an

ECOG performance status of 0, 43% had a value of 1 and 0.4% had a value of 2. 15.5% had receivedprior radiotherapy and 28.4% prior chemotherapy.

The primary efficacy variable of the trial was overall survival. The addition of bevacizumab to IFLresulted in statistically significant increases in overall survival, progression-free survival and overallresponse rate (see Table 4). The clinical benefit, as measured by overall survival, was seen in allpre-specified patient subgroups, including those defined by age, sex, performance status, location ofprimary tumour, number of organs involved and duration of metastatic disease.

The efficacy results of bevacizumab in combination with IFL-chemotherapy are displayed in Table 4.

Table 4 Efficacy results for trial AVF2107g

Arm 1 Arm 2

IFL + placebo IFL + bevacizumaba

Number of patients 411 402

Overall survival

Median time (months) 15.6 20.395% CI 14.29-16.99 18.46-24.18

Hazard ratiob 0.660(p-value = 0.00004)

Progression-free survival

Median time (months) 6.2 10.6

Hazard ratio 0.54(p-value < 0.0001)

Overall response rate

Rate (%) 34.8 44.8(p-value = 0.0036)a 5 mg/kg every 2 weeks.b Relative to control arm.

Among the 110 patients randomised to Arm 3 (5-FU/FA + bevacizumab) prior to discontinuation ofthis arm, the median overall survival was 18.3 months and the median progression free survival was8.8 months.

This was a phase II randomised, double-blind, active-controlled clinical trial evaluating the efficacyand safety of bevacizumab in combination with 5-FU/FA as first-line treatment for metastaticcolorectal cancer in patients who were not optimal candidates for first-line irinotecan treatment. Onehundred and five patients were randomised to 5-FU/FA + placebo arm and 104 patients to5-FU/FA + bevacizumab (5 mg/kg every 2 weeks) arm. All treatments were continued until diseaseprogression. The addition of bevacizumab 5 mg/kg every two weeks to 5-FU/FA resulted in higherobjective response rates, significantly longer progression-free survival, and a trend in longer survivalas compared to 5-FU/FA chemotherapy alone.

This was a phase II randomised, active-controlled, open-labelled clinical trial investigatingbevacizumab in combination with 5-FU/FA as first-line treatment of metastatic colorectal cancer. Themedian age was 64 years. 19% of the patients had received prior chemotherapy and 14% priorradiotherapy. Seventy-one patients were randomised to receive bolus 5-FU/FA or5-FU/FA + bevacizumab (5 mg/kg every 2 weeks). A third group of 33 patients received bolus5-FU/FA + bevacizumab (10 mg/kg every 2 weeks). Patients were treated until disease progression.

The primary endpoints of the trial were objective response rate and progression-free survival. Theaddition of bevacizumab 5 mg/kg every two weeks to 5-FU/FA resulted in higher objective responserates, longer progression-free survival, and a trend in longer survival, compared with 5-FU/FAchemotherapy alone (see Table 5). These efficacy data are consistent with the results from trial

The efficacy data from trials AVF0780g and AVF2192g investigating bevacizumab in combinationwith 5-FU/FA-chemotherapy are summarised in Table 5.

Table 5 Efficacy results for trials AVF0780g and AVF2192g

AVF0780g AVF2192g5-FU/FA + 5-FU/FA + 5-FU/FA +5-FU/FA +5-FU/FA bevacizum bevacizum bevacizuma placeboab abb ab

Number of patients 36 35 33 105 104

Overall survival

Median time (months) 13.6 17.7 15.2 12.9 16.695% CI 10.35- 13.63-16.95 19.32

Hazard ratioc - 0.52 1.01 0.79p-value 0.073 0.978 0.16

Progression-free survival

Median time (months) 5.2 9.0 7.2 5.5 9.2

Hazard ratio 0.44 0.69 0.5p-value - 0.0049 0.217 0.0002

Overall response rate

Rate (percent) 16.7 40.0 24.2 15.2 2695% CI 7.0-33.5 24.4-57.8 11.7-42.6 9.2-23.9 18.1-35.6p-value 0.029 0.43 0.055

Duration of response

Median time (months) NR 9.3 5.0 6.8 9.225-75 percentile 5.5-NR 6.1-NR 3.8-7.8 5.59-9.17 5.88-13.01(months)a 5 mg/kg every 2 weeks.b 10 mg/kg every 2 weeks.c Relative to control arm.

NR = not reached.

This was a phase III randomised, double-blind (for bevacizumab), clinical trial investigatingbevacizumab 7.5 mg/kg in combination with oral capecitabine and intravenous oxaliplatin (XELOX),administered on a 3- weekly schedule; or bevacizumab 5 mg/kg in combination with leucovorin with5-fluorouracil bolus, followed by 5-fluorouracil infusional, with intravenous oxaliplatin (FOLFOX-4),administered on a 2-weekly schedule. The trial contained two parts: an initial unblinded 2-arm part(Part I) in which patients were randomised to two different treatment groups (XELOX and

FOLFOX-4) and a subsequent 2 x 2 factorial 4-arm part (Part II) in which patients were randomised tofour treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + bevacizumab,

FOLFOX-4 + bevacizumab). In Part II, treatment assignment was double-blind with respect tobevacizumab.

Approximately 350 patients were randomised into each of the 4 trial arms in the Part II of the trial.

Table 6 Treatment regimens in trial NO16966 (mCRC)

Treatment Starting dose Schedule

FOLFOX-4 or Oxaliplatin 85 mg/m2 intravenous 2 h Oxaliplatin on day 1

FOLFOX-4 + Leucovorin 200 mg/m2 intravenous 2 h Leucovorin on day 1 and 2bevacizumab 5-Fluorouracil 400 mg/m2 intravenous 5-fluorouracil intravenousbolus, bolus/infusion, each on days 1600 mg/m2 intravenous 22 h and 2

Placebo or 5 mg/kg intravenous 30-90 Day 1, prior to FOLFOX-4,bevacizumab min every 2 weeks

XELOX Oxaliplatin 130 mg/m2 intravenous 2 h Oxaliplatin on day 1or XELOX + Capecitabine 1000 mg/m2 oral bid Capecitabine oral bid for 2bevacizumab weeks (followed by 1 week offtreatment)

Placebo or 7.5 mg/kg intravenous 30-90 Day 1, prior to XELOX, q 3bevacizumab min weeks5-Fluorouracil: intravenous bolus injection immediately after leucovorin

The primary efficacy parameter of the trial was the duration of progression-free survival. In this trial,there were two primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to showthat bevacizumab in combination with FOLFOX-4 or XELOX chemotherapy was superior tochemotherapy alone. Both co-primary objectives were met:

- Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing armsin the overall comparison was demonstrated in terms of progression-free survival and overallsurvival in the eligible per-protocol population.

- Superiority of the bevacizumab-containing arms versus the chemotherapy alone arms in theoverall comparison was demonstrated in terms of progression-free survival in the ITTpopulation (Table 7).

Secondary PFS analyses, based on ‘on-treatment’-based response assessments, confirmed thesignificantly superior clinical benefit for patients treated with bevacizumab (analyses shown in

Table 7), consistent with the statistically significant benefit observed in the pooled analysis.

Table 7 Key efficacy results for the superiority analysis (ITT population, trial NO16966)

Endpoint (months) FOLFOX-4 or FOLFOX-4 or P-value

XELOX XELOX+ placebo + bevacizumab(n = 701) (n = 699)

Primary endpoint

Median PFS** 8.0 9.4 0.0023

Hazard ratio (97.5% CI)a 0.83 (0.72-0.95)

Secondary endpoints

Median PFS (on treatment)** 7.9 10.4 < 0.0001

Hazard ratio (97.5% CI) 0.63 (0.52-0.75)

Overall response rate (invest. 49.2% 46.5%assessment)**

Median overall survival* 19.9 21.2 0.0769

Hazard ratio (97.5% CI) 0.89 (0.76-1.03)

* Overall survival analysis at clinical cut-off 31 January 2007

** Primary analysis at clinical cut-off 31 January 2006a Relative to control arm

In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months inbevacizumab-treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, thecorresponding results in the XELOX treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 97.5%

CI = [0.63; 0.94]; p-value = 0.0026.

The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab-treatedpatients in the FOLFOX treatment subgroup, HR = 0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937,the corresponding results in the XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84,97.5% CI = [0.68; 1.04]; p-value = 0.0698.

This was a phase III randomised, active-controlled, open-label trial investigating bevacizumab10 mg/kg in combination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional,with intravenous oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule in previously-treatedpatients (second line) with advanced colorectal cancer. In the chemotherapy arms, the FOLFOX-4regimen used the same doses and schedule as shown in Table 6 for trial NO16966.

The primary efficacy parameter of the trial was overall survival, defined as the time fromrandomisation to death from any cause. Eight hundred and twenty-nine patients were randomised (292

FOLFOX-4, 293 bevacizumab + FOLFOX-4 and 244 bevacizumab monotherapy). The addition ofbevacizumab to FOLFOX-4 resulted in a statistically significant prolongation of survival. Statisticallysignificant improvements in progression-free survival and objective response rate were also observed(see Table 8).

Table 8 Efficacy results for trial E3200

E3200

FOLFOX-4 FOLFOX-4 +bevacizumaba

Number of patients 292 293

Overall survival

Median (months) 10.8 13.095% CI 10.12-11.86 12.09-14.03

Hazard ratiob 0.751(p-value = 0.0012)

Progression-free survival

Median (months) 4.5 7.5

Hazard ratio 0.518(p-value < 0.0001)

Objective response rate

Rate 8.6% 22.2%(p-value < 0.0001)a 10 mg/kg every 2 weeksb Relative to control arm

No significant difference was observed in the duration of overall survival between patients whoreceived bevacizumab monotherapy compared to patients treated with FOLFOX-4. Progression-freesurvival and objective response rate were inferior in the bevacizumab monotherapy arm compared tothe FOLFOX-4 arm.

This was a phase III randomised, controlled, open-label trial investigating bevacizumab 5.0 mg/kgevery 2 weeks or 7.5 mg/kg every 3 weeks in combination with fluoropyrimidine-based chemotherapyversus fluoropyrimidine-based chemotherapy alone in patients with mCRC who have progressed on afirst- line bevacizumab-containing regimen.

Patients with histologically confirmed mCRC and disease progression were randomised 1:1 within3 months after discontinuation of bevacizumab first-line therapy to receivefluoropyrimidine/oxaliplatin- or fluoropyrimidine/irinotecan-based chemotherapy (chemotherapyswitched depending on first-line chemotherapy) with or without bevacizumab. Treatment was givenuntil progressive disease or unacceptable toxicity. The primary outcome measure was overall survivaldefined as the time from randomisation until death from any cause.

A total of 820 patients were randomised. The addition of bevacizumab to fluoropyrimidine-basedchemotherapy resulted in a statistically significant prolongation of survival in patients with mCRCwho have progressed on a first-line bevacizumab-containing regimen (ITT = 819) (see Table 9).

Table 9 Efficacy results for study ML18147 (ITT population)

Fluoropyrimidine/irinotecan

Fluoropyrimidine/irinotecanororfluoropyrimidine/oxaliplatinfluoropyrimidine/oxaliplatinbased chemotherapybased chemotherapy+ bevacizumaba

Number of patients 410 409

Overall survival

Median (months) 9.8 11.20.81 (0.69, 0.94)

Hazard ratio (95% confidence(p-value = 0.0062)interval)

Progression-free survival

Median (months) 4.1 5.70.68 (0.59, 0.78)

Hazard ratio (95% confidence(p-value < 0.0001)interval)

Objective response rate (ORR)

Patients included in analysis 406 404

Rate 3.9% 5.4%(p-value = 0.3113)a 5.0 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks

Statistically significant improvements in progression-free survival were also observed. Objectiveresponse rate was low in both treatment arms and the difference was not significant.

Study E3200 used a 5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-naïve patients,while study ML18147 used a 2.5 mg/kg/week equivalent dose of bevacizumab inbevacizumab-pretreated patients. A cross-trial comparison of the efficacy and safety data is limited bydifferences between these studies, most notably in patient populations, previous bevacizumab exposureand chemotherapy regimens. Both the 5 mg/kg/week and 2.5 mg/kg/week equivalent doses ofbevacizumab provided a statistically significant benefit with regards to OS (HR 0.751 in study E3200;

HR 0.81 in study ML18147) and PFS (HR 0.518 in study E3200; HR 0.68 in study ML18147). Interms of safety, there was a higher overall incidence of Grade 3-5 AEs in study E3200 relative to study

Metastatic breast cancer (mBC)

Two large phase III trials were designed to investigate the treatment effect of bevacizumab incombination with two individual chemotherapy agents, as measured by the primary endpoint of PFS.

A clinically meaningful and statistically significant improvement in PFS was observed in both trials.

Summarised below are PFS results for the individual chemotherapy agents included in the indication:

- Study E2100 (paclitaxel)o Median PFS increase 5.6 months, HR 0.421 (p < 0.0001, 95% CI 0.343; 0.516)

- Study AVF3694g (capecitabine)o Median PFS increase 2.9 months, HR 0.69 (p = 0.0002, 95% CI 0.56; 0.84)

Further details of each study and the results are provided below.

Trial E2100 was an open-label, randomised, active controlled, multicentre clinical trial evaluatingbevacizumab in combination with paclitaxel for locally recurrent or metastatic breast cancer in patientswho had not previously received chemotherapy for locally recurrent and metastatic disease. Patientswere randomised to paclitaxel alone (90 mg/m2 intravenously over 1 hour once weekly for three out offour weeks) or in combination with bevacizumab (10 mg/kg intravenous infusion every two weeks).

Prior hormonal therapy for the treatment of metastatic disease was allowed. Adjuvant taxane therapywas allowed only if it was completed at least 12 months prior to trial entry. Of the 722 patients in thetrial, the majority of patients had HER2-negative disease (90%), with a small number of patients withunknown (8%) or confirmed HER2-positive status (2%), who had previously been treated with or wereconsidered unsuitable for trastuzumab therapy. Furthermore, 65% of patients had received adjuvantchemotherapy including 19% prior taxanes and 49% prior anthracyclines. Patients with central nervoussystem metastases, including previously treated or resected brain lesions, were excluded.

In trial E2100, patients were treated until disease progression. In situations where early discontinuationof chemotherapy was required, treatment with bevacizumab as a single agent continued until diseaseprogression. The patient characteristics were similar across the trial arms. The primary endpoint of thistrial was progression free survival (PFS), based on trial investigators’ assessment of diseaseprogression. In addition, an independent review of the primary endpoint was also conducted. Theresults of this trial are presented in Table 10.

Table 10 Trial E2100 efficacy results

Progression-free survival

Investigator assessment* IRF assessment

Paclitaxel Paclitaxel/bevaciz Paclitaxel Paclitaxel/bevacizumab umab(n = 354) (n = 368) (n = 354) (n = 368)

Median PFS (months) 5.8 11.4 5.8 11.3

Hazard ratio 0.421 0.483(95% CI) (0.343; 0.516) (0.385; 0.607)p-value < 0.0001 < 0.0001

Response rates (for patients with measurable disease)

Investigator assessment IRF assessment

Paclitaxel Paclitaxel/bevaciz Paclitaxel Paclitaxel/beumab vacizumab(n = 273) (n = 252) (n = 243) (n = 229)% pts with objective 23.4 48.0 22.2 49.8responsep-value < 0.0001 < 0.0001

* primary analysis

Overall survival

Paclitaxel Paclitaxel/bevacizumab(n = 354) (n = 368)

Median OS (months) 24.8 26.5

Hazard ratio 0.869(95% CI) (0.722; 1.046)p-value 0.1374

The clinical benefit of bevacizumab as measured by PFS was seen in all pre-specified subgroups tested(including disease-free interval, number of metastatic sites, prior receipt of adjuvant chemotherapy andoestrogen receptor (ER) status).

Study AVF3694g was a phase III, multicentre, randomised, placebo-controlled trial designed toevaluate the efficacy and safety of bevacizumab in combination with chemotherapy compared tochemotherapy plus placebo as first-line treatment for patients with HER2-negative metastatic orlocally recurrent breast cancer.

Chemotherapy was chosen at the investigator's discretion prior to randomisation in a 2:1 ratio toreceive either chemotherapy plus bevacizumab or chemotherapy plus placebo. The choices ofchemotherapy included capecitabine, taxane (protein-bound paclitaxel, docetaxel), andanthracycline-based agents (doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide,5-fluorouracil/doxorubicin/cyclophosphamide, 5-fluorouracil/epirubicin/cyclophosphamide) givenevery three weeks (q3w). Bevacizumab or placebo was administered at a dose of 15 mg/kg q3w.

This study included a blinded treatment phase, an optional open-label post-progression phase, and asurvival follow-up phase. During the blinded treatment phase, patients received chemotherapy andmedicinal product (bevacizumab or placebo) every 3 weeks until disease progression,treatment-limiting toxicity, or death. On documented disease progression, patients who entered theoptional open-label phase could receive open-label bevacizumab together with a wide-range of secondline therapies.

Statistical analyses were performed independently for 1) patients who received capecitabine incombination with bevacizumab or placebo; 2) patients who received taxane-based oranthracycline-based chemotherapy in combination with bevacizumab or placebo. The primaryendpoint of the study was PFS by investigator assessment. In addition, the primary endpoint was alsoassessed by an independent review committee (IRC).

The results of this study from the final protocol defined analyses for progression free survival andresponse rates for the independently powered capecitabine cohort of Study AVF3694g are presented in

Table 11. Results from an exploratory overall survival analysis which include an additional 7 monthsof follow-up (approximately 46% of patients had died) are also presented. The percentage of patientswho received bevacizumab in the open-label phase was 62.1% in the capecitabine + placebo arm and49.9% in the capecitabine + bevacizumab arm.

Table 11 Efficacy results for study AVF3694g: - Capecitabinea and Bevacizumab/Placebo(Cap + Bevacizumab/Pl)

Progression-free survivalb

Investigator Assessment IRC Assessment

Cap + Pl Cap + Cap + Pl Cap +(n = 206) Bevacizumab (n = 206) Bevacizumab(n = 409) (n = 409)

Median PFS (months) 5.7 8.6 6.2 9.8

Hazard ratio vs 0.69 (0.56; 0.84) 0.68 (0.54; 0.86)placebo arm (95% CI)p-value 0.0002 0.0011

Response rate (for patients with measurable disease)b

Cap + Pl (n = 161) Cap + Bevacizumab (n = 325)

Progression-free survivalb

Investigator Assessment IRC Assessment

Cap + Pl Cap + Cap + Pl Cap +(n = 206) Bevacizumab (n = 206) Bevacizumab(n = 409) (n = 409)% pts with objective 23.6 35.4responsep-value 0.0097

Overall survivalb

Hazard ratio (95% CI) 0.88 (0.69; 1.13)p-value (exploratory) 0.33a 1 000 mg/m2 oral twice daily for 14 days administered every 3 weeks.b Stratified analysis included all progression and death events except those where non-protocol therapy (NPT)was initiated prior to documented progression; data from those patients were censored at the last tumourassessment prior to starting NPT.

An unstratified analysis of PFS (investigator assessed) was performed that did not censor fornon-protocol therapy prior to disease progression. The results of these analyses were very similar tothe primary PFS results.

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

The safety and efficacy of bevacizumab, in addition to platinum-based chemotherapy, in the first-linetreatment of patients with non-squamous non-small cell lung cancer (NSCLC), was investigated intrials E4599 and BO17704. An overall survival benefit has been demonstrated in trial E4599 with a15 mg/kg/q3wk dose of bevacizumab. Trial BO17704 has demonstrated that both 7.5 mg/kg/q3wk and15 mg/kg/q3wk bevacizumab doses increase progression free survival and response rate.

E4599 was an open-label, randomised, active-controlled, multicentre clinical trial evaluatingbevacizumab as first-line treatment of patients with locally advanced (stage IIIb with malignant pleuraleffusion), metastatic or recurrent NSCLC other than predominantly squamous cell histology.

Patients were randomised to platinum-based chemotherapy (paclitaxel 200 mg/m2) and carboplatin

AUC = 6.0, both by intravenous infusion (PC) on day 1 of every 3-week cycle for up to 6 cycles or PCin combination with bevacizumab at a dose of 15 mg/kg intravenous infusion day 1 of every 3-weekcycle. After completion of six cycles of carboplatin-paclitaxel chemotherapy or upon prematurediscontinuation of chemotherapy, patients on the bevacizumab + carboplatin-paclitaxel arm continuedto receive bevacizumab as a single agent every 3 weeks until disease progression. 878 patients wererandomised to the two arms.

During the trial, of the patients who received trial treatment, 32.2% (136/422) of patients received7-12 administrations of bevacizumab and 21.1% (89/422) of patients received 13 or moreadministrations of bevacizumab.

The primary endpoint was duration of survival. Results are presented in Table 12.

Table 12 Efficacy results for trial E4599

Arm 1 Arm 2

Carboplatin/Paclitaxel Carboplatin/Paclitaxel +bevacizumab15 mg/kg q 3 weeks

Number of patients 444 434

Overall survival

Median (months) 10.3 12.3

Hazard ratio 0.80 (p = 0.003)95% CI (0.69; 0.93)

Progression-free survival

Median (months) 4.8 6.4

Hazard ratio 0.65 (p < 0.0001)95% CI (0.56; 0.76)

Overall response rate

Rate (percent) 12.9 29.0 (p < 0.0001)

In an exploratory analysis, the extent of bevacizumab benefit on overall survival was less pronouncedin the subgroup of patients who did not have adenocarcinoma histology.

Trial BO17704 was a randomised, double-blind phase III trial of bevacizumab in addition to cisplatinand gemcitabine versus placebo, cisplatin and gemcitabine in patients with locally advanced (stage IIIbwith supraclavicular lymph node metastases or with malignant pleural or pericardial effusion),metastatic or recurrent non-squamous NSCLC, who had not received prior chemotherapy. The primaryendpoint was progression free survival, secondary endpoints for the trial included the duration ofoverall survival.

Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m2 intravenous infusion onday 1 and gemcitabine 1250 mg/m2 intravenous infusion on days 1 and 8 of every 3-week cycle for upto 6 cycles (CG) with placebo or CG with bevacizumab at a dose of 7.5 or 15 mg/kg intravenousinfusion day 1 of every 3-week cycle. In the bevacizumab-containing arms, patients could receivebevacizumab as a single-agent every 3 weeks until disease progression or unacceptable toxicity. Trialresults show that 94% (277/296) of eligible patients went on to receive single agent bevacizumab atcycle 7. A high proportion of patients (approximately 62%) went on to receive a variety ofnon-protocol specified anti- cancer therapies, which may have impacted the analysis of overallsurvival.

The efficacy results are presented in Table 13.

Table 13 Efficacy results for trial BO17704

Cisplatin/Gemcitabine + Cisplatin/Gemcitabine

Cisplatin/Gemcitabine bevacizumab 7.5 mg/kg + bevacizumab 15+ placebo q 3 weeks mg/kg q 3 weeks

Number of patients 347 345 351

Progression-freesurvival

Median (months) 6.1 6.7 6.5(p = 0.0026) (p = 0.0301)

Hazard ratio 0.75 0.82[0.62; 0.91] [0.68; 0.98]

Best overall 20.1% 34.1% 30.4%response (p < 0.0001) (p = 0.0023)ratea

Overall survival

Median (months) 13.1 13.6 13.4(p = 0.4203) (p = 0.7613)

Hazard ratio 0.93 1.03[0.78; 1.11] [0.86, 1.23]a patients with measurable disease at baseline

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination witherlotinib

Study JO25567 was a randomised, open-label, multicentre phase II study conducted in Japan toevaluate the efficacy and safety of bevacizumab used in addition to erlotinib in patients withnon-squamous NSCLC with EGFR activating mutations (exon 19 deletion or exon 21 L858Rmutation) who had not received prior systemic therapy for stage IIIB/IV or recurrent disease.

The primary endpoint was progression-free survival (PFS) based on independent review assessment.

Secondary endpoints included overall survival, response rate, disease control rate, duration ofresponse, and safety.

EGFR mutation status was determined for each patient prior to patient screening and 154 patients wererandomised to receive either erlotinib + bevacizumab (erlotinib 150 mg oral daily + bevacizumab[15 mg/kg intravenously every 3 weeks]) or erlotinib monotherapy (150 mg oral daily) until diseaseprogression (PD) or unacceptable toxicity. In the absence of PD, discontinuation of one component ofstudy treatment in the erlotinib + bevacizumab arm did not lead to discontinuation of the othercomponent of study treatment as specified in the study protocol.

The efficacy results of the study are presented in Table 14.

Table 14 Efficacy results for study JO25567

Erlotinib Erlotinib + Bevacizumab

N = 77# N = 75#

PFS^ (months)

Median 9.7 16.0

HR (95% CI) 0.54 (0.36; 0.79)p-value 0.0015

Overall response rate

Rate (n) 63.6% (49) 69.3% (52)p-value 0.4951

Overall survival* (months)

Median 47.4 47.0

HR (95% CI) 0.81 (0.53; 1.23)p-value 0.3267# A total of 154 patients (ECOG Performance Status 0 or 1) were randomised. However two of the randomisedpatients discontinued the study before receiving any study treatment.

^ Blinded independent review (protocol-defined primary analysis).

* Exploratory analysis: final OS analysis at clinical cut off on 31 October 2017, approx. 59% of patients haddied.

CI, confidence interval; HR, Hazard ratio from unstratified Cox regression analysis; NR, not reached.

Advanced and/or metastatic renal cell cancer (mRCC)

Bevacizumab in combination with interferon alfa-2a for the first-line treatment of advanced and/ormetastatic renal cell cancer (BO17705)

This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety ofbevacizumab in combination with interferon (IFN) alfa-2a versus IFN alfa-2a alone as first-linetreatment in mRCC. The 649 randomised patients (641 treated) had Karnofsky Performance Status(KPS) of ≥ 70%, no CNS metastases and adequate organ function. Patients were nephrectomised forprimary renal cell carcinoma. Bevacizumab 10 mg/kg was given every 2 weeks until diseaseprogression. IFN alfa-2a was given up to 52 weeks or until disease progression at a recommendedstarting dose of 9 MIU three times a week, allowing a dose reduction to 3 MIU three times a week in2 steps. Patients were stratified according to country and Motzer score and the treatment arms wereshown to be well balanced for the prognostic factors.

The primary endpoint was overall survival, with secondary endpoints for the trial includingprogression-free survival. The addition of bevacizumab to IFN-alpha-2a significantly increased PFSand objective tumour response rate. These results have been confirmed through an independentradiological review. However, the increase in the primary endpoint of overall survival by 2 monthswas not significant (HR = 0.91). A high proportion of patients (approximately 63% IFN/placebo; 55%bevacizumab/IFN) received a variety of non-specified post-trial anti-cancer therapies, includingantineoplastic agents, which may have impacted the analysis of overall survival.

The efficacy results are presented in Table 15.

Table 15 Efficacy results for trial BO17705

BO17705

Placebo + IFNa Bvb + IFNa

Number of patients 322 327

Progression-free survival

Median (months) 5.4 10.2

Hazard ratio 0.6395% CI 0.52, 0.75(p-value < 0.0001)

Objective response rate (%) in patients withmeasurable disease

N 289 306

Response rate 12.8% 31.4%(p-value < 0.0001)

Overall survival

Median (months) 21.3 23.3

Hazard ratio 0.9195% CI 0.76, 1.10(p-value 0.3360)a Interferon alfa-2a 9 MIU 3x/weekb Bevacizumab 10 mg/kg q 2 wk

An exploratory multivariate Cox regression model using backward selection indicated that thefollowing baseline prognostic factors were strongly associated with survival independent of treatment:gender, white blood cell count, platelets, body weight loss in the 6 months prior to trial entry, numberof metastatic sites, sum of longest diameter of target lesions, Motzer score. Adjustment for thesebaseline factors resulted in a treatment hazard ratio of 0.78 (95% CI [0.63; 0.96], p = 0.0219),indicating a 22% reduction in the risk of death for patients in the bevacizumab + IFN alfa-2a armcompared to IFN alfa-2a arm.

Ninety-seven (97) patients in the IFN alfa-2a arm and 131 patients in the bevacizumab arm reducedthe dose of IFN alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in theprotocol. Dose-reduction of IFN alfa-2a did not appear to affect the efficacy of the combination ofbevacizumab and IFN alfa-2a based on PFS event free rates over time, as shown by a sub-groupanalysis. The 131 patients in the bevacizumab + IFN alfa-2a arm who reduced and maintained the IFNalfa-2a dose at 6 or 3 MIU during the trial, exhibited at 6, 12 and 18 months PFS event free rates of 73,52 and 21% respectively, as compared to 61, 43 and 17% in the total population of patients receivingbevacizumab + IFN alfa-2a.

This was a randomised, double-blind, phase II clinical trial investigating bevacizumab 10 mg/kg in a2 weekly schedule with the same dose of bevacizumab in combination with 150 mg daily erlotinib, inpatients with metastatic clear cell RCC. A total of 104 patients were randomised to treatment in thistrial, 53 to bevacizumab 10 mg/kg every 2 weeks plus placebo and 51 to bevacizumab 10 mg/kg every2 weeks plus erlotinib 150 mg daily. The analysis of the primary endpoint showed no differencebetween the bevacizumab + Placebo arm and the bevacizumab + Erlotinib arm (median PFS 8.5 versus9.9 months). Seven patients in each arm had an objective response. The addition of erlotinib tobevacizumab did not result in an improvement in OS (HR = 1.764; p = 0.1789), duration of objectiveresponse (6.7 vs 9.1 months) or time to symptom progression (HR = 1.172; p = 0.5076).

This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumabversus placebo. A total of 116 patients were randomised to receive bevacizumab 3 mg/kg every2 weeks (n = 39), 10 mg/kg every 2 weeks; (n = 37), or placebo (n = 40). An interim analysis showedthere was a significant prolongation of the time to progression of disease in the 10 mg/kg group ascompared with the placebo group (hazard ratio, 2.55; p < 0.001). There was a small difference, ofborderline significance, between the time to progression of disease in the 3 mg/kg group and that in theplacebo group (hazard ratio, 1.26; p = 0.053). Four patients had objective (partial) response, and all ofthese had received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%.

Epithelial ovarian, fallopian tube and primary peritoneal cancer

Front-line treatment of ovarian cancer

The safety and efficacy of bevacizumab in the front-line treatment of patients with epithelial ovarian,fallopian tube or primary peritoneal cancer were studied in two phase III trials (GOG-0218 and

BO17707) that evaluated the effect of the addition of bevacizumab to carboplatin and paclitaxelcompared to the chemotherapy regimen alone.

The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, threearm study evaluating the effect of adding bevacizumab to an approved chemotherapy regimen(carboplatin and paclitaxel) in patients with advanced (stages IIIB, IIIC and IV according to FIGOstaging version dated 1988) epithelial ovarian, fallopian tube or primary peritoneal cancer.

Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy forovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, orhormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

A total of 1873 patients were randomised in equal proportions to the following three arms:

- CPP arm: Five cycles of placebo (started cycle 2) in combination with carboplatin (AUC 6) andpaclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months oftherapy

- CPB15 arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination withcarboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for atotal of up to 15 months of therapy

- CPB15+ arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination withcarboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles followed by continued use ofbevacizumab (15 mg/kg q3w) as single agent for a total of up to 15 months of therapy.

The majority of patients included in the study were White (87% in all three arms); the median age was60 years in CPP and CPB15 arms and 59 years in CPB15+ arm; and 29% of patients in CPP or CPB15and 26% in CPB15+ were over 65 years of age. Overall approximately 50% of patients had a GOG PSof 0 at baseline, 43% a GOG PS score of 1, and 7% a GOG PS score of 2. Most patients had EOC(82% in CPP and CPB15, 85% in CPB15+) followed by PPC (16% in CPP, 15% in CPB15, 13% in

CPB15+) and FTC (1% in CPP, 3% in CPB15, 2% in CPB15+). The majority of patients had serousadenocarcinoma histologic type (85% in CPP and CPB15, 86% in CPB15+). Overall approximately34% of patients were FIGO stage III optimally debulked with gross residual disease, 40% stage IIIsub-optimally debulked, and 26% were stage IV patients.

The primary endpoint was PFS based on investigator’s assessment of disease progression based onradiological scans or CA 125 levels, or symptomatic deterioration per protocol. In addition, aprespecified analysis of the data censoring for CA-125 progression events was conducted, as well as anindependent review of PFS as determined by radiological scans.

The trial met its primary objective of PFS improvement. Compared to patients treated withchemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who receivedbevacizumab at a dose of 15 mg/kg q3w in combination with chemotherapy and continued to receivebevacizumab alone (CPB15+), had a clinically meaningful and statistically significant improvement in

PFS.

In patients who only received bevacizumab in combination with chemotherapy and did not continue toreceive bevacizumab alone (CPB15), no clinically meaningful benefit in PFS was observed.

The results of this study are summarised in Table 16.

Table 16 Efficacy results from study GOG-0218

Progression-free survival1

CPP CPB15 CPB15+(n = 625) (n = 625) (n = 623)

Median PFS (months) 10.6 11.6 14.7

Hazard ratio (95% CI)2 0.89 0.70(0.78, 1.02) (0.61, 0.81)p-value3,4 0.0437 < 0.0001

Objective response rate5

CPP CPB15 CPB15+(n = 396) (n = 393) (n = 403)% pts with objective response 63.4 66.2 66.0p-value 0.2341 0.2041

Overall survival6

CPP CPB15 CPB15+(n = 625) (n = 625) (n = 623)

Median OS (months) 40.6 38.8 43.8

Hazard ratio (95% CI)2 1.07 (0.91, 1.25) 0.88 (0.75, 1.04)p-value3 0.2197 0.06411 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions norcensored for NPT prior to disease progression) with data cut-off date of 25 February, 2010.

2 Relative to the control arm; stratified hazard ratio.3 One-sided log-rank p-value4 Subject to a p-value boundary of 0.0116.5 Patients with measurable disease at baseline.6 Final overall survival analysis performed when 46.9% of the patients had died.

Prespecified PFS analyses were conducted, all with a cut-off date of 29 September 2009. The results ofthese prespecified analyses are as follows:

- The protocol specified analysis of investigator-assessed PFS (without censoring for CA-125progression or non-protocol therapy [NPT]) shows a stratified hazard ratio of 0.71 (95% CI: 0.61-0.83, 1-sided log-rank p-value < 0.0001) when CPB15+ is compared with CPP, with a median

PFS of 10.4 months in the CPP arm and 14.1 months in the CPB15+ arm.

- The primary analysis of investigator-assessed PFS (censoring for CA-125 progressions and

NPT) shows a stratified hazard ratio of 0.62 (95% CI: 0.52-0.75, 1-sided log-rank p-value< 0.0001) when CPB15+ is compared with CPP, with a median PFS of 12.0 months in the CPParm and 18.2 months in the CPB15+ arm.

- The analysis of PFS as determined by the independent review committee (censoring for NPT)shows a stratified hazard ratio of 0.62 (95% CI: 0.50-0.77, 1-sided log-rank p-value < 0.0001)when CPB15+ is compared with CPP, with a median PFS of 13.1 in the CPP arm and19.1 months in the CPB15+ arm.

PFS subgroup analyses by disease stage and debulking status are summarised in Table 17. Theseresults demonstrate robustness of the analysis of PFS as shown in Table 16.

Table 17 PFS1 results by disease stage and debulking status from study GOG-0218

Randomised patients stage III optimally debulked disease2,3

CPP CPB15 CPB15+(n = 219) (n = 204) (n = 216)

Median PFS (months) 12.4 14.3 17.5

Hazard ratio (95% CI)4 0.81 0.66(0.62, 1.05) (0.50, 0.86)

Randomised patients with stage III suboptimally debulked disease3

CPP CPB15 CPB15+(n = 253) (n = 256) (n = 242)

Median PFS (months) 10.1 10.9 13.9

Hazard ratio (95% CI)4 0.93 0.78(0.77, 1.14) (0.63, 0.96)

Randomised patients with stage IV disease

CPP CPB15 CPB15+(n = 153) (n = 165) (n = 165)

Median PFS (months) 9.5 10.4 12.8

Hazard Ratio (95% CI)4 0.90 0.64(0.70, 1.16) (0.49, 0.82)1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions norcensored for NPT prior to disease progression) with data cut-off date of 25 February, 2010.2 With gross residual disease.3 3.7% of the overall randomised patient population had stage IIIB disease.4 Relative to the control arm.

BO17707 was a phase III, two arm, multicentre, randomised, controlled, open-label study comparingthe effect of adding bevacizumab to carboplatin plus paclitaxel in patients with FIGO stage I or IIA(Grade 3 or clear cell histology only; n = 142), or FIGO stage IIB - IV (all Grades and all histologicaltypes, n = 1386) epithelial ovarian, fallopian tube or primary peritoneal cancer following surgery(NCI-CTCAE v.3). FIGO staging version dated 1988 was used in this trial.

Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy forovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, orhormonal therapy) or previous radiotherapy to the abdomen or pelvis were excluded from the study.

A total of 1528 patients were randomised in equal proportions to the following two arms:

- CP arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks duration

- CPB7.5+ arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m2) for 6 cycles of 3 weeks plusbevacizumab (7.5 mg/kg q3w) for up to 12 months (bevacizumab was started at cycle 2 ofchemotherapy if treatment was initiated within 4 weeks of surgery or at cycle 1 if treatment wasinitiated more than 4 weeks after surgery).

The majority of patients included in the study were White (96%), the median age was 57 years in bothtreatment arms, 25% of patients in each treatment arm were 65 years of age or over, and approximately50% of patients had an ECOG PS of 1; 7% of patients in each treatment arm had an ECOG PS of 2.

The majority of patients had EOC (87.7%) followed by PPC (6.9%) and FTC (3.7%) or a mixture ofthe three origins (1.7%). Most patients were FIGO stage III (both 68%) followed by FIGO stage IV(13% and 14%), FIGO stage II (10% and 11%) and FIGO stage I (9% and 7%). The majority of thepatients in each treatment arm (74% and 71%) had poorly differentiated (Grade 3) primary tumours atbaseline. The incidence of each histologic sub-type of EOC was similar between the treatment arms;69% of patients in each treatment arm had serous adenocarcinoma histologic type.

The primary endpoint was PFS as assessed by the investigator using RECIST.

The trial met its primary objective of PFS improvement. Compared to patients treated withchemotherapy (carboplatin and paclitaxel) alone in the front-line setting, patients who receivedbevacizumab at a dose of 7.5 mg/kg q3w in combination with chemotherapy and continued to receivebevacizumab for up to 18 cycles had a statistically significant improvement in PFS.

The results of this study are summarised in Table 18.

Table 18 Efficacy results from study BO17707 (ICON7)

Progression-free survival

CP CPB7.5+(n = 764) (n = 764)

Median PFS (months)2 16.9 19.3

Hazard ratio [95% CI]2 0.86 [0.75; 0.98](p-value = 0.0185)

Objective response rate1

CP CPB7.5+(n = 277) (n = 272)

Response rate 54.9% 64.7%(p-value = 0.0188)

Overall survival3

CP CPB7.5+(n = 764) (n = 764)

Median (months) 58.0 57.4

Hazard ratio [95% CI] 0.99 [0.85; 1.15](p-value = 0.8910)1 In patients with measurable disease at baseline.2 Investigator assessed PFS analysis with data cut-off date of 30 November 2010.3 Final overall survival analysis performed when 46.7% of the patients had died with data cut-off date of31 March 2013.

The primary analysis of investigator-assessed PFS with a data cut-off date of 28 February 2010 showsan unstratified hazard ratio of 0.79 (95% CI: 0.68-0.91, 2-sided log-rank p-value 0.0010) with amedian PFS of 16.0 months in the CP arm and 18.3 months in the CPB7.5+ arm.

PFS subgroup analyses by disease stage and debulking status are summarised in Table 19. Theseresults demonstrate robustness of the primary analysis of PFS as shown in Table 18.

Table 19 PFS1 results by disease stage and debulking status from study BO17707 (ICON7)

Randomised patients with stage III optimally debulked disease2,3

CP CPB7.5+(n = 368) (n = 383)

Median PFS (months) 17.7 19.3

Hazard ratio (95% CI)4 0.89(0.74, 1.07)

Randomised patients with stage III suboptimally debulked disease3

CP CPB7.5+(n = 154) (n = 140)

Median PFS (months) 10.1 16.9

Hazard ratio (95% CI)4 0.67(0.52, 0.87)

Randomised patients with stage IV disease

CP CPB7.5+(n = 97) (n = 104)

Median PFS (months) 10.1 13.5

Hazard ratio (95% CI)4 0.74(0.55, 1.01)1 Investigator assessed PFS analysis with data cut-off date of 30 November 2010.2 With or without gross residual disease.3 5.8% of the overall randomised patient population had stage IIIB disease.4 Relative to the control arm.

Recurrent ovarian cancer

The safety and efficacy of bevacizumab in the treatment of recurrent epithelial ovarian, fallopian tubeor primary peritoneal cancer was studied in three phase III trials (AVF4095g, MO22224 and

GOG-0213) with different patient populations and chemotherapy regimens.

- AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatinand gemcitabine, followed by bevacizumab as a single agent in patients with platinum-sensitiverecurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

- GOG-0213 evaluated the efficacy and safety of bevacizumab in combination with carboplatinand paclitaxel, followed by bevacizumab as a single agent in patients with platinum-sensitiverecurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

- MO22224 evaluated the efficacy and safety of bevacizumab in combination with paclitaxel,topotecan, or pegylated liposomal doxorubicin in patients with platinum-resistant recurrentepithelial ovarian, fallopian tube or primary peritoneal cancer.

The safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrentepithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received priorchemotherapy in the recurrent setting or prior bevacizumab treatment, was studied in a phase IIIrandomised, double-blind, placebo-controlled trial (AVF4095g). The study compared the effect ofadding bevacizumab to carboplatin and gemcitabine chemotherapy and continuing bevacizumab as asingle agent to progression, to carboplatin and gemcitabine alone.

Only patients with histologically documented ovarian, primary peritoneal, or fallopian tube carcinomathat had recurred > 6 months after platinum-based chemotherapy and who had not receivedchemotherapy in the recurrent setting and who have not received prior therapy with bevacizumab orother VEGF inhibitors or VEGF receptor-targeted agents were included in the study.

A total of 484 patients with measurable disease were randomised 1:1 to either:

- Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrentplacebo every 3 weeks for 6 and up to 10 cycles followed by placebo (every 3 weeks) aloneuntil disease progression or unacceptable toxicity

- Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m2 on Days 1 and 8) and concurrentbevacizumab (15 mg/kg Day 1) every 3 weeks for 6 and up to 10 cycles followed bybevacizumab (15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity

The primary endpoint was progression-free survival based on investigator assessment using modified

RECIST 1.0. Additional endpoints included objective response, duration of response, overall survivaland safety. An independent review of the primary endpoint was also conducted.

The results of this study are summarised in Table 20.

Table 20 Efficacy results from study AVF4095g

Progression-free survival

Investigator Assessment IRC Assessment

Placebo + Bevacizumab Placebo + Bevacizumab

C/G + C/G C/G + C/G(n = 242) (n = 242) (n = 242) (n = 242)

Not censored for NPT

Median PFS (months) 8.4 12.4 8.6 12.3

Hazard ratio0.524 [0.425, 0.645] 0.480 [0.377, 0.613](95% CI)p-value < 0.0001 < 0.0001

Censored for NPT

Median PFS (months) 8.4 12.4 8.6 12.3

Hazard ratio0.484 [0.388, 0.605] 0.451 [0.351, 0.580](95% CI)p-value < 0.0001 < 0.0001

Objective response rate

Investigator Assessment IRC Assessment

Placebo + Bevacizumab Placebo + Bevacizumab

C/G + C/G C/G + C/G(n = 242) (n = 242) (n = 242) (n = 242)% pts with objective57.4% 78.5% 53.7% 74.8%responsep -value < 0.0001 < 0.0001

Overall survival

Placebo+ Bevacizumab

C/G + C/G(n = 242) (n = 242)

Median OS (months) 32.9 33.6

Hazard ratio0.952 [0.771, 1.176](95% CI)p-value 0.6479

PFS subgroup analyses depending on recurrence since last platinum therapy are summarised in

Table 21.

Table 21 Progression-free survival by time from last platinum therapy to recurrence

Investigator Assessment

Time from last platinum Placebo + C/G Bevacizumab + C/Gtherapy to recurrence (n = 242) (n = 242)6-12 months (n = 202)

Median 8.0 11.9

Hazard ratio (95% CI) 0.41 (0.29-0.58)> 12 months (n = 282)

Median 9.7 12.4

Hazard ratio (95% CI) 0.55 (0.41-0.73)

GOG-0213, a phase III randomised controlled open-label trial, studied the safety and efficacy ofbevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopiantube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting.

There was no exclusion criterion for prior anti-angiogenic therapy. The study evaluated the effect ofadding bevacizumab to carboplatin + paclitaxel and continuing bevacizumab as a single agent untildisease progression or unacceptable toxicity compared to carboplatin + paclitaxel alone.

A total of 673 patients were randomised in equal proportions to the following two treatment arms:

- CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 intravenously) every 3 weeks for 6 andup to 8 cycles.

- CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 intravenously) and concurrentbevacizumab (15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by bevacizumab(15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity.

Most patients in both the CP arm (80.4%) and the CPB arm (78.9%) were White. The median age was60.0 years in the CP arm and 59.0 years in the CPB arm. The majority of patients (CP: 64.6%; CPB:68.8%) were in the age category < 65 years. At baseline, most patients in both treatment arms had a

GOG PS of 0 (CP: 82.4%: CPB; 80.7%) or 1 (CP: 16.7%: CPB; 18.1%). A GOG PS of 2 at baselinewas reported in 0.9% of patients in the CP arm and in 1.2% of patients in the CPB arm.

The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint wasprogression-free survival (PFS). Results are presented in Table 22.

Table 22 Efficacy results1,2 from study GOG-0213

Primary endpoint

Overall survival (OS) CP CPB(n = 336) (n = 337)

Median OS (months) 37.3 42.6

Hazard ratio (95% CI) (eCRF)a 0.823 [CI: 0.680, 0.996]p-value 0.0447

Hazard ratio (95% CI) (registration 0.838 [CI: 0.693, 1.014]form)bp-value 0.0683

Secondary endpoint

Progression-free survival (PFS) CP CPB(n = 336) (n = 337)

Median PFS (months) 10.2 13.8

Hazard ratio (95% CI) 0.613 [CI: 0.521, 0.721]p-value < 0.00011 Final Analysis2 Tumour assessments and response evaluations were determined by the investigators using the GOG RECISTcriteria (Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228Y247).a Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinumfree-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgicaldebulking status Yes/No (Yes = randomised to undergo cytoreduction or randomised to not undergocytoreduction; No = not a candidate or did not consent to cytoreduction).

b Stratified by the duration of treatment free-interval prior to enrolling onto this study per the registration form,and secondary surgical debulking status Yes/No.

The trial met its primary objective of OS improvement. Treatment with bevacizumab at 15 mg/kgevery 3 weeks in combination with chemotherapy (carboplatin and paclitaxel) for 6 and up to 8 cycles,followed by bevacizumab until disease progression or unacceptable toxicity resulted, when data werederived from eCRF, in a clinically meaningful and statistically significant improvement in OScompared to treatment with carboplatin and paclitaxel alone.

Study MO22224 evaluated the efficacy and safety of bevacizumab in combination with chemotherapyfor platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Thisstudy was designed as an open-label, randomised, two-arm phase III evaluation of bevacizumab pluschemotherapy (CT + BV) versus chemotherapy alone (CT).

A total of 361 patients were enrolled into this study and administered either chemotherapy (paclitaxel,topotecan, or pegylated liposomal doxorubicin (PLD) alone or in combination with bevacizumab:

- CT Arm (chemotherapy alone):o Paclitaxel 80 mg/m2 as a 1-hour intravenous infusion on Days 1, 8, 15, and 22 every4 weeks.o Topotecan 4 mg/m2 as a 30-minute intravenous infusion on Days 1, 8, and 15 every4 weeks. Alternatively, a 1.25 mg/m2 dose could be administered over 30 minutes on Days1-5 every 3 weeks.

o PLD 40 mg/m2 as a 1 mg/min intravenous infusion on Day 1 only every 4 weeks. After

Cycle 1, the medicinal product could be delivered as a 1-hour infusion.

- CT + BV Arm (chemotherapy plus bevacizumab):o The chosen chemotherapy was combined with bevacizumab 10 mg/kg intravenously every2 weeks (or bevacizumab 15 mg/kg every 3 weeks if used in combination with topotecan1.25 mg/m2 on Days 1-5 every 3 weeks).

Eligible patients had epithelial ovarian, fallopian tube or primary peritoneal cancer that progressedwithin < 6 months of previous platinum therapy consisting of a minimum of 4 platinum therapy cycles.

Patients should have had a life expectancy of ≥ 12 weeks and no prior radiotherapy to the pelvis orabdomen. Most patients were FIGO stage IIIC or stage IV. The majority of patients in both arms hadan ECOG Performance Status (PS) of 0 (CT: 56.4% vs. CT + BV: 61.2%). The percentage of patientswith an ECOG PS of 1 or ≥ 2 was 38.7% and 5.0% in the CT arm, and 29.8% and 9.0% in the

CT + BV arm. Information on race exists for 29.3% of patients and nearly all patients were white. Themedian age of patients was 61.0 (range: 25−84) years. A total of 16 patients (4.4%) were > 75 yearsold. The overall rates of discontinuation due to adverse events were 8.8% in the CT arm and 43.6% inthe CT + BV arm (mostly due to Grade 2-3 adverse events) and the median time to discontinuation inthe CT + BV arm was 5.2 months compared with 2.4 months in the CT arm. The rates ofdiscontinuation due to adverse events in the subgroup of patients > 65 years old were 8.8% in the

CT arm and 50.0% in the CT + BV arm. The HR for PFS was 0.47 (95% CI: 0.35, 0.62) and0.45 (95% CI: 0.31, 0.67) for the < 65 and ≥ 65 subgroups, respectively.

The primary endpoint was progression-free-survival, with secondary endpoints including objectiveresponse rate and overall survival. Results are presented in Table 23.

Table 23 Efficacy Results from Study MO22224

Primary endpoint

Progression-free survival*

CT CT + BV(n = 182) (n = 179)

Median (months) 3.4 6.7

Hazard ratio (95% CI) 0.379 [0.296, 0.485]p-value < 0.0001

Secondary endpoints

Objective response rate**

CT CT + BV(n = 144) (n = 142)% patients with objective response 18 (12.5%) 40 (28.2%)p-value 0.0007

Overall survival (final analysis)***

CT CT + BV(n = 182) (n = 179)

Median OS (months) 13.3 16.6

Hazard ratio (95% CI) 0.870 [0.678, 1.116]p-value 0.2711

All analyses presented in this table are stratified analyses.

* Primary analysis was performed with a data cut-off date of 14 November 2011.

** Randomised Patients with Measurable Disease at Baseline.

***The final analysis of overall survival was performed when 266 deaths, which account for 73.7% of enrolledpatients, were observed.

The trial met its primary objective of PFS improvement. Compared to patients treated withchemotherapy (paclitaxel, topotecan or PLD) alone in the recurrent platinum-resistant setting, patientswho received bevacizumab at a dose of 10 mg/kg every 2 weeks (or 15 mg/kg every 3 weeks if used incombination with 1.25 mg/m2 topotecan on Days 1-5 every 3 weeks) in combination withchemotherapy and continued to receive bevacizumab until disease progression or unacceptabletoxicity, had a statistically significant improvement in PFS. The exploratory PFS and OS analyses bychemotherapy cohort (paclitaxel, topotecan and PLD) are summarised in Table 24.

Table 24 Exploratory PFS and OS analyses by chemotherapy cohort

CT CT + BV

Paclitaxel n = 115

Median PFS (months) 3.9 9.2

Hazard ratio (95% CI) 0.47 [0.31, 0.72]

Median OS (months) 13.2 22.4

Hazard ratio (95% CI) 0.64 [0.41, 0.99]

Topotecan n = 120

Median PFS (months) 2.1 6.2

Hazard ratio (95% CI) 0.28 [0.18, 0.44]

Median OS (months) 13.3 13.8

Hazard ratio (95% CI) 1.07 [0.70, 1.63]

PLD n = 126

Median PFS (months) 3.5 5.1

Hazard ratio (95% CI) 0.53 [0.36, 0.77]

Median OS (months) 14.1 13.7

Hazard ratio (95% CI) 0.91 [0.61, 1.35]

Cervical cancer

The efficacy and safety of bevacizumab in combination with chemotherapy (paclitaxel and cisplatin orpaclitaxel and topotecan) in the treatment for patients with persistent, recurrent or metastaticcarcinoma of the cervix was evaluated in study GOG-0240, a randomised, four-arm, open-label,multi-centre phase III trial.

A total of 452 patients were randomised to receive either:

- Paclitaxel 135 mg/m2 intravenously over 24 hours on Day 1 and cisplatin 50 mg/m2intravenously on Day 2, every 3 weeks (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 2 (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 1 (q3w)

- Paclitaxel 135 mg/m2 intravenously over 24 hours on Day 1 and cisplatin 50 mg/m2intravenously on Day 2 plus bevacizumab 15 mg/kg intravenously on Day 2 (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 2 plus bevacizumab 15 mg/kg intravenously on Day 2 (q3w); or

Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and cisplatin 50 mg/m2 intravenouslyon Day 1 plus bevacizumab 15 mg/kg intravenously on Day 1 (q3w)

- Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and topotecan 0.75 mg/m2intravenously over 30 minutes on days 1-3 (q3w)

- Paclitaxel 175 mg/m2 intravenously over 3 hours on Day 1 and topotecan 0.75 mg/m2intravenously over 30 minutes on Days 1-3 plus bevacizumab 15 mg/kg intravenously on Day 1(q3w)

Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamouscarcinoma, or adenocarcinoma of the cervix which was not amenable to curative treatment withsurgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other

VEGF inhibitors or VEGF receptor-targeted agents.

The median age was 46.0 years (range: 20-83) in the Chemo alone group and 48.0 years (range: 22-85)in the Chemo + bevacizumab group; with 9.3% of patients in the Chemo alone group and 7.5% ofpatients in the Chemo + bevacizumab group over the age of 65 years.

Of the 452 patients randomised at baseline, the majority of patients were white (80.0% in the Chemoalone group and 75.3% in the Chemo + bevacizumab group), had squamous cell carcinoma (67.1% inthe Chemo alone group and 69.6% in the Chemo + bevacizumab group), had persistent/recurrentdisease (83.6% in the Chemo alone group and 82.8% in the Chemo + bevacizumab group), had1-2 metastatic sites (72.0% in the Chemo alone group and 76.2% in the Chemo + bevacizumab group),had lymph node involvement (50.2% in the Chemo alone group and 56.4% in the

Chemo + bevacizumab group), and had a platinum free interval ≥ 6 months (72.5% in the Chemoalone group and 64.4% in the Chemo + bevacizumab group).

The primary efficacy endpoint was overall survival. Secondary efficacy endpoints includedprogression-free survival and objective response rate. Results from the primary analysis and thefollow-up analysis are presented by bevacizumab Treatment and by Trial Treatment in Table 25 and

Table 26, respectively.

Table 25 Efficacy results from study GOG-0240 by bevacizumab treatment

Chemotherapy Chemotherapy + bevacizumab(n = 225) (n = 227)

Primary endpoint

Overall survival - Primary analysis6

Median (months)1 12.9 16.8

Hazard ratio [95% CI] 0.74 [0.58, 0.94](p-value5 = 0.0132)

Overall survival - Follow-up analysis7

Median (months)1 13.3 16.8

Hazard ratio [95% CI] 0.76 [0.62, 0.94](p-value5,8 = 0.0126)

Secondary endpoints

Progression-free survival - Primary analysis6

Median PFS (months)1 6.0 8.3

Hazard ratio [95% CI] 0.66 [0.54, 0.81](p-value5 < 0.0001)

Best overall response - Primary analysis6

Responders (response rate2) 76 (33.8%) 103 (45.4%)95% CI for response rates3 [27.6%, 40.4%] [38.8%, 52.1%]

Difference in response rates 11.60%95% CI for difference in response rates4 [2.4%, 20.8%]p-value (chi-squared test) 0.01171 Kaplan-Meier estimates2 Patients and percentage of patients with best overall response of confirmed CR or PR; percentage calculatedon patients with measurable disease at baseline3 95% CI for one sample binomial using Pearson-Clopper method4 Approximate 95% CI for difference of two rates using Hauck-Anderson method5 Log-rank test (stratified)6 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the finalanalysis7 Follow-up analysis was performed with a data cut-off date of 07 March 20148 p-value displayed for descriptive purpose only

Table 26 Overall survival results from study GOG-0240 by trial treatment

Treatment Overall survival - primary Overall survival - follow-upcomparison Other factor analysis1 analysis2

Hazard ratio (95% CI) Hazard ratio (95% CI)

Bevacizumab Cisplatin + 0.72 (0.51, 1.02) 0.75 (0.55, 1.01)vs. No Paclitaxel (17.5 vs.14.3 months; p = 0.0609) (17.5 vs.15.0 months; p = 0.0584)

Bevacizumab

Topotecan + 0.76 (0.55, 1.06) 0.79 (0.59, 1.07)

Paclitaxel (14.9 vs. 11.9 months; p = (16.2 vs. 12.0 months; p = 0.1342)0.1061)

Topotecan + Bevacizumab 1.15 (0.82, 1.61) 1.15 (0.85, 1.56)

Paclitaxel vs. (14.9 vs. 17.5 months; p = (16.2 vs 17.5 months; p = 0.3769)0.4146)

Cisplatin + No 1.13 (0.81, 1.57) 1.08 (0.80, 1.45)

Paclitaxel Bevacizumab (11.9 vs.14.3 months; p = 0.4825) (12.0 vs 15.0 months; p = 0.6267)1 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the finalanalysis2 Follow-up analysis was performed with a data cut-off date of 07 March 2014; all p-values are displayed fordescriptive purpose only

The European Medicines Agency has waived the obligation to submit the results of studies, in allsubsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum,lung carcinoma (small cell and non-small cell carcinoma), kidney and renal pelvis carcinoma(excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renalmedullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excludingrhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcomaand germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix andcorpus uteri carcinoma.

High-grade glioma

Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged> 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab andirinotecan (CPT-11). There is insufficient information to determine the safety and efficacy ofbevacizumab in children with newly-diagnosed high-grade glioma.

- In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontinehigh-grade glioma (including 8 with glioblastoma [WHO Grade IV], 9 with anaplasticastrocytoma [Grade III] and 1 with anaplastic oligodendroglioma [Grade III]) were treated withbevacizumab (10 mg/kg) two weeks apart and then with bevacizumab in combination with

CPT-11 (125-350 mg/m2) once every two weeks until progression. There were no objective(partial or complete) radiological responses (MacDonald criteria). Toxicity and adversereactions included arterial hypertension and fatigue as well as CNS ischaemia with acuteneurological deficit.

- In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsedor progressive high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated withbevacizumab (10 mg/kg) and irinotecan (125 mg/m2) every 2 weeks. There were no completeresponses and 2 partial responses (MacDonald criteria).

In a randomised phase II study (BO25041) a total of 121 patients aged ≥ 3 years to < 18 years withnewly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG)were treated with post-operative radiation therapy (RT) and adjuvant temozolomide (T) with andwithout bevacizumab: 10 mg/kg every 2 weeks intravenously.

The study did not meet its primary endpoint of demonstrating a significant improvement of EFS(Central Radiology Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/Tarm compared with RT/T alone (HR = 1.44; 95% CI: 0.90, 2.30). These results were consistent withthose from various sensitivity analyses and in clinically relevant subgroups. The results for allsecondary endpoints (investigator assessed EFS, and ORR and OS) were consistent in showing noimprovement associated with the addition of bevacizumab to the RT/T arm compared with the RT/Tarm alone.

Addition of bevacizumab to RT/T did not demonstrate clinical benefit in study BO25041 in60 evaluable children patients with newly diagnosed supratentorial or infratentorial cerebellar orpeduncular high- grade glioma (HGG) (see section 4.2 for information on paediatric use).

Soft tissue sarcoma

In a randomised phase II study (BO20924) a total of 154 patients aged ≥ 6 months to < 18 years withnewly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma weretreated with standard of care (Induction IVADO/IVA +/- local therapy followed by Maintenance

Vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a totalduration of treatment of approximately 18 months. At the time of the final primary analysis, theprimary endpoint of EFS by independent central review did not show a statistically significantdifference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72).

The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the twotreatment arms in the few patients who had evaluable tumour at baseline and had a confirmed responseprior to receiving any local therapy: 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the Chemo armand 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the Bv + Chemo arm. The final overall survival(OS) analyses showed no significant clinical benefit from addition of bevacizumab to chemotherapy inthis patient population.

Addition of bevacizumab to standard of care did not demonstrate clinical benefit in clinical trial

BO20924, in 71 evaluable children (from age 6 months to less than 18 years old) patients withmetastatic Rhabdomyosarcoma and non-Rhabdomyosarcoma Soft Tissue Sarcoma.(See section 4.2 for information on paediatric use).

The incidence of AEs, including Grade ≥ 3 AEs and SAEs, was similar between the two treatmentarms. No AEs leading to death occurred in either treatment arm; all deaths were attributed to diseaseprogression. Bevacizumab addition to multimodal standard of care treatment seemed to be tolerated inthis paediatric population.

The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solidtumours. In all clinical trials, bevacizumab was administered as an intravenous infusion. The rate ofinfusion was based on tolerability, with an initial infusion duration of 90 minutes. Thepharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 mg/kg.

The typical value for central volume (Vc) was 2.73 l and 3.28 l for female and male patientsrespectively, which is in the range that has been described for IgGs and other monoclonal antibodies.

The typical value for peripheral volume (Vp) was 1.69 l and 2.35 l for female and male patientsrespectively, when bevacizumab is co-administered with anti-neoplastic agents. After correcting forbody weight, male patients had a larger Vc (+ 20%) than female patients.

Assessment of bevacizumab metabolism in rabbits following a single intravenous dose of125I-bevacizumab indicated that its metabolic profile was similar to that expected for a native IgGmolecule which does not bind VEGF. The metabolism and elimination of bevacizumab is similar toendogenous IgG i.e., primarily via proteolytic catabolism throughout the body, including endothelialcells, and does not rely primarily on elimination through the kidneys and liver. Binding of the IgG tothe FcRn receptor results in protection from cellular metabolism and the long terminal half-life.

The value for clearance is, on average, equal to 0.188 and 0.220 l/day for female and male patients,respectively. After correcting for body weight, male patients had a higher bevacizumab clearance(+ 17%) than females. According to the two-compartmental model, the elimination half-life is 18 daysfor a typical female patient and 20 days for a typical male patient.

Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumabclearance was approximately 30% faster in patients with low levels of serum albumin and 7% faster insubjects with higher tumour burden when compared with a typical patient with median values ofalbumin and tumour burden.

The population pharmacokinetics were analysed in adult and paediatric patients to evaluate the effectsof demographic characteristics. In adults, the results showed no significant difference in thepharmacokinetics of bevacizumab in relation to age.

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally impairedpatients since the kidneys are not a major organ for bevacizumab metabolism or excretion.

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients withhepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion.

The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults(7 months to 21 years, 5.9 to 125 kg) across 4 clinical studies using a population pharmacokineticmodel. The pharmacokinetic results show that the clearance and volume of distribution ofbevacizumab were comparable between paediatric and young adult patients when normalised by bodyweight, with exposure trending lower as body weight decreased. Age was not associated with thepharmacokinetics of bevacizumab when body weight was taken into account.

The pharmacokinetics of bevacizumab was well characterised by the paediatric population PK modelfor 70 patients in Study BO20924 ((1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in Study

BO25041 (1 to 17 years; 11.2 to 82.3 kg). In Study BO20924, bevacizumab exposure was generallylower compared to a typical adult patient at the same dose. In Study BO25041, bevacizumab exposurewas similar compared to a typical adult at the same dose. In both studies, bevacizumab exposuretrended lower as body weight decreased.

In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed inyoung animals with open growth plates, at bevacizumab average serum concentrations below theexpected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown toinhibit wound healing at doses below the proposed clinical dose. Effects on wound healing wereshown to be fully reversible.

Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not beenperformed.

No specific studies in animals have been conducted to evaluate the effect on fertility. An adverse effecton female fertility can however be expected as repeat dose toxicity studies in animals have showninhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and associateddecrease in ovarian and uterus weight as well as a decrease in the number of menstrual cycles.

Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits.

Observed effects included decreases in maternal and foetal body weights, an increased number offoetal resorptions and an increased incidence of specific gross and skeletal foetal malformations.

Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted inaverage serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every2 weeks. Information on foetal malformations observed in the post-marketing setting are provided insection 4.6 Fertility, Pregnancy and Lactation and 4.8 Undesirable Effects.

Sucrose

Succinic acid

Disodium edetate

Polysorbate 80

Sodium hydroxide (for pH adjustment)

Water for injections

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

A concentration dependent degradation profile of bevacizumab was observed when diluted withglucose solutions (5%).

Vial (unopened)3 years.

Chemical and physical in-use stability has been demonstrated for a period of up to 35 days at 2 °C to8 °C after dilution and a period of up to 48 hours at temperatures not exceeding 30 °C in sodiumchloride 9 mg/ml (0.9%) solution for injection. From a microbiological point of view, the productshould be used immediately. If not used immediately, in-use storage times and conditions are theresponsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unlessdilution 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.

4 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 100 mg of bevacizumab.16 ml solution in a vial (Type I glass) with a stopper (butyl rubber) containing 400 mg ofbevacizumab.

Pack of 1 vial.

Do not shake the vial.

Zirabev should be prepared by a healthcare professional using aseptic technique to ensure the sterilityof the prepared solution. A sterile needle and syringe should be used to prepare Zirabev.

The necessary amount of bevacizumab should be withdrawn and diluted to the required administrationvolume with sodium chloride 9 mg/ml (0.9%) solution for injection. The concentration of the finalbevacizumab solution should be kept within the range of 1.4 mg/ml to 16.5 mg/ml. In the majority ofthe occasions the necessary amount of Zirabev can be diluted with 0.9% sodium chloride solution forinjection to a total volume of 100 ml.

Parenteral medicinal products should be inspected visually for particulate matter and discolourationprior to administration.

No incompatibilities between Zirabev and polyvinyl chloride or polyolefine bags or infusion sets havebeen observed.

Zirabev is for single-use only, as the product contains no preservatives. Any unused medicinal productor waste material should be disposed in accordance with local requirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/18/1344/001 100 mg/4 ml vial

EU/1/18/1344/002 400 mg/16 ml vial

Date of first authorisation: 14 February 2019

Date of latest renewal: 06 November 2023

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

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