PHESGO 600mg / 600mg injectible solution medication leaflet

Phesgo 600 mg/600 mg solution for injection

Phesgo 1200 mg/600 mg solution for injection

Phesgo 600 mg/600 mg solution for injection

One vial of 10 mL solution contains 600 mg of pertuzumab and 600 mg of trastuzumab.

Each mL of solution contains 60 mg of pertuzumab and 60 mg of trastuzumab

Phesgo 1200 mg/600 mg solution for injection

One vial of 15 mL solution contains 1200 mg of pertuzumab and 600 mg of trastuzumab.

Each mL of solution contains 80 mg of pertuzumab and 40 mg of trastuzumab

Pertuzumab and trastuzumab are humanised immunoglobulin (Ig)G1 monoclonal antibodies producedin mammalian (Chinese hamster ovary) cells by recombinant deoxyribonucleic acid (DNA)technology.

Each 15 mL vial of Phesgo contains 6.0 mg of polysorbate 20.

Each 10mL vial of Phesgo contains 4.0 mg of polysorbate 20.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear to opalescent solution, colourless to slightly brownish, pH 5.2-5.8, osmolality of 270-370 and275-375 mOsmol/kg for the 1200 mg/600 mg and 600 mg/600 mg solutions, respectively.

Early breast cancer (EBC)

Phesgo is indicated for use in combination with chemotherapy in:

* the neoadjuvant treatment of adult patients with HER2-positive, locally advanced,inflammatory, or early stage breast cancer at high risk of recurrence (see section 5.1)

* the adjuvant treatment of adult patients with HER2-positive early breast cancer at high risk ofrecurrence (see section 5.1)

Metastatic breast cancer (MBC)

Phesgo is indicated for use in combination with docetaxel in adult patients with HER2-positivemetastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2therapy or chemotherapy for their metastatic disease.

Phesgo should only be initiated under the supervision of a physician experienced in the administrationof anti-cancer agents. Phesgo should be administered by a healthcare professional prepared to manageanaphylaxis and in an environment where full resuscitation facilities are immediately available.

Once pertuzumab-based therapy has been safely established, the physician may determine thesuitability of administration of Phesgo outside of the clinical setting (e.g. at home) by a healthcareprofessional (see section 4.4).

In order to prevent medication errors, it is important to check the vial label to ensure that the medicinalproduct being prepared and administered is Phesgo.

Patients currently receiving intravenous pertuzumab and trastuzumab can switch to Phesgo.

Switching treatment from intravenous pertuzumab and trastuzumab to Phesgo (or vice versa) wasinvestigated in study MO40628 (see sections 4.8 and 5.1).

Patients treated with Phesgo must have HER2-positive tumour status, defined as a score of 3+ byimmunohistochemistry (IHC) and/or a ratio of ≥ 2.0 by in situ hybridization (ISH), assessed by avalidated test.

To ensure accurate and reproducible results, the testing must be performed in a specialized laboratory,which can ensure validation of the testing procedures. For full instructions on assay performance andinterpretation, please refer to the package leaflet of validated HER2 testing assays.

For Phesgo dose recommendations in early and metastatic breast cancer please refer to Table 1.

Table 1: Phesgo recommended dosing and administration

Dose (irrespective of Approximate duration of Observation time abbody weight) subcutaneous injection

Loading dose 1200 mg pertuzumab/ 8 minutes 30 minutes600 mg trastuzumab

Maintenance dose 600 mg pertuzumab/ 5 minutes 15 minutes(every 3 weeks) 600 mg trastuzumabaPatients should be observed for injection-related reactions and hypersensitivity reactionsbObservation period should start following administration of Phesgo and be completed prior to anysubsequent administration of chemotherapy

In patients receiving a taxane, Phesgo should be administered prior to the taxane.

When administered with Phesgo, the recommended initial dose of docetaxel is 75 mg/m2 andsubsequently escalated to 100 mg/m2 depending on the chosen regimen and tolerability of the initialdose. Alternatively, docetaxel can be given at 100 mg/m2 on a 3-weekly schedule from the start, againdepending on the chosen regimen. If a carboplatin-based regimen is used, the recommended dose fordocetaxel is 75 mg/m2 throughout (no dose escalation). When administered with Phesgo in theadjuvant setting, the recommended dose of paclitaxel is 80 mg/m2 once weekly for 12 weekly cycles.

In patients receiving an anthracycline-based regimen, Phesgo should be administered followingcompletion of the entire anthracycline regimen (see section 4.4).

Metastatic breast cancer

Phesgo should be administered in combination with docetaxel. Treatment with Phesgo may continueuntil disease progression or unmanageable toxicity even if treatment with docetaxel is discontinued(see section 4.4).

Early breast cancer

In the neoadjuvant setting, Phesgo should be administered for 3 to 6 cycles in combination withchemotherapy, as part of a complete treatment regimen for early breast cancer (see section 5.1).

In the adjuvant setting, Phesgo should be administered for a total of one year (up to 18 cycles or untildisease recurrence, or unmanageable toxicity, whichever occurs first), as part of a complete regimenfor early breast cancer and regardless of the timing of surgery. Treatment should include standardanthracycline- and/or taxane-based chemotherapy. Phesgo should start on Day 1 of the first taxane-containing cycle and should continue even if chemotherapy is discontinued.

If the time between two sequential injections is:

* less than 6 weeks, the maintenance dose of Phesgo 600 mg/600 mg should be administered assoon as possible. Thereafter, continue with the 3-weekly schedule.

* 6 weeks or more, a loading dose of Phesgo 1200 mg/600 mg should be re-administeredfollowed by maintenance dose of Phesgo 600 mg/600 mg every 3 weeks thereafter.

Dose reductions are not recommended for Phesgo. Discontinuation of treatment with Phesgo may beneeded at the discretion of the physician.

Patients may continue therapy during periods of reversible chemotherapy-induced myelosuppressionbut they should be monitored carefully for complications of neutropenia during this time.

For docetaxel and other chemotherapy dose modifications, see relevant summary of productcharacteristics (SmPC).

Switching from intravenous pertuzumab and trastuzumab administration to Phesgo

* In patients receiving intravenous pertuzumab and trastuzumab with less than 6 weeks since theirlast dose, Phesgo should be administered as a maintenance dose of 600 mg pertuzumab/600 mgtrastuzumab and every 3 weeks for subsequent administrations.

* In patients receiving intravenous pertuzumab and trastuzumab with 6 weeks or more since theirlast dose, Phesgo should be administered as a loading dose of 1200 mg pertuzumab/600 mgtrastuzumab, followed by a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab every3 weeks for subsequent administrations.

Phesgo should be withheld for at least 3 weeks for any signs and symptoms suggestive of congestiveheart failure. Phesgo should be discontinued if symptomatic heart failure is confirmed (see section 4.4for more details).

Patients with metastatic breast cancer

Patients should have a pre-treatment left ventricular ejection fraction (LVEF) of ≥ 50 %. Phesgoshould be withheld for at least 3 weeks for:

* a drop in LVEF to less than 40 %

* a LVEF of 40 %-45 % associated with a fall of ≥ 10 % points below pre-treatment value.

Phesgo may be resumed if the LVEF has recovered to > 45 %, or to 40-45 % associated with adifference of < 10 % points below pre-treatment values.

Patients with early breast cancer

Patients should have a pre-treatment LVEF of ≥ 55 % (≥ 50 % after completion of the anthracyclinecomponent of chemotherapy, if given).

Phesgo should be withheld for at least 3 weeks for a drop in LVEF to less than 50 % associated with afall of ≥ 10 % points below pre-treatment values.

Phesgo may be resumed if the LVEF has recovered to ≥ 50 % or to a difference of < 10 % pointsbelow pre-treatment values.

No overall differences in efficacy of Phesgo were observed in patients ≥ 65 and < 65 years of age. Nodose adjustment of Phesgo is required in patients ≥ 65 years of age. Limited data are available inpatients > 75 years of age.

Please see section 4.8 for assessment of safety in elderly patients.

Dose adjustments of Phesgo are not needed in patients with mild or moderate renal impairment. Nodose recommendations can be made for patients with severe renal impairment because of the limitedpharmacokinetic (PK) data available (see section 5.2).

The safety and efficacy of Phesgo have not been studied in patients with hepatic impairment. Patientswith hepatic impairment are unlikely to require Phesgo dose adjustment. No specific dose adjustmentare recommended (see section 5.2).

The safety and efficacy of Phesgo in children and adolescents below 18 years of age have not beenestablished. There is no relevant use of Phesgo in the paediatric population in the indication of breastcancer.

Phesgo should be administered as a subcutaneous injection only. Phesgo is not intended forintravenous administration.

The injection site should be alternated between the left and right thigh only. New injections should begiven at least 2.5 cm from the previous site on healthy skin and never into areas where the skin is red,bruised, tender, or hard. The dose should not be split between two syringes or between two sites ofadministration. During the treatment course with Phesgo, other medicinal products for subcutaneousadministration should preferably be injected at different sites.

The loading dose and maintenance dose should be administered over 8 and 5 minutes, respectively.

An observation period of 30 minutes after completion of Phesgo loading dose and 15 minutes aftercompletion of the maintenance dose is recommended for injection-related reactions (see sections 4.4and 4.8).

Injection-related reactions

The injection may be slowed or paused if the patient experiences injection-related symptoms (seesection 4.4 and section 4.8). Treatment including oxygen, beta agonists, antihistamines, rapidintravenous fluids and antipyretics may also help alleviate systemic symptoms.

Hypersensitivity reactions /anaphylaxis

The injection should be discontinued immediately and permanently if the patient experiences a NCI-

CTCAE Grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome (seesection 4.4 and section 4.8).

For instructions on use and handling of the medicinal product before administration, see section 6.6.

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

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

Left ventricular dysfunction (including congestive heart failure)

Decreases in LVEF have been reported with medicinal products that block HER2 activity, includingpertuzumab and trastuzumab. The incidence of symptomatic left ventricular systolic dysfunction(LVD [congestive heart failure]) was higher in patients treated with pertuzumab in combination withtrastuzumab and chemotherapy compared to trastuzumab and chemotherapy. In the adjuvant setting,the majority of cases of symptomatic heart failure reported were in patients who receivedanthracycline-based chemotherapy (see section 4.8). Patients who have received prior anthracyclinesor prior radiotherapy to the chest area may be at higher risk of LVEF declines based on studies withintravenous pertuzumab in combination with trastuzumab and chemotherapy.

Patients with history of serious cardiac illness or medical conditions, history of ventriculardysrhythmias or risk factors for ventricular dysrhythmias were excluded from the (neo-)adjuvant EBCpivotal trial FEDERICA with Phesgo.

Phesgo has not been studied in patients with: a pretreatment LVEF value of < 55 % (EBC) or < 50 %(MBC); a prior history of congestive heart failure (CHF); conditions that could impair left ventricularfunction such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmiarequiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or itsequivalent. In addition, pertuzumab in combination with trastuzumab and chemotherapy has not beenstudied in patients with decreases in LVEF < 50 % during prior trastuzumab adjuvant therapy.

Assess LVEF prior to initiation of Phesgo and at regular intervals during treatment (e.g. once duringneoadjuvant treatment and every 12 weeks in the adjuvant and metastatic setting) to ensure that LVEFis within normal limits. If the LVEF has declined as indicated in section 4.2 and has not improved, orhas declined further at the subsequent assessment, discontinuation of Phesgo should be stronglyconsidered, unless the benefits for the individual patient are deemed to outweigh the risks.

Cardiac risk should be carefully considered and balanced against the medical need of the individualpatient before use of Phesgo with an anthracycline. Based on the pharmacological actions of

HER2-targeted agents and anthracyclines, the risk of cardiac toxicity might be expected to be higherwith concomitant use of Phesgo and anthracyclines than with sequential use.

Sequential use of Phesgo (in combination with a taxane) has been evaluated following the doxorubicincomponent of two anthracycline-based regimens in the FEDERICA study while sequential use ofintravenous pertuzumab (in combination with trastuzumab and a taxane) has been evaluated followingthe epirubicin or doxorubicin component of many anthracycline-based regimens in the APHINITYand BERENICE studies. Only limited safety data are available on concurrent use of intravenouspertuzumab in combination with trastuzumab and an anthracycline. In the TRYPHAENA study,intravenous pertuzumab in combination with trastuzumab was given concurrently with epirubicin, aspart of the FEC (5-fluorouracil, epirubicin, cyclophosphamide) regimen (see sections 4.8 and 5.1).

Only chemotherapy-naive patients were treated and they received low cumulative doses of epirubicin(up to 300 mg/m2). In this study, cardiac safety was similar to that observed in patients given the sameregimen but with pertuzumab administered sequentially (following FEC chemotherapy).

Injection-related reactions/infusion-related reactions (IRRs)

Phesgo has been associated with injection-related reactions (see section 4.8). Injection-relatedreactions were defined as any systemic reaction with symptoms such as fever, chills, headache, likelydue to a release of cytokines occurring within 24 hour of administration of Phesgo. Close observationof the patient during and for 30 minutes after administration of the loading dose and during and for15 minutes following the administration of the maintenance dose of Phesgo is recommended. If asignificant injection-related reaction occurs, the injection should be slowed down or paused andappropriate medical therapies should be administered. Patients should be evaluated and carefullymonitored until complete resolution of signs and symptoms. Permanent discontinuation should beconsidered in patients with severe injection-related reactions. This clinical assessment should be basedon the severity of the preceding reaction and response to administered treatment for the adversereaction (see section 4.2). Although fatal outcomes resulting from injection-related reactions have notbeen observed with Phesgo, caution should be exercised, as fatal infusion related-reactions have beenassociated with intravenous pertuzumab in combination with intravenous trastuzumab andchemotherapy.

Hypersensitivity reactions/anaphylaxis

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity reactions,including anaphylaxis and events with fatal outcomes, have been observed with pertuzumab incombination with trastuzumab and chemotherapy (see section 4.8). The majority of anaphylacticreactions occurred within the first 6-8 cycles of treatment when pertuzumab and trastuzumab weregiven in combination with chemotherapy. Medicinal products to treat such reactions, as well asemergency equipment, should be available for immediate use.

For administration outside of the clinical setting, appropriate medications for the management ofhypersensitivity reactions in line with local standard clinical practice (depending on severity and typeof reaction e.g. epinephrine, beta-agonists, antihistamines and corticosteroids) should be available forimmediate use.

Phesgo must be permanently discontinued in case of NCI-CTCAE Grade 4 hypersensitivity reactions(anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.2). Phesgo iscontraindicated in patients with known hypersensitivity to pertuzumab, trastuzumab or to any of itsexcipients (see section 4.3).

Patients treated with Phesgo in combination with a taxane are at increased risk of febrile neutropenia.

Patients treated with intravenous pertuzumab in combination with trastuzumab and docetaxel are atincreased risk of febrile neutropenia compared with patients treated with placebo, trastuzumab anddocetaxel, especially during the first 3 cycles of treatment (see section 4.8). In the CLEOPATRA trialin metastatic breast cancer, nadir neutrophil counts were similar in pertuzumab-treated and placebo-treated patients. The higher incidence of febrile neutropenia in pertuzumab-treated patients wasassociated with the higher incidence of mucositis and diarrhoea in these patients. Symptomatictreatment for mucositis and diarrhoea should be considered. No events of febrile neutropenia werereported after cessation of docetaxel.

Phesgo may elicit severe diarrhoea. Diarrhoea is most frequent during concurrent administration withtaxane therapy. Elderly patients (≥ 65 years) have a higher risk of diarrhoea compared with youngerpatients (< 65 years). Treat diarrhoea according to standard practice and guidelines. Early interventionwith loperamide, fluids and electrolyte replacement should be considered, particularly in elderlypatients, and in case of severe or prolonged diarrhoea. Interruption of treatment with Phesgo should beconsidered if no improvement in the patient’s condition is achieved. When the diarrhoea is undercontrol treatment with Phesgo may be reinstated.

Pulmonary events

Severe pulmonary events have been reported with the use of trastuzumab in the post-marketingsetting. These events have occasionally been fatal. In addition, cases of interstitial lung diseaseincluding lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleuraleffusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency also have beenreported. Risk factors associated with interstitial lung disease include prior or concomitant therapywith other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine,vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction orwith a delayed onset. Patients experiencing dyspnoea at rest due to complications of advancedmalignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patientsshould not be treated with Phesgo. Caution should be exercised for pneumonitis, especially in patientsbeing treated concomitantly with taxanes.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

This medicinal product contains polysorbate 20. Each vial of 15 mL solution contains 6.0 mg ofpolysorbate 20. Each vial of 10mL solution contains 4.0 mg of polysorbate 20. Polysorbate 20 maycause allergic reactions.

No formal drug interaction studies have been performed.

Pertuzumab

No PK interactions were observed between pertuzumab and trastuzumab, or between pertuzumab anddocetaxel in a sub-study of 37 patients in the randomised, pivotal trial CLEOPATRA in metastaticbreast cancer. In addition, in the population PK analysis, no evidence of a drug-drug interaction hasbeen shown between pertuzumab and trastuzumab or between pertuzumab and docetaxel. Thisabsence of drug-drug interaction was confirmed by PK data from the NEOSPHERE and APHINITYstudies.

Five studies evaluated the effects of pertuzumab on the PK of co-administered cytotoxic agents,docetaxel, paclitaxel, gemcitabine, capecitabine, carboplatin and erlotinib. There was no evidence ofany PK interaction between pertuzumab and any of these agents. The PK of pertuzumab in thesestudies was comparable to those observed in single-agent studies.

Trastuzumab

No formal drug interaction studies have been performed. Clinically significant interactions betweentrastuzumab and the concomitant medicinal products used in clinical trials have not been observed.

Effect of trastuzumab on the pharmacokinetics of other antineoplastic agents

PK data from studies BO15935 and M77004 in women with HER2-positive metastatic breast cancersuggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-αhydroxylpaclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab(8 mg/kg or 4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous,respectively). However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite,(7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of theelevation of this metabolite were unclear.

Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and2 mg/kg intravenous weekly) and docetaxel (60 mg/m2 intravenous) in Japanese women with

HER2-positive metastatic breast cancer, suggested that concomitant administration of trastuzumab hadno effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of

BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer tostudy the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. Theresults of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) ofcapecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plustrastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life whencombined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were notaffected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.

PK data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable

HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.

Effect of antineoplastic agents on trastuzumab pharmacokinetics

By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy(4 mg/kg loading/2 mg/kg q1w intravenous) and observed serum concentrations in Japanese womenwith HER2-positive metastatic breast cancer (study JP16003) no evidence of a PK effect of concurrentadministration of docetaxel on the pharmacokinetics of trastuzumab was found. Comparison of PKresults from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in whichpatients were treated concomitantly with trastuzumab and paclitaxel and two Phase II studies in whichtrastuzumab was administered as monotherapy (W016229 and MO16982), in women with

HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrationsvaried within and across studies but there was no clear effect of the concomitant administration ofpaclitaxel on the pharmacokinetics of trastuzumab.

Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positivemetastatic breast cancer were treated concomitantly with trastuzumab, paclitaxel and doxorubicin totrastuzumab PK data in studies where trastuzumab was administered as monotherapy (H0649g) or incombination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested noeffect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab.

Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the

PK of trastuzumab.

The administration of concomitant anastrozole did not appear to influence the pharmacokinetics oftrastuzumab.

Women of childbearing potential should use effective contraception while receiving Phesgo and for7 months following the last dose.

In animal studies pertuzumab has shown reproductive toxicity. There is only a limited amount of datafrom the use of pertuzumab in pregnant women.

From animal studies, it is not known whether trastuzumab can affect reproductive capacity (seesection 5.3). However, in the post-marketing setting, cases of foetal renal growth and/or functionimpairment in association with oligohydramnios, some of which resulted in fatal pulmonaryhypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab.

Based on the aforementioned animal studies and post-marketing data, Phesgo should therefore beavoided during pregnancy unless the potential benefit for the mother outweighs the potential risk tothe foetus. Women who become pregnant should be advised of the possibility of harm to the foetus. Ifa pregnant woman is treated with Phesgo, or if a patient becomes pregnant while receiving Phesgo orwithin 7 months following the last dose of Phesgo, close monitoring by a multidisciplinary team isdesirable.

As human IgG is secreted into human milk and the potential for absorption and harm to the infant isunknown, women should not breast-feed during Phesgo therapy and for at least 7 months followingthe last dose.

Pertuzumab

No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. Noadverse effects on male and female reproductive organs were observed in repeat-dose toxicity studiesof pertuzumab for up to six-month duration in cynomolgus monkeys (see section 5.3).

Trastuzumab

Reproduction studies conducted in cynomolgus monkeys with trastuzumab revealed no evidence ofimpaired fertility in female cynomolgus monkeys (see section 5.3).

Phesgo has minor influence on the ability to drive and use machines (see section 4.8). Patientsexperiencing injection-related reactions or dizziness (see section 4.4) should be advised not to driveand use machines until symptoms abate.

The most common ADRs (≥ 30 %) reported in patients treated with Phesgo or intravenous pertuzumabin combination with trastuzumab and chemotherapy were alopecia, diarrhoea, nausea, anemia,asthenia and arthralgia.

The most common serious adverse events (SAE) (≥ 1 %) reported in patients treated with Phesgo orintravenous pertuzumab in combination with trastuzumab were febrile neutropenia, cardiac failure,pyrexia, neutropenia, neutropenic sepsis, neutrophil count decreased and pneumonia.

The safety profile of Phesgo was overall consistent to the known safety profile of intravenouspertuzumab in combination with trastuzumab, with an additional ADR of injection site reaction(15.3 % vs. 0.4 %).

In the pivotal trial FEDERICA, SAEs were equally distributed between the Phesgo treatment arm andthe intravenous pertuzumab in combination with trastuzumab treatment arm. The following adversedrug reactions were reported with a higher frequency (≥ 5 %) with Phesgo compared to intravenouspertuzumab in combination with trastuzumab: alopecia 79 % vs 73 %, myalgia 27.0 % vs 20.6 %, anddyspnea 12.1 % vs 6 %.

The safety of pertuzumab in combination with trastuzumab has been evaluated in 3834 patients with

HER2-positive breast cancers in the pivotal trials CLEOPATRA, NEOSPHERE, TRYPHAENA

APHINITY and FEDERICA. It was generally consistent across studies, although the incidence andmost common adverse drug reactions (ADRs) varied depending on whether pertuzumab incombination with trastuzumab were administered with or without concomitant anti-neoplastic agent.

Table 2 presents, in the first column, ADRs that have been reported in association with the use ofpertuzumab in combination with trastuzumab and chemotherapy in the below mentioned pivotalclinical trials (n= 3834) and in the post-marketing setting. As pertuzumab is used in combination withtrastuzumab and chemotherapy, it is difficult to ascertain the causal relationship of an adverse reactionto a particular medicinal product. The last two columns detail ADRs reported in the Phesgo arm of

FEDERICA study (n=243) when Phesgo is administered with chemotherapy agent and asmonotherapy.

* CLEOPATRA, in which pertuzumab was given in combination with trastuzumab and docetaxelto patients with metastatic breast cancer (n= 453)

* NEOSPHERE (n= 309) and TRYPHAENA (n= 218), in which neoadjuvant pertuzumab wasgiven in combination with trastuzumab and chemotherapy to patients with locally advanced,inflammatory or early breast cancer

* APHINITY, in which adjuvant pertuzumab was given in combination with trastuzumab andanthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patientswith early breast cancer (n= 2364)

* FEDERICA, in which Phesgo (n= 243) or intravenous pertuzumab and trastuzumab (n= 247)was firstly administered in combination with chemotherapy (neoadjuvant phase) andsubsequently as monotherapy (adjuvant phase) to patients with early breast cancer.

These ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency:

* 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)

Within each frequency grouping and SOC, ADRs are presented in the order of decreasing seriousness.

Table 2 Summary of ADRs in patients treated with pertuzumab, trastuzumab in pivotalclinical trials^, ^^, and in the post-marketing setting†

N = 3834^ N = 243^^

Pertuzumab+trastuzumab Phesgo with Phesgo monotherapychemotherapy

ADR Frequency category Frequency category Frequency category(MedDRA Preferred

Term)

System Organ Class

Blood and lymphaticsystem disorders

Neutropenia Very common Very common Common

Anemia Very common Very common Common

Febrile neutropenia* Very common Common Not known

Leukopenia Very common Common Common

Left ventricular Common Uncommon Uncommondysfunction**

Cardiac failure** Common Uncommon Common

Lacrimation increased Very common Common Uncommon

Diarrhea Very common Very common Very common

Nausea Very common Very common Common

N = 3834^ N = 243^^

Pertuzumab+trastuzumab Phesgo with Phesgo monotherapychemotherapy

Vomiting Very common Very common Common

Stomatitis Very common Very common Common

Constipation Very common Very common Common

Dyspepsia Very common Very common Common

Abdominal pain Very common Common Common

General disorders andadministration siteconditions

Fatigue Very common Very common Common

Mucosal inflammation Very common Very common Uncommon

Asthenia Very common Very common Very common

Pyrexia Very common Common Common

Edema peripheral Very common Common Common

Injection site reaction°°° Very common Common Very common

Hypersensitivity*° Common Uncommon Not known

Drug hypersensitivity*° Common Uncommon Uncommon

Anaphylactic reaction*° Uncommon Not known Not known

Cytokine release syndrome° Rare Not known Not known

Nasopharyngitis Very common Common Common

Upper respiratory tract Common Common Commoninfection

Paronychia Common Common Common

N = 3834^ N = 243^^

Pertuzumab+trastuzumab Phesgo with Phesgo monotherapychemotherapy

Metabolism and nutritiondisorders

Decreased appetite Very common Very common Common

Tumour lysis syndrome† Rare Not known Not known

Musculoskeletal andconnective tissue disorders

Arthralgia Very common Very common Very common

Myalgia Very common Very common Common

Pain in extremity Very common Common Common

Dysgeusia Very common Very common Common

Headache Very common Very common Common

Peripheral sensory Very common Very common Commonneuropathy

Neuropathy peripheral Very common Very common Common

Dizziness Very common Common Common

Paraesthesia Very common Common Common

Insomnia Very common Very common Common

Respiratory, thoracic andmediastinal disorders

Epistaxis Very common Very common Common

Cough Very common Very common Common

Dyspnea Very common Common Common

Interstitial lung disease°° Uncommon Not known Not known

N = 3834^ N = 243^^

Pertuzumab+trastuzumab Phesgo with Phesgo monotherapychemotherapy

Skin and subcutaneoustissue disorders

Alopecia Very common Very common Uncommon

Rash Very common Very common Common

Dry skin Very common Very common Common

Nail disorder Very common Common Common

Pruritus Very common Common Common

Hot flush Very common Common Very common^ Shows pooled data from the overall treatment period in CLEOPATRA (data cut off 11 February 2014; mediannumber of cycles of pertuzumab was 24); and from the neoadjuvant treatment period in NEOSPHERE (mediannumber of cycles of pertuzumab was 4, across all treatment arms) and TRYPHAENA (median number of cyclesof pertuzumab was 3-6 across treatment arms); from the treatment period of APHINITY (median number ofcycles of pertuzumab was 18) and from the overall treatment period of FEDERICA (median number of cycles of

Phesgo was 18).^^Shows Phesgo data from the overall treatment period of FEDERICA (median number of cycles of Phesgo was18)

* Including ADRs with a fatal outcome have been reported.

** For the overall treatment period across the 5 studies (CLEOPATRA, NEOSPHERE, TRYPHAENA,

APHINITY, FEDERICA). The incidence of left ventricular dysfunction and cardiac failure congestive reflectthe MedDRA Preferred Terms reported in the individual studies.

° Terms that are the most frequently reported in the medical concepts of Anaphylactic reaction and

Injection/Infusion-related Reaction which are further described in the Description of selected adverse reactionssection.

°° No events of Interstitial lung disease were reported in the FeDeriCa study but these events have beenobserved with trastuzumab.

°°°Observed with Phesgo only (subcutaneous administration related). The higher frequency observed in theadjuvant phase is related to a longer period of treatment when Phesgo is administered as monotherapy.

† ADRs reported in the post marketing setting of pertuzumab and trastuzumab IV.

Phesgo

In the pivotal trial FEDERICA, the incidence of symptomatic heart failure (NYHA class III or IV)with a LVEF decline of at least 10 % points from baseline and to < 50 % was 0.4% of Phesgo treatedpatients vs 0% of intravenous pertuzumab and trastuzumab-treated patients during neoadjuvant phase(when concomitantly administered with chemotherapy). Of the patients who experienced symptomaticheart failure, none of the Phesgo-treated patients had recovered at the data cut-off and one patient waswithdrawn from Phesgo due to an event of symptomatic heart failure. The incidences of symptomaticheart failure with a LVEF decline of at least 10 % points from baseline and to < 50 % were similar inthe adjuvant (when Phesgo was administered alone) and in the follow-up phases. Asymptomatic ormildly symptomatic (NYHA class II) declines in LVEF of at least 10 %-points from baseline and to< 50 % (confirmed by secondary LVEF) were not reported in Phesgo-treated patients and werereported in 0.4% of intravenous pertuzumab and trastuzumab-treated patients during the neoadjuvantphase (see sections 4.2 and 4.4). There was no report of asymptomatic or mildly symptomatic (NYHAclass II) declines in LVEF of at least 10 % points from baseline and to < 50 % (confirmed bysecondary LVEF) in both arms in the adjuvant phase. In the follow up phase, 1.6 % of Phesgo treatedpatients and 3.6 % of intravenous pertuzumab and trastuzumab-treated patients had this type of cardiacevent.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA, the incidence of LVD during study treatment was higher in theplacebo-treated group than the pertuzumab-treated group (8.6 % and 6.6 %, respectively). Theincidence of symptomatic LVD was also lower in the pertuzumab treated group (1.8 % in the placebo-treated group vs. 1.5 % in the pertuzumab-treated group) (see section 4.4).

In the neoadjuvant trial NEOSPHERE, in which patients received four cycles of pertuzumab asneoadjuvant treatment, the incidence of LVD (during the overall treatment period) was higher in thepertuzumab, trastuzumab and docetaxel-treated group (7.5 %) compared to the trastuzumab anddocetaxel-treated group (1.9 %). There was one case of symptomatic LVD in the pertuzumab andtrastuzumab-treated group.

In the neoadjuvant trial TRYPHAENA, the incidence of LVD (during the overall treatment period)was 8.3 % in the group treated with pertuzumab plus trastuzumab and FEC (5-fluorouracil, epirubicin,cyclophosphamide) followed by pertuzumab plus trastuzumab and docetaxel; 9.3 % in the grouptreated with pertuzumab plus trastuzumab and docetaxel following FEC; and 6.6 % in the grouptreated with pertuzumab in combination with TCH (docetaxel, carboplatin and trastuzumab). Theincidence of symptomatic LVD (congestive heart failure) was 1.3 % in the group treated withpertuzumab plus trastuzumab and docetaxel following FEC (this excludes a patient who experiencedsymptomatic LVD during FEC treatment prior to receiving pertuzumab plus trastuzumab anddocetaxel) and also 1.3 % in the group treated with pertuzumab in combination with TCH. No patientsin the group treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab plustrastuzumab and docetaxel experienced symptomatic LVD.

In the neoadjuvant period of the BERENICE trial, the incidence of NYHA Class III/IV symptomatic

LVD (congestive heart failure according to NCI-CTCAE v.4) was 1.5 % in the group treated with dosedense doxorubicin and cyclophosphamide (AC) followed by pertuzumab plus trastuzumab andpaclitaxel and none of the patients (0 %) experienced symptomatic LVD in the group treated with FECfollowed by pertuzumab in combination with trastuzumab and docetaxel. The incidence ofasymptomatic LVD (ejection fraction decrease according to NCI-CTCAE v.4) was 7 % in the grouptreated with dose dense AC followed by pertuzumab plus trastuzumab and paclitaxel and 3.5 % in thegroup treated with FEC followed by pertuzumab plus trastuzumab and docetaxel.

In APHINITY, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEFdecline of at least 10 % points from baseline and to < 50 % was < 1 % (0.6 % of pertuzumab-treatedpatients vs 0.3 % of placebo-treated patients). Of the patients who experienced symptomatic heartfailure, 46.7 % of pertuzumab-treated patients and 57.1 % of placebo-treated patients had recovered(defined as 2 consecutive LVEF measurements above 50 %) at the data cutoff. The majority of theevents were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHAclass II) declines in LVEF of at least 10 % points from baseline and to < 50 % were reported in 2.7 %of pertuzumab-treated patients and 2.8 % of placebo-treated patients, of whom 79.7 % of pertuzumab-treated patients and 80.6 % of placebo-treated patients had recovered at the data cutoff.

Injection/infusion-related reactions

Phesgo

In the pivotal trial FEDERICA, an injection/infusion-related reaction was defined as any systemicreaction reported within 24 hours of Phesgo or intravenous pertuzumab in combination withtrastuzumab administration (see sections 4.2 and 4.4).

Injection-related reactions were reported in 0.4 % of Phesgo treated patients and infusion relatedreactions were reported in 10.7 % of intravenous pertuzumab and trastuzumab-treated patients in theneoadjuvant phase. In the adjuvant phase, there were no injection-related reactions reported in Phesgo

- treated patients, and infusion related reactions were reported in 1.6 % of intravenous pertuzumab andtrastuzumab-treated patients. Most of the systemic injection/infusion related reactions seen with

Phesgo or intravenous pertuzumab and trastuzumab were chills, nausea or vomiting.

Injection site reactions defined as any local reaction reported within 24 hours of Phesgoadministration, were reported in 6.9 %, and in 12.9% of Phesgo treated patients in the neoadjuvantphase and the adjuvant phase, respectively, and were all grade 1 or 2 events. Most of the localinjection site reactions seen with Phesgo were either injection site pain or injection site erythema.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

An administration-related reaction was defined in the pivotal trials as any event reported ashypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurringduring an infusion or on the same day as the infusion. In the pivotal trial CLEOPATRA, the initialdose of pertuzumab was given the day before trastuzumab and docetaxel to allow for the examinationof pertuzumab associated reactions. On the first day when only pertuzumab was administered, theoverall frequency of infusion-related reactions was 9.8 % in the placebo-treated group and 13.2 % inthe pertuzumab-treated group, with the majority of reactions being mild or moderate. The mostcommon infusion-related reactions (≥ 1.0 %) in the pertuzumab-treated group were pyrexia, chills,fatigue, headache, asthenia, hypersensitivity, and vomiting.

During the second cycle when all medicinal products were administered on the same day, the mostcommon infusion related reactions (≥ 1.0 %) in the pertuzumab-treated group were fatigue, drughypersensitivity, dysgeusia, hypersensitivity, myalgia, and vomiting (see section 4.4).

In neoadjuvant and adjuvant trials, pertuzumab was administered on the same day as the other studytreatment. Infusion-related reactions occurred in 18.6 %-25.0 % of patients on the first day ofpertuzumab administration (in combination with trastuzumab and chemotherapy). The type andseverity of events were consistent with those observed in CLEOPATRA, with a majority of reactionsbeing mild or moderate in severity.

Hypersensitivity reactions/anaphylaxis

Phesgo

In the pivotal trial FEDERICA, the overall frequency of hypersensitivity/anaphylaxis reported eventsrelated to HER2-targeted therapy was 1.2 % in the Phesgo-treated patients vs. 0.8 % in the intravenouspertuzumab and trastuzumab-treated patients, of which none were NCI-CTCAE (version 4.0) grade3-4 (see section 4.4). One patient experienced a hypersensitivity/anaphylaxis event during orimmediately after administration of Phesgo; at the first cycle which led to withdrawal from therapy(see sections 4.2 and 4.4).

During the neoadjuvant phase, 0.4 % of Phesgo treated patients and 0.4 % of intravenous pertuzumaband trastuzumab-treated patients had drug hypersensitivity. During the adjuvant phase, 0.4 % of

Phesgo treated patients had drug hypersensitivity, and none of the intravenous pertuzumab andtrastuzumab-treated patients had hypersensitivity or drug hypersensitivity.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA in metastatic breast cancer, the overall frequency of investigatorreported hypersensitivity/anaphylaxis events during the entire treatment period was 9.3 % in theplacebo-treated group and 11.3 % in the pertuzumab-treated group, of which 2.5 % and 2.0 % were

NCI-CTCAE Grade 3-4, respectively. Overall, 2 patients in the placebo-treated group and 4 patients inthe pertuzumab-treated group experienced events described as anaphylaxis by the investigator (seesection 4.4).

Overall, the majority of hypersensitivity reactions were mild or moderate in severity and resolvedupon treatment. Based on modifications made to the study treatment, most reactions were assessed assecondary to docetaxel infusions.

In the neoadjuvant and adjuvant trials, hypersensitivity/anaphylaxis events were consistent with thoseobserved in CLEOPATRA. In NEOSPHERE, two patients in the pertuzumab and docetaxel-treatedgroup experienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overallfrequency of hypersensitivity/anaphylaxis was highest in the pertuzumab and TCH treated group(13.2 % and 7.6 %, respectively), of which 2.6 % and 1.3 % of events, respectively, were NCI-

CTCAE Grade 3-4.

Phesgo

In the pivotal trial FEDERICA, febrile neutropenia (Grade 3 or 4) occurred in 6.6 % of Phesgo -treated patients and 5.6 % of intravenous pertuzumab and trastuzumab-treated patients during theneoadjuvant phase. No febrile neutropenia events (Grade 3 or 4) occurred during the adjuvant phase.

As in intravenous pertuzumab and trastuzumab pivotal trials, a higher incidence of febrile neutropenia(Grade 3 or 4) was observed among intravenous pertuzumab and trastuzumab -treated Asian patients(13.0 %), similarly, the incidence of febrile neutropenia in Phesgo-treated Asian patients was alsohigher (13.7 %) during the neoadjuvant phase. During the adjuvant phase, no events of febrileneutropenia (Grade 3 or 4) were observed in either arm.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA, the majority of patients in both treatment groups experienced atleast one leucopenic event (63.0 % of patients in the pertuzumab-treated group and 58.3 % of patientsin the placebo-treated group), of which the majority were neutropenic events (see section 4.4). Febrileneutropenia occurred in 13.7 % of pertuzumab-treated patients and 7.6 % of placebo-treated patients.

In both treatment groups, the proportion of patients experiencing febrile neutropenia was highest in thefirst cycle of therapy and declined steadily thereafter. An increased incidence of febrile neutropeniawas observed among Asian patients in both treatment groups compared with patients of other racesand from other geographic regions. Among Asian patients, the incidence of febrile neutropenia washigher in the Pertuzumab-treated group (25.8 %) compared with the placebo-treated group (11.3 %).

In the NEOSPHERE trial, 8.4 % of patients treated with neoadjuvant pertuzumab, trastuzumab anddocetaxel experienced febrile neutropenia compared with 7.5 % of patients treated with trastuzumaband docetaxel. In the TRYPHAENA trial, febrile neutropenia occurred in 17.1 % of patients treatedwith neoadjuvant pertuzumab + TCH, and 9.3 % of patients treated with neoadjuvant pertuzumab,trastuzumab and docetaxel following FEC. In TRYPHAENA, the incidence of febrile neutropenia washigher in patients who received six cycles of pertuzumab compared with patients who received threecycles of pertuzumab, independent of the chemotherapy given. As in the CLEOPATRA trial, a higherincidence of neutropenia and febrile neutropenia was observed among Asian patients compared withother patients in both neoadjuvant trials. In NEOSPHERE, 8.3 % of Asian patients treated withneoadjuvant pertuzumab, trastuzumab and docetaxel experienced febrile neutropenia compared with4.0 % of Asian patients treated with neoadjuvant trastuzumab and docetaxel.

In the APHINITY trial, febrile neutropenia occurred in 12.1 % of pertuzumab-treated patients and11.1 % of placebo-treated patients. As in the CLEOPATRA, TRYPHAENA, and NEOSPHERE trials,a higher incidence of febrile neutropenia was observed among pertuzumab-treated Asian patientscompared with other races in the APHINITY trial (15.9 % of pertuzumab-treated patients and 9.9 % ofplacebo-treated patients).

Phesgo

In the pivotal trial FEDERICA during the neoadjuvant phase, diarrhoea occurred in 60.5 % of Phesgo-treated patients and 54.8 % of intravenous pertuzumab and trastuzumab-treated patients. Grade ≥ 3diarrhoea was reported in 6.6 % of patients in the Phesgo arm vs. 4.0 % in the intravenous pertuzumaband trastuzumab arm (see section 4.4).

During the adjuvant phase, diarrhoea occurred in 17.7 % of Phesgo-treated patients and 20.6 % ofintravenous pertuzumab and trastuzumab-treated patients. Grade ≥ 3 diarrhoea was reported in 0 % ofpatients in the Phesgo arm vs. 1.2 % in the intravenous pertuzumab and trastuzumab arm.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA in metastatic breast cancer, diarrhoea occurred in 68.4 % ofpertuzumab-treated patients and 48.7 % of placebo-treated patients (see section 4.4). Most events weremild to moderate in severity and occurred in the first few cycles of treatment. The incidence of NCI-

CTCAE Grade 3-4 diarrhoea was 9.3 % in pertuzumab-treated patients vs. 5.1 % in placebo-treatedpatients. The median duration of the longest episode was 18 days in pertuzumab-treated patients and 8days in placebo-treated patients. Diarrhoeal events responded well to proactive management with anti-diarrhoeal agents.

In the NEOSPHERE trial, diarrhoea occurred in 45.8 % of patients treated with neoadjuvantpertuzumab, trastuzumab and docetaxel compared with 33.6 % of patients treated with trastuzumaband docetaxel. In the TRYPHAENA trial, diarrhoea occurred in 72.3 % of patients treated withneoadjuvant pertuzumab+ TCH and 61.4 % of patients treated with neoadjuvant pertuzumab,trastuzumab and docetaxel following FEC. In both studies most events were mild to moderate inseverity.

In the APHINITY trial, a higher incidence of diarrhoea was reported in the pertuzumab-treated arm(71.2 %) compared to the placebo arm (45.2 %). Grade ≥ 3 diarrhoea was reported in 9.8 % ofpatients in the pertuzumab arm vs. 3.7 % in the placebo arm. The majority of the reported events were

Grade 1 or 2 in severity. The highest incidence of diarrhoea (all Grades) was reported during thetargeted therapy+ taxane chemotherapy period (61.4 % of patients in the pertuzumab arm vs. 33.8 %of patients in the placebo arm). The incidence of diarrhoea was much lower after chemotherapycessation, affecting 18.1 % of patients in the pertuzumab arm vs. 9.2 % of patients in the placebo armin the post-chemotherapy targeted therapy period.

Phesgo

In the pivotal trial FEDERICA rash occurred in 10.7 % of Phesgo-treated patients and 15.5 % ofintravenous pertuzumab and trastuzumab-treated patients during the neoadjuvant phase. During theadjuvant phase, rash occurred in 8.2 % of Phesgo-treated patients and 8.7 % of intravenouspertuzumab and trastuzumab-treated patients. The majority of rash events were Grade 1 or 2.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA in metastatic breast cancer, rash occurred in 51.7 % of pertuzumab-treated patients, compared with 38.9 % of placebo-treated patients. Most events were Grade 1 or 2 inseverity, occurred in the first two cycles, and responded to standard therapies, such as topical or oraltreatment for acne.

In the NEOSPHERE trial, rash occurred in 40.2 % of patients treated with neoadjuvant pertuzumab,trastuzumab and docetaxel compared with 29.0 % of patients treated with trastuzumab and docetaxel.

In the TRYPHAENA trial, rash occurred in 36.8 % of patients treated with neoadjuvant pertuzumab +

TCH and 20.0 % of patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxelfollowing FEC. The incidence of rash was higher in patients who received six cycles of pertuzumabcompared with patients who received three cycles of pertuzumab, independent of the chemotherapygiven.

In the APHINITY trial, the adverse reaction of rash occurred in 25.8 % of patients in pertuzumab armvs. 20.3 % of patients in placebo arm. The majority of rash events were Grade 1 or 2.

Phesgo

In the pivotal trial FEDERICA, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was balancedin the two treatment groups (13.6 % of Phesgo -treated patients and 13.9 % of intravenous pertuzumaband trastuzumab-treated patients) during the neoadjuvant phase and were significantly lower duringthe adjuvant phase (0.8% of Phesgo -treated patients and 0 % of intravenous pertuzumab andtrastuzumab-treated patients).

Pertuzumab intravenous in combination with trastuzumab and chemotherapy

In the pivotal trial CLEOPATRA in metastatic breast cancer, the incidence of NCI-CTCAE v.3 Grade3-4 neutropenia was balanced in the two treatment groups (86.3 % of pertuzumab-treated patients and86.6 % of placebo-treated patients, including 60.7 % and 64.8 % Grade 4 neutropenia, respectively).

In the NEOSPHERE trial, the incidence of NCI-CTCAE v.3 Grade 3-4 neutropenia was 74.5 % inpatients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel compared with 84.5 % inpatients treated with trastuzumab and docetaxel, including 50.9 % and 60.2 % Grade 4 neutropenia,respectively. In the TRYPHAENA trial, the incidence of NCI-CTCAE v.3 Grade 3-4 neutropenia was85.3 % in patients treated with neoadjuvant pertuzumab+ TCH and 77.0 % in patients treated withneoadjuvant pertuzumab, trastuzumab and docetaxel following FEC, including 66.7 % and 59.5 %

Grade 4 neutropenia, respectively.

In the APHINITY trial, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was 40.6 % inpatients treated with pertuzumab, trastuzumab and chemotherapy compared with 39.1 % in patientstreated with placebo, trastuzumab and chemotherapy, including 28.3 % and 26.5 % Grade 4neutropenia, respectively.

As with all therapeutic proteins, there is the potential for an immune response to pertuzumab andtrastuzumab in patients treated with Phesgo.

In the FEDERICA study, the incidence of treatment-emergent anti-pertuzumab and anti-trastuzumabantibodies was 10.6 % (26/245) and 0.4 % (1/245), respectively, in patients treated with intravenouspertuzumab and trastuzumab. Among patients that tested positive to anti-pertuzumab antibodies,neutralizing anti-pertuzumab antibodies were detected in three patients.

The incidence of treatment-emergent anti-pertuzumab, anti-trastuzumab, and anti-vorhyaluronidasealfa antibodies was 12.9 % (31/241), 2.1 % (5/241), and 6.3 % (15/238), respectively, in patientstreated with Phesgo. Among these patients, neutralizing anti-pertuzumab antibodies were detected intwo patients, and neutralizing anti-trastuzumab antibodies were detected in one patient.

The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or anti-vorhyaluronidase alfa antibodies after treatment with Phesgo is unknown.

Switching treatment from intravenous pertuzumab and trastuzumab to Phesgo (or vice versa)

Study MO40628 investigated the safety of switching between intravenous pertuzumab andtrastuzumab and Phesgo subcutaneous (Arm A) and vice versa (Arm B) with a primary objective toevaluate patient preference for Phesgo (see section 5.1 for study design details).

Among the patients in Arm A, the incidence of AEs during Cycles 1-3 (intravenous treatment) was77.5 % (62/80 patients) compared to Cycles 4-6 (subcutaneous treatment) which was 72.5 % (58/80patients). Among the patients in Arm B, the incidence of AEs during Cycles 1-3 (subcutaneoustreatment) was 77.5 % (62/80 patients) compared to Cycles 4-6 (intravenous treatment) which was63.8 % (51/80 patients), mainly due to higher incidence of local injection site reactions (all grade 1 or2) during Phesgo administration. Pre-switching rates (Cycles 1-3) for serious adverse events, grade 3adverse events and treatment discontinuations due to adverse events were low (< 6 %) and similar topost-switching rates (Cycles 4-6).

No grade 4 or grade 5 adverse events were reported.

In FEDERICA, no overall differences in safety of Phesgo were observed in patients ≥ 65 and < 65years of age.

However, in the pivotal pertuzumab clinical trials with intravenous pertuzumab in combination withtrastuzumab, decreased appetite, anaemia, weight decreased, asthenia, dysgeusia, neuropathyperipheral, hypomagnesemia and diarrhoea, occurred with an incidence of ≥ 5 % higher in patients≥ 65 years of age (n= 418) compared to patients < 65 years of age (n= 2926).

Limited clinical trial data are available in patients > 75 years of age treated with Phesgo or intravenouspertuzumab and trastuzumab. Post-marketing data shows no differences in safety of pertuzumab incombination with trastuzumab in patients ≥ 65 and < 65 years of age.

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 Phesgo dose tested is 1200 mg pertuzumab/600 mg trastuzumab. In case of overdose,patients must be closely monitored for signs or symptoms of adverse reactions and appropriatesymptomatic treatment instituted.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FY01

Phesgo contains pertuzumab and trastuzumab which provides the therapeutic effect of this medicinalproduct and vorhyaluronidase alfa, an enzyme used to increase the dispersion and absorption of co-formulated substances when administered subcutaneously.

Pertuzumab and trastuzumab are recombinant humanised IgG1 monoclonal antibodies which targetthe human epidermal growth factor receptor 2 (HER2). Both substances bind to distinct HER2subdomains without competing and have complementary mechanisms for disrupting HER2 signalling:

* Pertuzumab specifically targets the extracellular dimerization domain (subdomain II) of HER2and thereby blocks ligand-dependent heterodimerization of HER2 with other HER familymembers, including epidermal growth factor receptor (EGFR), HER3 and HER4. As a result,pertuzumab inhibits ligand-activated intracellular signalling through two major signallingpathways, mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K).

Inhibition of these signalling pathways can result in cell growth arrest and apoptosis,respectively

* Trastuzumab binds to sub-domain IV, of the extracellular domain of the HER2 protein to inhibitthe ligand-independent, HER2 mediated proliferation and survival signals in human tumourcells that over express HER2.

Additionally, both substances mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Invitro, both pertuzumab and trastuzumab ADCC are exerted preferentially on HER2-overexpressingcancer cells compared with cancer cells that do not overexpress HER2.

This section is presenting the clinical experience from Phesgo fixed dose combination of pertuzumaband trastuzumab and from intravenous pertuzumab in combination with trastuzumab in patients with

HER2 overexpressing early and metastatic breast cancer.

Clinical experience of Phesgo in patients with HER2 positive early breast cancer

The clinical experience of Phesgo is based on data from a Phase III clinical trial (FEDERICA

WO40324) and a Phase II clinical trial (PHRANCESCA MO40628) in patients with HER2overexpressing early breast cancer. HER2 overexpression was determined at a central laboratory anddefined as a score of 3+ by IHC or an ISH amplification ratio ≥ 2.0 in the trial outlined below.

FEDERICA (WO40324)

FEDERICA was an open-label, multicenter, randomized study conducted in 500 patients with HER2-positive early breast cancer that was operable or locally advanced (including inflammatory) with atumour size > 2 cm or node-positive in the neoadjuvant and adjuvant settings. Patients wererandomized to receive 8 cycles of neoadjuvant chemotherapy with concurrent administration of4 cycles of either Phesgo or intravenous pertuzumab and trastuzumab during cycles 5-8. Investigatorsselected one of the two following neoadjuvant chemotherapy for individual patients:

* 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeksfollowed by paclitaxel (80 mg/m2) weekly for 12 weeks

* 4 cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeksfollowed by 4 cycles of docetaxel (75 mg/m2 for the first cycle and then 100 mg/m2 atsubsequent cycles at the investigator’s discretion) every 3 weeks

Following surgery, patients continued therapy with Phesgo or intravenous pertuzumab andtrastuzumab as treated prior to surgery for an additional 14 cycles, to complete 18 cycles of HER2targeted therapy. Patients also received adjuvant radiotherapy and endocrine therapy as per localpractice. In adjuvant period, substitution of intravenous trastuzumab for subcutaneous trastuzumabwas permitted at investigator discretion. HER2-targeted therapy was administered every 3 weeksaccording to Table 3 as follows:

Table 3: Dosing and administration of Phesgo, intravenous pertuzumab, intravenoustrastuzumab, and subcutaneous trastuzumab

Medicinal Administration Dose

Products Loading Maintenance

Phesgo Subcutaneous injection 1200 mg/600 mg 600 mg/600 mg

Pertuzumab Intravenous infusion 840 mg 420 mg

Trastuzumab Intravenous infusion 8 mg/kg 6 mg/kg

Trastuzumab Subcutaneous injection 600 mg

FEDERICA was designed to demonstrate non-inferiority of the pertuzumab Cycle 7 (i.e., pre-dose

Cycle 8) serum Ctrough of pertuzumab within Phesgo compared with intravenous pertuzumab (primaryendpoint). Key secondary endpoints at the time of primary analysis included non-inferiority of the

Cycle 7 serum trastuzumab Ctrough of trastuzumab within Phesgo compared with intravenoustrastuzumab, efficacy (locally assessed total pathological complete response, tpCR), and safetyoutcomes. Other secondary endpoints included long-term safety and clinical outcomes (iDFS and OS).

Demographics were well balanced between the two treatment arms and the median age of patientstreated in the study was 51 years. The majority of patients had hormone receptor-positive disease(61.2 %), node-positive disease (57.6 %), and were Caucasian (65.8 %).

For non-inferiority of the pertuzumab and trastuzumab exposures from Phesgo refer to section 5.2. Forsafety profile refer to section 4.8.

The analysis of secondary efficacy endpoint, tpCR (locally assessed), defined as an absence ofinvasive disease in the breast and axilla (ypT0/is, ypN0) is shown in Table 4. Results from the finalanalysis of iDFS and OS with clinical cut-off date of 2 June 2023 and a median follow up of 51months is also shown in Table 4.

Table 4: Summary of efficacy

Phesgo Intravenous(n= 248) pertuzumab +trastuzumab(n= 252)

Total pathological Complete Response (tpCR)n 248 252tpCR (ypT0/is, ypN0) 148 (59.7 %) 150 (59.5 %)95 % CI 1 (53.28; 65.84) (53.18; 65.64)

Invasive Disease Free survival (iDFS)n 234 239

Patients with event (%) 26 (11.1 %) 2 3 (9.6 %)

Unstratified Hazard Ratio (95% CI) 1.13 (0.64, 1.97)

Overall Survival (OS)n 248 252

Patients with event (%) 14 (5.6 %) 12 (4.8 %)

Hazard Ratio2 (95% CI) 1.26 (0.58, 2.72)1 Confidence interval for one sample binomial using Pearson-Clopper method2 Analysis stratified by central hormone receptor status, clinical stage and type of chemotherapy

PHRANCESCA (MO40628)

Study MO40628 investigated the safety of switching between intravenous pertuzumab andtrastuzumab and Phesgo subcutaneous and vice versa (see section 4.8) with a primary objective toevaluate patient preference for either the intravenous or the subcutaneous route of administration:85 % of patients preferred the subcutaneous route, whereas 13.8 % preferred the IV administration,and 1.2 % had no preference. A total of 160 patients were included in this 2-arm, cross-over study: 80patients were randomized to Arm A (3 cycles of intravenous pertuzumab and trastuzumab followed by3 cycles of Phesgo) and 80 patients were randomized to Arm B (3 cycles of Phesgo followed by 3cycles intravenous pertuzumab and trastuzumab). At primary analysis, the median exposure toadjuvant pertuzumab and trastuzumab (both IV and SC administration) was 11 cycles (range: 6 to 15).

Clinical experience of intravenous pertuzumab in combination with trastuzumab in HER2 positivebreast cancer

The clinical experience of intravenous pertuzumab in combination with trastuzumab is based on datafrom two randomised neoadjuvant phase II trials in early breast cancer (one controlled), a non-randomised neoadjuvant phase II trial, a randomised phase III trial in the adjuvant setting and arandomised phase III trial and a single-arm phase II trial in metastatic breast cancer. HER2overexpression was determined at a central laboratory and defined as a score of 3+ by IHC or an ISHamplification ratio ≥ 2.0 in the trials outlined below.

Early breast cancer

Neoadjuvant treatment

In the neoadjuvant setting, locally advanced and inflammatory breast cancers are considered as high-risk irrespective of hormone receptor status. In early stage breast cancer, tumour size, grade, hormonereceptor status and lymph node metastases should be taken into account in the risk assessment.

The indication in the neoadjuvant treatment of breast cancer is based on demonstration of animprovement in pathological complete response rate, and trends to improvement in disease-freesurvival (DFS) that nevertheless do not establish or precisely measure a benefit with regard to long-term outcomes, such as overall survival (OS) or DFS.

NEOSPHERE (WO20697)

NEOSPHERE is a phase II, multicentre, multinational randomised controlled trial with pertuzumaband was conducted in 417 adult female patients with newly diagnosed, early, inflammatory or locallyadvanced HER2-positive breast cancer (T2-4d; primary tumour > 2 cm in diameter) who had notreceived prior trastuzumab, chemotherapy or radiotherapy. Patients with metastases, bilateral breastcancer, clinically important cardiac risk factors (see section 4.4) or LVEF < 55 % were not included.

The majority of patients were less than 65 years old.

Patients were randomised to receive one of the following neoadjuvant regimens for 4 cycles prior tosurgery:

* Trastuzumab plus docetaxel

* Pertuzumab plus trastuzumab and docetaxel

* Pertuzumab plus trastuzumab

* Pertuzumab plus docetaxel.

Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) andoestrogen receptor (ER) or progesterone (PgR) positivity.

Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every threeweeks. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg everythree weeks. Docetaxel was given intravenously at an initial dose of 75 mg/m2 followed by 75 mg/m2or 100 mg/m2 (if tolerated) every 3 weeks. Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m2), epirubicin (90 mg/m2), cyclophosphamide (600 mg/m2) (FEC) givenintravenously every three weeks, and trastuzumab administered intravenously every three weeks tocomplete one year of therapy. Patients who only received pertuzumab plus trastuzumab prior tosurgery subsequently received both FEC and docetaxel post-surgery.

The primary endpoint of the study was pathological complete response (pCR) rate in the breast(ypT0/is). Secondary efficacy endpoints were clinical response rate, breast conserving surgery rate(T2-3 tumours only), DFS, and progression-free survival (PFS). Additional exploratory pCR ratesincluded nodal status (ypT0/isN0 and ypT0N0).

Demographics were well balanced (median age was 49-50 years, the majority were caucasian (71 %))and all patients were female. Overall 7 % of patients had inflammatory breast cancer, 32 % had locallyadvanced breast cancer and 61 % had operable breast cancer. Approximately half the patients in eachtreatment group had hormone receptor-positive disease (defined as ER positive and/or PgR positive).

The efficacy results are presented in Table 5. A statistically significant improvement in pCR rate(ypT0/is) was observed in patients receiving pertuzumab plus trastuzumab and docetaxel compared topatients receiving trastuzumab and docetaxel (45.8 % vs. 29.0 %, p value= 0.0141). A consistentpattern of results was observed regardless of pCR definition. The difference in pCR rate is consideredlikely to translate into a clinically meaningful difference in long term outcomes and is supported bypositive trends in PFS (hazard ratio [HR] = 0.69; 95 % CI 0.34; 1.40) and DFS (HR = 0.60; 95 % CI0.28; 1.27).

The pCR rates as well as the magnitude of benefit with pertuzumab (pertuzumab plus trastuzumab anddocetaxel compared to patients receiving trastuzumab and docetaxel) were lower in the subgroup ofpatients with hormone receptor-positive tumours (difference of 6 % in pCR in the breast) than inpatients with hormone receptor-negative tumours (difference of 26.4 % in pCR in the breast).pCR rates were similar in patients with operable versus locally advanced disease. There were too fewpatients with inflammatory breast cancer to draw any firm conclusions but the pCR rate was higher inpatients who received pertuzumab plus trastuzumab and docetaxel.

TRYPHAENA (BO22280)

TRYPHAENA is a multicentre, randomised phase II clinical trial conducted in 225 adult femalepatients with HER2-positive locally advanced, operable, or inflammatory breast cancer (T2-4d;primary tumour > 2 cm in diameter) who had not received prior trastuzumab, chemotherapy orradiotherapy. Patients with metastases, bilateral breast cancer, clinically important cardiac risk factors(see section 4.4) or LVEF < 55 % were not included. The majority of patients were less than 65 yearsold. Patients were randomised to receive one of three neoadjuvant regimens prior to surgery asfollows:

* 3 cycles of FEC followed by 3 cycles of docetaxel, all given concurrently with pertuzumab andtrastuzumab

* 3 cycles of FEC alone followed by 3 cycles of docetaxel, with trastuzumab and pertuzumabgiven concurrently

* 6 cycles of TCH in combination with pertuzumab.

Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) and

ER and /or PgR positivity.

Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every threeweeks. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kgevery three weeks. FEC (5-fluorouracil [500 mg/m2], epirubicin [100 mg/m2], cyclophosphamide[600 mg/m2]) were given intravenously every three weeks for 3 cycles. Docetaxel was given as aninitial dose of 75 mg/m2 intravenous infusion every three weeks with the option to escalate to100 mg/m2 at the investigator’s discretion if the initial dose was well tolerated. However, in the grouptreated with pertuzumab in combination with TCH, docetaxel was given intravenously at 75 mg/m2(no escalation was permitted) and carboplatin (AUC 6) was given intravenously every three weeks.

Following surgery all patients received trastuzumab to complete one year of therapy.

The primary endpoint of this study was cardiac safety during the neoadjuvant treatment period of thestudy. Secondary efficacy endpoints were pCR rate in the breast (ypT0/is), DFS, PFS and OS.

Demographics were well balanced between arms (median age was 49-50 years, the majority were

Caucasian [77 %]) and all patients were female. Overall 6 % of patients had inflammatory breastcancer, 25 % had locally advanced breast cancer and 69 % had operable breast cancer. Approximatelyhalf the patients in each treatment group had ER-positive and/or PgR-positive disease.

Compared with published data for similar regimens without pertuzumab, high pCR rates wereobserved in all 3 treatment arms (see Table 5). A consistent pattern of results was observed regardlessof pCR definition used. The pCR rates were lower in the subgroup of patients with hormone receptor-positive tumours (range 46.2 % to 50.0 %) than in patients with hormone receptor-negative tumours(range 65.0 % to 83.8 %).

pCR rates were similar in patients with operable and locally advanced disease. There were too fewpatients with inflammatory breast cancer to draw any firm conclusions.

Table 5 NEOSPHERE (WO20697) and TRYPHAENA (BO22280): Overview of efficacy(Intent to treat population)

NEOSPHERE (WO20697) TRYPHAENA (BO22280)

Pertuzumab+trastuzu

Pertuzuma mab+ FEC

Trastuzu b+ Pertuzuma Pertuzuma FEC Pertuzumabmab b+ 

Paramete b + Pertuzumab+docetax trastuzuma pertuzur b+ trastuzumael b +docetaxel mab+ trastuzuma +TCHb+

N= 107 docetaxel

N= 107 N= 96 trastuzu N= 77

N= 107 mab+ docetaxeldocetax N= 75el

N= 73pCR ratein the 31 45breast (29.0 %) 49 (45.8 %) 18 (16.8 %) 23 (24.0 %) (61.6 %) 43 (57.3 %) 51 (66.2 %)(ypT0/is) [20.6; [36.1; 55.7] [10.3; 25.3] [15.8; 33.7] [49.5; [45.4; 68.7] [54.6; 76.6]n (%) 38.5] 72.8][95 % CI]1

Differencein pCR + 16.8 % - 12.2 % - 21.8 %rates2 NA NA NA[3.5; 30.1] [- 23.8; - 0.5] [- 35.1; - 8.5][95 % CI]3p-value 0.0030(with 0.0141 0.0198(vs.

Simes(vs. (vs. pertuzumab+ NA NA NAcorr. for trastuzumab trastuzumab

CMH +docetaxel) +docetaxel) trastuzumab+test)4 docetaxel)pCR ratein thebreast andlymph 23 41(21.5 %) 42 (39.3 %) 12 (11.2 %) 17 (17.7 %)node (56.2 %) 41 (54.7 %) 49 (63.6 %)(ypT0/is [14.1; [30.3; 49.2] [5.9; 18.8] [10.7; 26.8] [44.1; [42.7; 66.2] [51.9; 74.3]30.5]

N0) 67.8]n (%)[95 % CI]ypT0 N0 13 37n (%) (12.1 %) 35 (32.7 %) 6 (5.6 %) 13 (13.2 %) (50.7 %) 34 (45.3 %) 40 (51.9 %)[95 % CI] [6.6; [24.0; 42.5] [2.1; 11.8] [7.4; 22.0] [38.7; [33.8; 57.3] [40.3; 63.5]19.9] 62.6]

Clinical 79 675 89 (88.1 %) 69 (67.6 %) 65 (71.4 %) 71 (94.7 %) 69 (89.6 %)

Response (79.8 %) (91.8 %)

FEC: 5-fluorouracil, epirubicin, cyclophosphamide; TCH: docetaxel, carboplatin and trastuzumab, CMH:

Cochran-Mantel-Haenszel1. 95% CI for one sample binomial using Pearson-Clopper method.2. Treatment pertuzumab+trastuzumab+docetaxel and pertuzumab+trastuzumab are compared to Trastuzumab+

Docetaxel while pertuzumab+docetaxel is compared to pertuzumab+trastuzumab+docetaxel.

3. Approximate 95 % CI for difference of two response rates using Hauck-Anderson method.4. p-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.5. Clinical response represents patients with a best overall response of CR or PR during the neoadjuvant period(in the primary breast lesion).

BERENICE (WO29217)

BERENICE is a non-randomized, open-label, multicentre, multinational, Phase II trial conducted in401 patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (withprimary tumours > 2 cm in diameter or node-positive disease).

The BERENICE study included two parallel groups of patients. Patients considered suitable forneoadjuvant treatment with trastuzumab plus anthracycline/taxane-based chemotherapy were allocatedto receive one of the two following regimens prior to surgery as follows:

* Cohort A - 4 cycles of two weekly dose-dense doxorubicin and cyclophosphamide followed by4 cycles of pertuzumab in combination with trastuzumab and paclitaxel.

* Cohort B - 4 cycles of FEC followed by 4 cycles of pertuzumab in combination withtrastuzumab and docetaxel.

Following surgery all patients received pertuzumab and trastuzumab intravenously every 3 weeks tocomplete 1 year of therapy.

The primary endpoint of the BERENICE trial is cardiac safety in the neoadjuvant period of the trial.

The primary endpoint of cardiac safety, i.e. the incidence of NYHA Class III/IV LVD and LVEFdeclines, was consistent with previous data in the neoadjuvant setting (see sections 4.4. and 4.8).

Adjuvant treatment

In the adjuvant setting, based on data from the APHINITY study, HER2-positive early breast cancerpatients at high risk of recurrence are defined as those with lymph node-positive or hormone receptor-negative disease.

APHINITY (BO25126)

APHINITY is a multicentre, randomised, double-blind, placebo-controlled Phase III trial conducted in4804 patients with HER2-positive early breast cancer who had their primary tumour excised prior torandomisation. Patients were then randomised to receive pertuzumab or placebo, in combination withadjuvant trastuzumab and chemotherapy. Investigators selected one of the following anthracycline-based or non-anthracycline-based chemotherapy regimens for individual patients:

* 3 or 4 cycles of FEC or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), followed by3 or 4 cycles of docetaxel or 12 cycles of weekly paclitaxel

* 4 cycles of AC or epirubicin and cyclophosphamide (EC), followed by 3 or 4 cycles ofdocetaxel or 12 cycles of weekly paclitaxel

* 6 cycles of docetaxel in combination with carboplatin

Pertuzumab and trastuzumab were administered intravenously (see section 4.2) every 3 weeks startingon Day 1 of the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or untilrecurrence, withdrawal of consent or unmanageable toxicity. Standard doses of 5-fluorouracil,epirubicin, doxorubicin, cyclophosphamide, docetaxel, paclitaxel and carboplatin were administered.

After completion of chemotherapy, patients received radiotherapy and/or hormone therapy as per localclinical standard.

The primary endpoint of the study was invasive disease-free survival (IDFS), defined as the time fromrandomisation to first occurrence of ipsilateral local or regional invasive breast cancer recurrence,distant recurrence, contralateral invasive breast cancer, or death from any cause. Secondary efficacyendpoints were IDFS including second primary non-breast cancer, OS, DFS, recurrence-free interval(RFI) and distant recurrence-free interval (DRFI).

Demographics were well balanced between the two treatment arms. The median age was 51 years, andover 99 % of patients were female. The majority of patients had node-positive (63 %) and/or hormonereceptor-positive disease (64 %), and were Caucasian (71 %).

After a median follow-up of 45.4 months, the APHINITY study showed a 19 % (HR = 0.81; 95 % CI0.66; 1.00 p-value 0.0446) reduction in risk of recurrence or death in patients randomised to receivepertuzumab compared with patients randomised to receive placebo.

The efficacy results from the APHINITY trial are summarised in Table 6 and in Figure 1.

Table 6 Overall efficacy: Intent to treat population

Pertuzumab + Placebo +trastuzumab + trastuzumab +chemotherapy chemotherapy

N= 2400 N= 2404

Primary Endpoint

Invasive disease free survival (IDFS)

Number (%) of patients with event 171 (7.1 %) 210 (8.7 %)

HR [95 % CI] 0.81 [0.66; 1.00]p-value (Log-Rank test, stratified1) 0.04463 year event-free rate2 [95 % CI] 94.1 [93.1; 95.0] 93.2 [92.2; 94.3]

Secondary Endpoints1

IDFS including second primary non-breastcancer

Number (%) of patients with event 189 (7.9 %) 230 (9.6 %)

HR [95% CI] 0.82 [0.68; 0.99]p-value (Log-Rank test, stratified1) 0.04303 year event-free rate2 [95 % CI] 93.5 [92.5; 94.5] 92.5 [91.4; 93.6]

Disease free survival (DFS)

Number (%) of patients with event 192 (8.0 %) 236 (9.8 %)

HR [95 % CI] 0.81 [0.67; 0.98]p-value (Log-Rank test, stratified1) 0.03273 year event-free rate2 [95 % CI] 93.4 [92.4; 94.4] 92.3 [91.2; 93.4]

Overall survival (OS)3

Number (%) of patients with event 80 (3.3 %) 89 (3.7 %)

HR [95 % CI] 0.89 [0.66; 1.21]p-value (Log-Rank test, stratified1) 0.46733 year event-free rate2 [95 % CI] 97.7 [97.0; 98.3] 97.7 [97.1; 98.3]

Key to abbreviations (Table 6): HR: Hazard Ratio; CI: Confidence Interval1. All analyses stratified by nodal status, protocol version, central hormone receptor status, and adjuvantchemotherapy regimen.2. 3-year event-free rate derived from Kaplan-Meier estimates.3. Data from first interim analysis.

Figure 1 Kaplan-Meier curve of invasive disease free survival

IDFS= invasive disease free survival; CI= confidence interval; Pla= placebo; Ptz= pertuzumab ; T= trastuzumab.

The estimate of IDFS at 4-years was 92.3 % in the pertuzumab-treated group versus 90.6 % in theplacebo-treated group. At the time of the estimate the median follow-up was 45.4 months.

Results of subgroup analysis

At the time of the primary analysis, the benefits of pertuzumab were more apparent in subgroups ofpatients a high risk of recurrence: patients with node-positive or hormone receptor-negative disease(see table 7).

Table 7 Efficacy results in subgroups by nodal status and hormone receptor status1

Number of IDFS events/Total N (%) Unstratified HR

Pertuzumab + Placebo + (95 % CI)

Population trastuzumab + trastuzumab +chemotherapy chemotherapy

Nodal status

Positive 139/1503 181/1502 0.77(9.2 %) (12.1 %) (0.62; 0.96)

Negative 32/897 29/902 1.13(3.6 %) (3.2 %) (0.68; 1.86)

Hormone receptorstatus

Negative 71/864 91/858 0.76(8.2 %) (10.6 %) (0.56; 1.04)

Positive 100/1536 119/1546 0.86(6.5 %) (7.7 %) (0.66; 1.13)1 Prespecified subgroup analyses without adjusting for multiple comparisons, therefore, results are considereddescriptive.

Estimates of IDFS rates in the lymph node-positive subgroup were 92.0 % versus 90.2 % at 3 yearsand 89.9 % vs. 86.7 % at 4 years in pertuzumab-treated patients versus placebo-treated patients,respectively. In the lymph node- negative subgroup, estimates of IDFS rates were 97.5 % versus98.4 % at 3 years and 96.2 % versus 96.7 % at 4 years in pertuzumab-treated patients versus placebo-treated patients, respectively. In the hormone receptor-negative subgroup, estimates of IDFS rateswere 92.8 % versus 91.2 % at 3 years and 91.0 % versus 88.7 % at 4 years in pertuzumab-treatedpatients versus placebo-treated patients, respectively. In the hormone receptor-positive subgroupestimates of IDFS rates were 94.8 % versus 94.4 % at 3 years and 93.0 % versus 91.6 % at 4 years inpertuzumab-treated patients versus placebo-treated patients, respectively.

Patient Reported Outcomes (PRO)

Secondary endpoints included the assessment of patient-reported global health status, role andphysical function, and treatment symptoms using the EORTC QLQ-C30 and EORTC QLQ-BR23questionnaires. In the analyses of patient-reported outcomes, a 10-point difference was consideredclinically meaningful.

Patients’ physical function, global health status and diarrhoea scores showed a clinically meaningfulchange during chemotherapy in both treatment arms. The mean decrease from baseline at that time forphysical function was - 10.7 (95 % CI - 11.4; - 10.0) in the pertuzumab arm and - 10.6 (95 %

CI - 11.4; - 9.9) in the placebo arm; global health status was - 11.2 (95 % CI - 12.2; - 10.2) in thepertuzumab arm and - 10.2 (95 % CI - 11.1; - 9.2) in the placebo arm. Change in diarrhoea symptomsincreased to + 22.3 (95 % CI 21.0; 23.6) in the pertuzumab arm versus + 9.2 (95 % CI 8.2; 10.2) in theplacebo arm.

Thereafter in both arms physical function and global health status scores returned to baseline levelsduring targeted treatment. Diarrhoea symptoms returned to baseline after HER2 therapy in thepertuzumab arm. The addition of pertuzumab to trastuzumab plus chemotherapy did not affectpatients’ overall role function over the course of the study.

Metastatic breast cancer

Pertuzumab in combination with trastuzumab and docetaxel

CLEOPATRA (WO20698) is a multicentre, randomised, double-blind, placebo-controlled phase IIIclinical trial conducted in 808 patients with HER2-positive metastatic or locally recurrent unresectablebreast cancer. Patients with clinically important cardiac risk factors were not included (see section4.4). Due to the exclusion of patients with brain metastases no data are available on pertuzumabactivity on brain metastases. There is very limited data available in patients with unresectable locallyrecurrent disease. Patients were randomised 1:1 to receive placebo + trastuzumab + docetaxel orpertuzumab + trastuzumab + docetaxel.

Pertuzumab and trastuzumab were given at standard doses in a 3-weekly regimen. Patients weretreated with pertuzumab and trastuzumab until disease progression, withdrawal of consent orunmanageable toxicity. Docetaxel was given as an initial dose of 75 mg/m2 as an intravenous infusionevery three weeks for at least 6 cycles. The dose of docetaxel could be escalated to 100 mg/m2 at theinvestigator’s discretion if the initial dose was well tolerated.

The primary endpoint of the study was PFS as assessed by an independent review facility (IRF) anddefined as the time from the date of randomisation to the date of disease progression or death (fromany cause) if the death occurred within 18 weeks of the last tumour assessment. Secondary efficacyendpoints were OS, PFS (investigator-assessed), objective response rate (ORR), duration of response,and time to symptom progression according to the FACT B Quality of Life questionnaire.

Approximately half the patients in each treatment group had hormone receptor-positive disease(defined as ER-positive and/or PgR-positive) and approximately half of the patients in each treatmentgroup had received prior adjuvant or neoadjuvant therapy. Most of these patients had received prioranthracycline therapy and 11 % of all patients had received prior trastuzumab. A total of 43 % ofpatients in both treatment groups had previously received radiotherapy. Patients’ median LVEF atbaseline was 65.0 % (range 50 % - 88 %) in both groups.

The efficacy results from the CLEOPATRA study are summarised in Table 8. A statisticallysignificant improvement in IRF-assessed PFS was demonstrated in the pertuzumab-treated groupcompared with the placebo-treated group. The results for investigator-assessed PFS were similar tothose observed for IRF-assessed PFS.

Table 8 Summary of efficacy from CLEOPATRA study

Parameter Placebo+ Pertuzumab HR p-valuetrastuzumab + (95 % CI)+ docetaxel trastuzumabn= 406 + docetaxeln= 402

Progression-free furvival(independent review) - primaryendpoint*no. of patients with an event 242 (59 %) 191 (47.5 %) 0.62 < 0.0001

Median months 12.4 18.5 [0.51; 0.75]

Overall survival - secondaryendpoint**no. of patients with an event 221 (54.4 %) 168 (41.8 %) 0.68 0.0002

Median months 40.8 56.5 [0.56; 0.84]

Objective response rate (ORR)^

- secondary endpointno. of patients with measurabledisease 336 343 Difference 0.0011

Responders*** 2 3 3 (69.3 %) 275 (80.2 %) in ORR:95 % CI for ORR [64.1; 74.2] [75.6; 84.3] 10.8 %

Complete response (CR) 1 4 ( 4.2 %) 19 (5.5 %) [4.2; 17.5]

Partial response (PR) 2 1 9 (65.2 %) 256 (74.6 %)

Stable disease (SD) 7 0 (20.8 %) 50 (14.6 %)

Progressive disease (PD) 2 8 (8.3 %) 13 (3.8 %)

Duration of response †^n= 233 275

Median weeks 54.1 87.695 % CI for median [46; 64] [71; 106]

* Primary progression-free survival analysis, cutoff date 13th May 2011.

** Event-driven final overall survival, cutoff date 11th February 2014.

*** Patients with best overall response of confirmed CR or PR by RECIST.† Evaluated in patients with best overall response of CR or PR.^ Objective response rate and duration of response are based on IRF-assessed tumour assessments.

Consistent results were observed across pre-specified patient subgroups including the subgroups basedon stratification factors of geographic region and prior adjuvant/neoadjuvant therapy or de novometastatic breast cancer (see Figure 2). A post hoc exploratory analysis revealed that for patients whohad received prior trastuzumab (n= 88), the hazard ratio for IRF-assessed PFS was 0.62 (95 % CI 0.35;1.07), compared with 0.60 (95 % CI 0.43; 0.83) for patients who had received prior therapy which didnot include trastuzumab (n= 288).

Figure 2 IRF-assessed PFS by patient subgroup

The event-driven final analysis of OS was performed when 389 patients had died (221 in the placebo-treated group and 168 in the pertuzumab-treated group). The statistically significant OS benefit infavour of the pertuzumab-treated group, previously observed at an interim analysis of OS (performedone year after the primary analysis), was maintained (HR = 0.68; p= 0.0002 log-rank test). The mediantime to death was 40.8 months in the placebo-treated group and 56.5 months in the pertuzumab-treatedgroup (see Table 8, Figure 3).

A descriptive analysis of OS performed at the end of the study when 515 patients had died (280 in theplacebo-treated group and 235 in the pertuzumab-treated group) showed that the statisticallysignificant OS benefit in favour of the pertuzumab-treated group was maintained over time after amedian follow-up of 99 months (HR = 0.69; p < 0.0001 log-rank test; median time to death40.8 months [placebo-treated group] versus 57.1 months [pertuzumab-treated group]). Landmarksurvival estimates at 8 years were 37 % in the pertuzumab-treated group and 23 % in the placebo-treated group.

Figure 3 Kaplan-Meier curve of event-driven overall survival

HR= hazard ratio; CI= confidence interval; Pla= placebo; Ptz= pertuzumab ; T= trastuzumab; D= docetaxel.

No statistically significant differences were found between the two treatment groups in Health Related

Quality of Life as assessed by FACT-B TOI-PFB scores.

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

Phesgo in all subsets of the paediatric population in breast cancer (see section 4.2 for information onpaediatric use).

The PK results for the primary endpoint of pertuzumab Cycle 7 Ctrough (i.e., pre-dose cycle 8), showednon-inferiority of pertuzumab within Phesgo (geometric mean 88.7 mcg/mL) compared to intravenouspertuzumab (geometric mean 72.4 mcg/mL) with a geometric mean ratio of 1.22 (90 % CI: 1.14-1.31).

The lower boundary of the two-sided 90 % confidence interval for the geometric mean ratio ofpertuzumab within Phesgo and intravenous pertuzumab was 1.14, i.e., greater than the predefinedmargin of 0.8.

The PK results for the secondary endpoint, trastuzumab Cycle 7 Ctrough (i.e., predose Cycle 8), showednon-inferiority of trastuzumab within Phesgo (geometric mean 57.5 mcg/mL) compared to intravenoustrastuzumab (geometric mean 43.2 mcg/mL) with a geometric mean ratio of 1.33 (90 % CI:1.24-1.43).

The median maximum serum concentration (Cmax) of pertuzumab within Phesgo and time to maximalconcentration (Tmax) were 157 mcg/mL and 3.82 days, respectively. Based on population PK analysis,the absolute bioavailability was 0.712 and the first-order absorption rate (Ka) is 0.348 (1/day).

The median Cmax of trastuzumab within Phesgo and Tmax were 114 mcg/mL and 3.84 days,respectively. Based on population PK analysis, the absolute bioavailability was 0.771 and the Ka is0.404 (1/day).

Based on population PK analysis, the volume of distribution of the central (Vc) compartment ofpertuzumab within Phesgo in the typical patient, was 2.77 litres.

Based on population PK analysis, the Vc compartment of subcutaneous trastuzumab in the typicalpatient was 2.91 litres.

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

Based on population PK analysis, the clearance of pertuzumab within Phesgo was 0.163 L/day and theelimination half-life (t1/2) was approximately 24.3 days.

Based on population PK analysis, the clearance of trastuzumab within Phesgo was 0.111 L/day.

Trastuzumab is estimated to reach concentrations that are < 1 mcg/mL (approximately 3 % of thepopulation predicted Cmin,ss, or about 97 % washout) in at least 95 % patients 7 months after the lastdose.

No studies have been conducted to investigate the pharmacokinetics of Phesgo in elderly patients.

In population PK analyses of pertuzumab within Phesgo and intravenous pertuzumab, age was notfound to significantly affect PK of pertuzumab.

In population PK analyses of subcutaneous or intravenous trastuzumab, age has been shown to haveno effect on the disposition of trastuzumab.

No studies have been conducted to investigate the pharmacokinetics of Phesgo in patients with renalimpairment.

Based on population PK analyses of pertuzumab within Phesgo and intravenous pertuzumab, renalimpairment was shown not to affect pertuzumab exposure; however, only limited data from patientswith severe renal impairment were included in population pharmacokinetic analyses.

In a population PK analysis of subcutaneous and intravenous trastuzumab, renal impairment was shownnot to affect trastuzumab disposition.

No formal PK study has been conducted in patients with hepatic impairment. Based on population PKanalyses of pertuzumab within Phesgo, mild hepatic impairment was shown not to affect pertuzumabexposure. However, only limited data from patients with mild hepatic impairment were included inpopulation PK analyses. IgG1 molecules such as pertuzumab and trastuzumab are catabolised bywidely distributed proteolytic enzymes not restricted to hepatic tissue. Therefore, changes in hepaticfunction are unlikely to have an effect on the elimination of pertuzumab and trastuzumab.

No dedicated studies were conducted with the combination of subcutaneous pertuzumab, trastuzumab,and vorhyaluronidase alfa.

Pertuzumab

No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. Nodefinitive conclusion on adverse effects can be drawn on the male reproductive organs in cynomolgusmonkey repeated dose toxicity.

Reproductive toxicology studies have been conducted in pregnant cynomolgus monkeys (Gestational

Day (GD) 19 through to GD 50) at initial doses of 30 to 150 mg/kg followed by bi weekly doses of 10to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater thanthe recommended human subcutaneous dose, based on Cmax. Intravenous administration of pertuzumabfrom GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increasesin embryo-foetal death between GD25 to GD70. The incidences of embryo-foetal loss were 33, 50,and 85 % for pregnant female monkeys treated with bi weekly pertuzumab doses of 10, 30, and100 mg/kg, respectively (4- to 35-fold greater than the recommended human dose, based on Cmax). At

Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights andmicroscopic evidence of renal hypoplasia consistent with delayed renal development were identified inall pertuzumab dose groups. In addition, consistent with foetal growth restrictions, secondary tooligohydramnios, lung hypoplasia (1 of 6 in 30 mg/kg and 1 of 2 in 100 mg/kg groups), ventricularseptal defects (1 of 6 in 30 mg/kg group), thin ventricular wall (1 of 2 in 100 mg/kg group) and minorskeletal defects (external - 3 of 6 in 30 mg/kg group) were also noted. Pertuzumab exposure wasreported in offspring from all treated groups, at levels of 29 % to 40 % of maternal serum levels at

GD100.

Subcutaneous pertuzumab (250 mg/kg/week for 4 weeks) and intravenous pertuzumab (up to150 mg/kg weekly for up to 26 weeks) was well tolerated in cynomolgus monkeys (binding species),except for the development of diarrhoea. With intravenous pertuzumab doses of 15 mg/kg and higher,intermittent mild treatment-associated diarrhoea was noted. In a subset of monkeys, chronic dosing(26 weekly doses) resulted in episodes of severe secretory diarrhoea. The diarrhoea was managed(with the exception of euthanasia of one animal, 50 mg/kg/dose) with supportive care includingintravenous fluid replacement therapy.

Trastuzumab

Reproduction studies have been conducted in Cynomolgus monkeys via the intravenous route at dosesup to 16 times that of the human maintenance trastuzumab dose in Phesgo of 600 mg formulation andhave revealed no evidence of impaired fertility or harm to the foetus. Placental transfer of trastuzumabduring the early (days 20-50 of gestation) and late (days 120-150 of gestation) foetal developmentperiod was observed.

There was no evidence of acute or multiple dose-related toxicity in studies of up to 6 months, orreproductive toxicity in teratology, female fertility or late gestational toxicity/placental transferstudies. Trastuzumab is not genotoxic. A study of trehalose, a major formulation excipient did notreveal any toxicities.

No long-term animal studies have been performed to establish the carcinogenic potential oftrastuzumab, or to determine its effects on fertility in males.

A study conducted in lactating Cynomolgus monkeys administered intravenous trastuzumab doses upto 16 times that of the human maintenance dose of 600 mg trastuzumab in the Phesgo formulationdemonstrated that trastuzumab is secreted in the milk post partum. The exposure to trastuzumab inutero and the presence of trastuzumab in the serum of infant monkeys was not associated with anyadverse effects on their growth or development from birth to 1 month of age.

Hyaluronidase

Hyaluronidase is found in most tissues of the human body. Non-clinical data for recombinant humanhyaluronidase reveal no special hazard for humans based on conventional studies of repeated dosetoxicity including safety pharmacology endpoints. Reproductive toxicology studies withvorhyaluronidase alfa revealed embryofetal toxicity in mice at high systemic exposure, but did notshow teratogenic potential.

A single dose study in rabbits and a 13-week repeat dose toxicity study in Cynomolgus monkeys wereconducted with trastuzumab subcutaneous formulation. The rabbit study was performed to specificallyexamine local tolerance aspects. The 13-week study was performed to confirm that the change to thesubcutaneous route of administration and the use of the excipient vorhyaluronidase alfa did not havean effect on the trastuzumab safety characteristics. Trastuzumab subcutaneous formulation was locallyand systemically well tolerated.

Vorhyaluronidase alfa

L-histidine

L-histidine hydrochloride monohydrateα,α-trehalose dihydrate

Sucrose

L-methionine

Polysorbate 20 (E432)

Water for injections

Phesgo is a ready to use solution which should not be mixed or diluted with other products.

18 months.

Once transferred from the vial to the syringe the medicinal product is physically and chemically stablefor 28 days at 2 °C-8 °C protected from light and for 24 hours (cumulative time in the vial and thesyringe) at ambient temperature (maximum 30 °C) in diffused daylight.

As Phesgo does not contain any antimicrobial-preservative, from a microbiological point of view, themedicinal product should be used immediately. If not used immediately, in-use storage times andconditions prior to use are the responsibility of the user and would normally not be longer than24 hours at 2 °C to 8 °C, unless preparation of the syringe has taken place in controlled and validatedaseptic conditions.

Store in a refrigerator (2 °C-8 °C).

Do not freeze.

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

For storage conditions of the opened medicinal product, see sections 6.3 and 6.6.

Phesgo 600 mg/600 mg solution for injection

Pack of one 15 mL type I borosilicate glass vial tapered with fluororesin-laminated rubber stopper,containing 10 mL solution of 600 mg of pertuzumab and 600 mg of trastuzumab.

The stopper is sealed with aluminium and covered by an orange plastic flip-off cap.

Phesgo 1200 mg/600 mg solution for injection

Pack of one 20 mL type I borosilicate glass vial tapered with fluororesin-laminated rubber stopper,containing 15 mL solution of 1200 mg of pertuzumab and 600 mg of trastuzumab.

The stopper is sealed with aluminum and covered by a cool green plastic flip-off cap.

Phesgo should be inspected visually to ensure there is no particulate matter or discolouration prior tothe administration. If particulate matter or discoloration is observed the vial should be discarded perlocal disposal guidelines.

Do not shake the vial.

A syringe, a transfer needle and an injection needle are needed to withdraw Phesgo solution from thevial and inject it subcutaneously. Phesgo may be injected using hypodermic injection needles withgauges between 25G-27G and lengths between 3/8'(10 mm)-5/8'(16 mm). Phesgo is compatible withstainless steel, polypropylene, polycarbonate, polyethylene, polyurethane, polyvinyl chloride andfluorinated ethylene polypropylene.

As Phesgo does not contain any antimicrobial-preservative, from a microbiological point of view, themedicinal product should be used immediately. If not used immediately, preparation should take placein a controlled and validated aseptic conditions. After transfer of the solution to the syringe, it isrecommended to replace the transfer needle by a syringe closing cap to avoid drying of the solution inthe syringe and not compromise the quality of the medicinal product. Label the syringe with the peel-off sticker. The hypodermic injection needle must be attached to the syringe immediately prior toadministration followed by volume adjustment to 15 mL if Phesgo 1200 mg/600 mg is used or 10 mLif Phesgo 600 mg/600 mg is used.

Phesgo is for single use only. Any unused medicinal product or waste material should be disposed ofin accordance with local requirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/20/1497/001 (1200 mg/600 mg)

EU/1/20/1497/002 (600 mg/600 mg)

Date of first authorisation: 21 December 2020

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

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