PERJETA 420mg concentrate for solution for infusion medication leaflet

Perjeta 420 mg concentrate for solution for infusion

One 14 ml vial of concentrate contains 420 mg of pertuzumab at a concentration of 30 mg/ml.

After dilution, one ml of solution contains approximately 3.02 mg of pertuzumab for the initial doseand approximately 1.59 mg of pertuzumab for the maintenance dose (see section 6.6).

Pertuzumab is a humanised IgG1 monoclonal antibody produced in mammalian (Chinese hamsterovary) cells by recombinant DNA technology.

Each 14 ml vial contains 2.8 mg of polysorbate 20

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear to slightly opalescent, colourless to pale yellow, liquid.

Early breast cancer

Perjeta is indicated for use in combination with trastuzumab and 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

Perjeta is indicated for use in combination with trastuzumab and docetaxel in adult patients with

HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not receivedprevious anti-HER2 therapy or chemotherapy for their metastatic disease.

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

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

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

The recommended initial loading dose of pertuzumab is 840 mg administered as a 60 minuteintravenous infusion, followed every 3 weeks thereafter by a maintenance dose of 420 mgadministered over a period of 30 to 60 minutes. An observation period of 30 - 60 minutes isrecommended after completion of each infusion. The observation period should be completed prior toany subsequent infusion of trastuzumab or chemotherapy (see section 4.4).

Perjeta and trastuzumab should be administered sequentially and not mixed in the same infusion bag.

Perjeta and trastuzumab can be given in any order. When administered with Perjeta therecommendation is to follow a 3 weekly schedule for trastuzumab administered as either:

* an IV infusion with an initial loading dose of trastuzumab 8 mg/kg body weight followed every3 weeks thereafter by a maintenance dose of 6 mg/kg body weightor

* a fixed subcutaneous dose of trastuzumab by injection (600 mg) every 3 weeks irrespective ofthe patient’s body weight.

In patients receiving a taxane, Perjeta and trastuzumab should be administered prior to the taxane.

When administered with Perjeta, docetaxel can be started at 75 mg/m2, and subsequently escalated to100 mg/m2 depending on the chosen regimen and tolerability of the initial dose. Alternatively,docetaxel can be given at 100 mg/m2 on a 3 weekly schedule from the start, again depending on thechosen regimen. If a carboplatin-based regimen is used, the recommended dose for docetaxel is75 mg/m2 throughout (no dose escalation). When administered with Perjeta in the adjuvant setting, therecommended dose of paclitaxel is 80 mg/m2 once weekly for 12 weekly cycles.

In patients receiving an anthracycline-based regimen, Perjeta and trastuzumab should be administeredfollowing completion of the entire anthracycline regimen (see section 4.4).

Metastatic breast cancer

Perjeta should be administered in combination with trastuzumab and docetaxel . Treatment with

Perjeta and trastuzumab may continue until disease progression or unmanageable toxicity even iftreatment with docetaxel is discontinued.

Early breast cancer

In the neoadjuvant setting, Perjeta should be administered for 3 to 6 cycles in combination withtrastuzumab and chemotherapy, as part of a complete treatment regimen for early breast cancer (seesection 5.1).

In the adjuvant setting, Perjeta should be administered in combination with trastuzumab for a total ofone year (up to 18 cycles or until disease recurrence, or unmanageable toxicity, whichever occurs first)as part of a complete regimen for early breast cancer and regardless of the timing of surgery.

Treatment should include standard anthracycline- and/or taxane-based chemotherapy. Perjeta andtrastuzumab should start on Day 1 of the first taxane-containing cycle and should continue even ifchemotherapy is discontinued.

For recommendations on delayed or missed doses, please refer to Table 1 below.

Table 1 Recommendations regarding delayed or missed doses

Time between two Perjeta trastuzumabsequential IV SCinfusions< 6 weeks The 420 mg dose of The 6 mg/kg dose of The fixed dose ofpertuzumab should be trastuzumab IV should 600 mg trastuzumabadministered as soon as be administered as soon SC should bepossible. Do not wait as possible. Do not wait administered as soonuntil the next planned until the next planned as possible.dose. Thereafter, revert dose. Thereafter, revert Do not wait until theto the original planned to the original planned next planned dose.schedule. schedule.

≥ 6 weeks The 840 mg loading dose The loading dose ofof pertuzumab should be 8 mg/kg of trastuzumabre-administered as a 60 IV should be re-minute infusion, administered overfollowed by a approximatelymaintenance dose of 420 90 minutes, followed bymg IV administered a maintenance dose ofevery 3 weeks thereafter. 6 mg/kg IV administeredevery 3 weeksthereafter.

Dose reductions are not recommended for Perjeta or trastuzumab. For details regarding trastuzumab,please refer to the summary of product characteristics (SmPC).

Patients may continue therapy during periods of reversible chemotherapy-induced myelosuppressionbut they should be monitored carefully for complications of neutropenia during this time. Fordocetaxel and other chemotherapy dose modifications, see relevant SmPC.

If trastuzumab treatment is discontinued, treatment with Perjeta should be discontinued.

Perjeta and trastuzumab should be withheld for at least 3 weeks for any signs and symptomssuggestive of congestive heart failure. Perjeta should be discontinued if symptomatic heart failure isconfirmed (see section 4.4 for more details).

Patients with metastatic breast cancer

Patients should have a pre-treatment left ventricular ejection fraction (LVEF) of ≥ 50%. Perjeta andtrastuzumab should 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.

Perjeta and trastuzumab may be resumed if the LVEF has recovered to > 45%, or to 40-45%associated with a difference 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). Perjeta and trastuzumab should be withheld for at least 3weeks for:

* a drop in LVEF to less than 50% associated with a fall of ≥ 10% points below pre-treatmentvalues.

Perjeta and trastuzumab may be resumed if the LVEF has recovered to ≥50% or to a difference of< 10% points below pre-treatment values.

No overall differences in efficacy of Perjeta were observed in patients ≥ 65 and < 65 years of age. Nodose adjustment is necessary in the elderly population ≥ 65 years of age. Limited data are available inpatients > 75 years of age. Please see section 4.8 for assessment of safety of Perjeta in elderly patients.

Dose adjustments of pertuzumab are not needed in patients with mild or moderate renal impairment.

No dose recommendations can be made for patients with severe renal impairment because of thelimited pharmacokinetic data available (see section 5.2).

The safety and efficacy of Perjeta have not been studied in patients with hepatic impairment. Nospecific dose recommendations can be made.

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

Perjeta is administered intravenously by infusion. It should not be administered as an intravenous pushor bolus. For instructions on dilution of Perjeta prior to administration, see sections 6.2 and 6.6.

For the initial dose, the recommended infusion period is 60 minutes. If the first infusion is welltolerated, subsequent infusions may be administered over a period of 30 minutes to 60 minutes (seesection 4.4).

The infusion rate may be slowed or interrupted if the patient develops an infusion-related reaction (seesection 4.8). The infusion may be resumed when symptoms abate. Treatment including oxygen, betaagonists, antihistamines, rapid i.v. fluids and antipyretics may also help alleviate symptoms.

Hypersensitivity reactions/anaphylaxis

The infusion 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).

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

In order to improve the traceability of biological medicinal products, the name and batch number ofthe 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, including

Perjeta. The incidence of symptomatic left ventricular systolic dysfunction (LVD) [congestive heartfailure] was higher in patients treated with Perjeta in combination with trastuzumab and chemotherapycompared with trastuzumab and chemotherapy . Patients who have received prior anthracyclines orprior radiotherapy to the chest area may be at higher risk of LVEF declines. The majority of cases ofsymptomatic heart failure reported in the adjuvant setting were in patients who received anthracycline-based chemotherapy (see section 4.8).

Perjeta has not been studied in patients with: a pre-treatment LVEF value of < 50%; a prior history ofcongestive heart failure (CHF); LVEF declines to < 50% during prior trastuzumab adjuvant therapy; orconditions that could impair left ventricular function such as uncontrolled hypertension, recentmyocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prioranthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent.

Assess LVEF prior to initiation of Perjeta and at regular intervals during treatment with Perjeta (e.g.once during neoadjuvant treatment and every 12 weeks in the adjuvant or metastatic setting) to ensurethat LVEF is within normal limits. If the LVEF has declined as indicated in section 4.2 and has notimproved, or has declined further at the subsequent assessment, discontinuation of Perjeta andtrastuzumab should be strongly considered, unless the benefits for the individual patient are deemed tooutweigh the risks.

Cardiac risk should be carefully considered and balanced against the medical need of the individualpatient before use of Perjeta 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 Perjeta and anthracyclines than with sequential use.

Sequential use of Perjeta (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. However, only limited safety data are available on concurrent use of Perjetaand an anthracycline. In the TRYPHAENA study, Perjeta 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 Perjeta administered sequentially (following FEC chemotherapy).

Perjeta has been associated with infusion-related reactions, including events with a fatal outcome (seesection 4.8). Close observation of the patient during and for 60 minutes after the first infusion andduring and for 30-60 minutes after subsequent infusions of Perjeta is recommended. If a significantinfusion-related reaction occurs, the infusion should be slowed down or interrupted and appropriatemedical therapies should be administered. Patients should be evaluated and carefully monitored untilcomplete resolution of signs and symptoms. Permanent discontinuation should be considered inpatients with severe infusion-related reactions. This clinical assessment should be based on theseverity of the preceding reaction and response to administered treatment for the adverse reaction (seesection 4.2).

Hypersensitivity reactions/anaphylaxis

Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, includinganaphylaxis and events with a fatal outcome, has been observed with Perjeta (see section 4.8).

Medicinal products to treat such reactions, as well as emergency equipment, should be available forimmediate use. Perjeta must be permanently discontinued in case of NCI-CTCAE Grade 4hypersensitivity reactions (anaphylaxis), bronchospasm or acute respiratory distress syndrome (seesection 4.2).

Patients treated with Perjeta, trastuzumab and docetaxel are at increased risk of febrile neutropeniacompared with patients treated with placebo, trastuzumab and docetaxel, especially during the first 3cycles of treatment (see section 4.8). In the CLEOPATRA trial in metastatic breast cancer, nadirneutrophil counts were similar in Perjeta-treated and placebo-treated patients. The higher incidence offebrile neutropenia in Perjeta-treated patients was associated with the higher incidence of mucositisand diarrhoea in these patients. Symptomatic treatment for mucositis and diarrhoea should beconsidered. No events of febrile neutropenia were reported after cessation of docetaxel.

Perjeta 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 pertuzumabshould be considered if no improvement in the patient’s condition is achieved. When the diarrhoea isunder control treatment with pertuzumab may be reinstated.

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

Perjeta contains polysorbate 20. Each 14 ml vial contains 2.8 mg of polysorbate 20. Polysorbates maycause allergic reactions.

No pharmacokinetic (PK) interactions were observed between pertuzumab and trastuzumab, orbetween pertuzumab and docetaxel in a sub-study of 37 patients in the randomised, pivotal trial

CLEOPATRA in metastatic breast cancer. In addition, in the population PK analysis, no evidence of adrug-drug interaction has been shown between pertuzumab and trastuzumab or between pertuzumaband docetaxel. This absence of drug-drug interaction was confirmed by pharmacokinetic data from the

NEOSPHERE and APHINITY studies.

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.

Women of childbearing potential should use effective contraception while receiving Perjeta and for 6months following the last dose of pertuzumab.

There is limited amount of data from the use of pertuzumab in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Perjeta is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

Because human IgG is secreted in human milk and the potential for absorption and harm to the infantis unknown, a decision should be made to discontinue breast-feeding or to discontinue treatment,taking into account the benefit of breast-feeding for the child and the benefit of Perjeta therapy for thewoman (see section 5.2).

No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. Inrepeated dose toxicity studies in cynomolgus monkeys, no definitive conclusions could be drawn onthe adverse effect on male reproductive organs. No adverse reactions were observed in sexuallymature female cynomolgus monkeys exposed to pertuzumab (see section 5.3).

On the basis of reported adverse reactions, Perjeta has a minor influence on the ability to drive or usemachines. Dizziness may occur during treatment with Perjeta (see section 4.8). Patients experiencinginfusion-related reactions should be advised not to drive and use machines until symptoms abate.

The safety of Perjeta has been evaluated in more than 6,000 patients in Phase I, II, and III trials inpatients with various malignancies and predominantly treated with Perjeta in combination with otherantineoplastic agents. Those studies included the pivotal trials CLEOPATRA (n=808), NEOSPHERE(n=417), TRYPHAENA (n=225), and APHINITY (n=4804) [pooled in Table 2]. The safety of Perjetawas generally consistent across studies, although the incidence and most common adverse drugreactions (ADRs) varied depending on whether Perjeta was administered as monotherapy or withconcomitant anti-neoplastic agents.

Table 2 summarizes the ADRs from the Perjeta-treated groups of the following pivotal clinical trials:

* CLEOPATRA, in which Perjeta was given in combination with docetaxel and trastuzumab topatients with metastatic breast cancer (n=453)

* NEOSPHERE (n=309) and TRYPHAENA (n=218), in which neoadjuvant Perjeta was given incombination with trastuzumab and chemotherapy to patients with locally advanced,inflammatory, or early breast cancer

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

In addition, ADRs reported in the post-marketing setting are included in Table 2. As Perjeta was usedwith trastuzumab and chemotherapy in these trials, it is difficult to ascertain the causal relationship ofan adverse event to a particular medicinal product.

The 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.

The most common ADRs (≥30%) from this pooled data were diarrhoea, alopecia, nausea, fatigue,neutropenia, and vomiting. The most common NCI-CTCAE Grade 3-4 ADRs (≥10%) wereneutropenia and febrile neutropenia.

Table 2 Summary of ADRs in patients treated with Perjeta in clinical trials^, and in the Post-marketing setting†

System organ class Very Common Common Uncommon Rare

Infections and infestations Nasopharyngitis Paronychia

Upper respiratory tractinfection

Blood and lymphatic Febrile neutropenia*system Neutropeniadisorders Leucopenia

Immune system disorders Infusion-related Hypersensitivity°, * Anaphylactic reaction°, Cytokine releasereaction°°, * Drug hypersensitivity°, * syndrome°°

*

Metabolism and nutrition Decreased appetite Tumour lysisdisorders syndrome†

Psychiatric disorders Insomnia

Nervous system disorders Neuropathy peripheral

Dysgeusia

Peripheral sensoryneuropathy

Dizziness

Paraesthesia

Eye disorders Lacrimation increased

Cardiac disorders Left ventricular Cardiac failuredysfunction ** congestive**

Vascular disorders Hot flush

Respiratory, thoracic and Cough Interstitial lung diseasemediastinal disorders Epistaxis Pleural effusion

Gastrointestinal disorders Diarrhoea

Stomatitis

Nausea

System organ class Very Common Common Uncommon Rare

Dyspepsia

Abdominal pain

Skin and subcutaneous Alopeciatissue disorders Rash

Nail disorder

Pruritus

Dry skin

Musculoskeletal and Myalgiaconnective tissue disorders Arthralgia

Pain in extremity

General disorders and Mucosal inflammation Chillsadministration site Oedema peripheral Painconditions Pyrexia Oedema

Asthenia^ Table 2 shows pooled data from the overall treatment period in CLEOPATRA (data cutoff 11 February 2014;median number of cycles of Perjeta was 24); and from the neoadjuvant treatment period in NEOSPHERE(median number of cycles of Perjeta was 4, across all treatment arms) and TRYPHAENA (median number ofcycles of Perjeta was 3 - 6 across treatment arms) and from the treatment period of APHINITY (median numberof cycles of Perjeta was 18).

* ADRs with a fatal outcome have been reported.

** For the overall treatment period across the 4 studies. The incidence of left ventricular dysfunction and cardiacfailure congestive reflect the MedDRA Preferred Terms reported in the individual studies.° Hypersensitivity/anaphylactic reaction is based on a group of terms.°° Infusion-related reaction (IRRs) includes a range of different terms within a time window, see “Description ofselected adverse reactions” below.† ADRs reported in the post marketing setting-

In the pivotal trial CLEOPATRA in metastatic breast cancer, the incidence of LVD during studytreatment was higher in the placebo-treated group than in the Perjeta-treated group (8.6% and 6.6%,respectively). The incidence of symptomatic LVD was also lower in the Perjeta-treated group (1.8% inthe placebo-treated group vs. 1.5% in the Perjeta-treated group) (see section 4.4).

In the neoadjuvant trial NEOSPHERE, in which patients received 4 cycles of Perjeta as neoadjuvanttreatment, the incidence of LVD (during the overall treatment period) was higher in the Perjeta,trastuzumab and docetaxel-treated group (7.5%) compared to the trastuzumab and docetaxel-treatedgroup (1.9%). There was one case of symptomatic LVD in the Perjeta and trastuzumab-treated group.

In the neoadjuvant trial TRYPHAENA, the incidence of LVD (during the overall treatment period) was8.3% in the group treated with Perjeta plus trastuzumab and FEC (5-fluorouracil, epirubicin,cyclophosphamide) followed by Perjeta plus trastuzumab and docetaxel; 9.3% in the group treated with

Perjeta plus trastuzumab and docetaxel following FEC; and 6.6% in the group treated with Perjeta incombination with TCH (docetaxel, carboplatin and trastuzumab). The incidence of symptomatic LVD(congestive heart failure) was 1.3% in the group treated with Perjeta plus trastuzumab and docetaxelfollowing FEC (this excludes a patient who experienced symptomatic LVD during FEC treatment priorto receiving Perjeta plus trastuzumab and docetaxel) and also 1.3% in the group treated with Perjeta incombination with TCH. No patients in the group treated with Perjeta plus trastuzumab and FEC followedby Perjeta plus trastuzumab 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 Perjeta plus trastuzumab and paclitaxeland none of the patients (0%) experienced symptomatic LVD in the group treated with FEC followedby Perjeta in combination with trastuzumab and docetaxel. The incidence of asymptomatic LVD(ejection fraction decrease according to NCI-CTCAE v.4) was 7% in the group treated with dosedense AC followed by Perjeta plus trastuzumab and paclitaxel and 3.5% in the group treated with FECfollowed by Perjeta plus trastuzumab and docetaxel.

In APHINITY, the incidence of symptomatic heart failure (NYHA class III or IV) with a LVEF declineof at least 10% points from baseline and to <50% was <1% (0.9% of Perjeta-treated patients vs 0.5% ofplacebo-treated patients). Of the patients who experienced symptomatic heart failure, 55.6% of Perjeta-treated patients and 71.4% of placebo-treated patients had recovered (defined as 2 consecutive LVEFmeasurements above 50%) at the data cutoff. The majority of the events were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least10% points from baseline and to <50% were reported in 2.9% of Perjeta-treated patients and 3.0% ofplacebo-treated patients, of whom 82.4% of Perjeta-treated patients and 83.3% of placebo-treatedpatients had recovered at the data cutoff.

An infusion-related reaction was defined in the pivotal trials as any event reported as hypersensitivity,anaphylactic reaction, acute infusion-related reaction or cytokine release syndrome occurring duringan infusion or on the same day as the infusion. In the pivotal trial CLEOPATRA, the initial dose of

Perjeta was given the day before trastuzumab and docetaxel to allow for the examination of Perjeta-associated reactions. On the first day when only Perjeta was administered, the overall frequency ofinfusion-related reactions was 9.8% in the placebo-treated group and 13.2% in the Perjeta-treatedgroup, with the majority of infusion-related reactions being mild or moderate. The most commoninfusion-related reactions (≥ 1.0%) in the Perjeta-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 in the Perjeta-treated group (≥ 1.0%) were fatigue, dysgeusia, drughypersensitivity, myalgia and vomiting (see section 4.4).

In neoadjuvant and adjuvant trials, Perjeta was administered on the same day as other study treatmentsin all cycles. Infusion-related reactions occurred in 18.6% - 25.0% of patients on the first day of

Perjeta administration (in combination with trastuzumab and chemotherapy). The type and severity ofevents were consistent with those observed in CLEOPATRA at the cycles when Perjeta was given onthe same day as trastuzumab and docetaxel, with the majority of reactions being mild or moderate inseverity.

Hypersensitivity reactions/anaphylaxis

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 Perjeta-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 Perjeta-treated group experienced events described as anaphylaxis by the investigator (see section4.4).

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 Perjeta and docetaxel-treated groupexperienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overall frequency ofhypersensitivity/anaphylaxis was highest in the Perjeta 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.

In the pivotal trial CLEOPATRA, the majority of patients in both treatment groups experienced atleast one leucopenic event (63.0% of patients in the Perjeta-treated group and 58.3% of patients in theplacebo-treated group), of which the majority were neutropenic events (see section 4.4). Febrileneutropenia occurred in 13.7% of Perjeta-treated patients and 7.6% of placebo-treated patients. In bothtreatment groups, the proportion of patients experiencing febrile neutropenia was highest in the firstcycle of therapy and declined steadily thereafter. An increased incidence of febrile neutropenia wasobserved among Asian patients in both treatment groups compared with patients of other races andfrom other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higherin the Perjeta-treated group (25.8%) compared with the placebo-treated group (11.3%).

In the NEOSPHERE trial, 8.4% of patients treated with neoadjuvant Perjeta, 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 Perjeta + TCH, and 9.3% of patients treated with neoadjuvant Perjeta, trastuzumaband docetaxel following FEC. In TRYPHAENA, the incidence of febrile neutropenia was higher inpatients who received six cycles of Perjeta compared with patients who received three cycles of

Perjeta, independent of the chemotherapy given. As in the CLEOPATRA trial, a higher incidence ofneutropenia and febrile neutropenia was observed among Asian patients compared with other patientsin both neoadjuvant trials. In NEOSPHERE, 8.3% of Asian patients treated with neoadjuvant Perjeta,trastuzumab and docetaxel experienced febrile neutropenia compared with 4.0% of Asian patientstreated with neoadjuvant trastuzumab and docetaxel.

In the APHINITY trial, febrile neutropenia occurred in 12.1% of Perjeta-treated patients and 11.1% ofplacebo-treated patients. As in the CLEOPATRA, TRYPHAENA, and NEOSPHERE trials, a higherincidence of febrile neutropenia was observed among Perjeta-treated Asian patients compared withother races in the APHINITY trial (15.9% of Perjeta-treated patients and 9.9% of placebo-treatedpatients).

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

Grade 3-4 diarrhoea was 9.3% in Perjeta-treated patients vs 5.1% in placebo-treated patients. Themedian duration of the longest episode was 18 days in Perjeta-treated patients and 8 days in placebo-treated patients. Diarrhoeal events responded well to proactive management with anti-diarrhoealagents.

In the NEOSPHERE trial, diarrhoea occurred in 45.8% of patients treated with neoadjuvant Perjeta,trastuzumab and docetaxel compared with 33.6% of patients treated with trastuzumab and docetaxel.

In the TRYPHAENA trial, diarrhoea occurred in 72.3% of patients treated with neoadjuvant

Perjeta+TCH and 61.4% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxelfollowing FEC. In both studies most events were mild to moderate in severity.

In the APHINITY trial, a higher incidence of diarrhoea was reported in the Perjeta-treated arm(71.2%) compared to the placebo arm (45.2%). Grade ≥ 3 diarrhoea was reported in 9.8% of patientsin the Perjeta arm vs. 3.7% in the placebo arm. The majority of the reported events were Grade 1 or 2in severity. The highest incidence of diarrhoea (all Grades) was reported during the targetedtherapy+taxane chemotherapy period (61.4% of patients in the Perjeta arm vs. 33.8% of patients in theplacebo arm).The incidence of diarrhoea was much lower after chemotherapy cessation, affecting18.1% of patients in the Perjeta arm vs. 9.2% of patients in the placebo arm in the post-chemotherapytargeted therapy period.

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

In the NEOSPHERE trial, rash occurred in 40.2% of patients treated with neoadjuvant Perjeta,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 Perjeta + TCHand 20.0% of patients treated with neoadjuvant Perjeta, trastuzumab and docetaxel following FEC.

The incidence of rash was higher in patients who received six cycles of Perjeta compared with patientswho received three cycles of Perjeta, independent of the chemotherapy given.

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

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 Perjeta-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 Perjeta, trastuzumab and docetaxel compared with 84.5% in patientstreated 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 Perjeta + TCH and 77.0% in patients treated withneoadjuvant Perjeta, trastuzumab and docetaxel following FEC, including 66.7% and 59.5% Grade 4neutropenia, respectively.

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

Elderly Patients

The incidence of the following all grade adverse events was at least 5% higher in patients ≥ 65 yearsof age, compared to patients < 65 years of age: decreased appetite, anaemia, weight decreased,asthenia, dysgeusia, peripheral neuropathy, hypomagnesemia and diarrhoea. Limited data are availablein patients > 75 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 maximum tolerated dose of pertuzumab has not been determined. In clinical trials, single doseshigher than 25 mg/kg (1727 mg) have not been tested.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactionsand appropriate symptomatic treatment instituted.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FD02

Pertuzumab is a recombinant humanised monoclonal antibody that specifically targets the extracellulardimerization domain (subdomain II) of the human epidermal growth factor receptor 2 protein (HER2),and thereby, blocks ligand-dependent heterodimerisation of HER2 with other HER family members,including EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellularsignalling through two major signal pathways, mitogen-activated protein (MAP) kinase andphosphoinositide 3-kinase (PI3K). Inhibition of these signalling pathways can result in cell growtharrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediatedcytotoxicity (ADCC).

While pertuzumab alone inhibited the proliferation of human tumour cells, the combination ofpertuzumab and trastuzumab significantly augmented antitumour activity in HER2-overexpressingxenograft models.

The efficacy of Perjeta in HER2-positive breast cancer is supported by a randomised phase III trial anda single-arm phase II trial in metastatic breast cancer, two randomised neoadjuvant phase II trials inearly breast cancer (one controlled), a non-randomised neoadjuvant phase II trial, and a randomisedphase III trial in the adjuvant setting.

HER2 overexpression was determined at a central laboratory and defined as a score of 3+ by IHC oran ISH amplification ratio ≥2.0 in the trials outlined below.

Metastatic breast cancer

Perjeta 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 Perjeta activity onbrain metastases. There is very limited data available in patients with unresectable locally recurrentdisease. Patients were randomised 1:1 to receive placebo + trastuzumab + docetaxel or Perjeta +trastuzumab + docetaxel.

Perjeta and trastuzumab were given at standard doses in a 3-weekly regimen. Patients were treatedwith Perjeta and trastuzumab until disease progression, withdrawal of consent or unmanageabletoxicity. Docetaxel was given as an initial dose of 75 mg/m2 as an intravenous infusion every threeweeks for at least 6 cycles. The dose of docetaxel could be escalated to 100 mg/m2 at the investigator’sdiscretion if the initial dose was well tolerated.

The primary endpoint of the study was progression-free survival (PFS) as assessed by an independentreview facility (IRF) and defined as the time from the date of randomisation to the date of diseaseprogression or death (from any cause) if the death occurred within 18 weeks of the last tumourassessment. Secondary efficacy endpoints were overall survival (OS), PFS (investigator-assessed),objective response rate (ORR), duration of response, and time to symptom progression according tothe FACT B Quality of Life questionnaire.

Approximately half the patients in each treatment group had hormone receptor-positive disease(defined as oestrogen receptor (ER) positive and/or progesterone receptor (PgR) positive) andapproximately half of the patients in each treatment group had received prior adjuvant or neoadjuvanttherapy. Most of these patients had received prior anthracycline therapy and 11% of all patients hadreceived prior trastuzumab. A total of 43% of patients in both treatment groups had previouslyreceived radiotherapy. Patients’ median LVEF at baseline was 65.0% (range 50% - 88%) in bothgroups.

The efficacy results from the CLEOPATRA study are summarised in Table 3. A statisticallysignificant improvement in IRF-assessed PFS was demonstrated in the Perjeta-treated group comparedwith the placebo-treated group. The results for investigator-assessed PFS were similar to thoseobserved for IRF-assessed PFS.

Table 3 Summary of efficacy from CLEOPATRA study

Parameter Placebo+ Perjeta+ HR p-valuetrastuzumab trastuzumab (95% CI)+ docetaxel + docetaxeln=406 n=402

Progression-Free Survival(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*** 233 (69.3%) 275 (80.2%) in ORR:95% CI for ORR [64.1; 74.2] [75.6; 84.3] 10.8%

Complete response (CR) 14 (4.2%) 19 (5.5%) [4.2; 17.5]

Partial Response (PR) 219 (65.2%) 256 (74.6%)

Stable disease (SD) 70 (20.8%) 50 (14.6%)

Progressive disease (PD) 28 (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 analysis, 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 1). 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 1 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 Perjeta-treated group). The statistically significant OS benefit in favour ofthe Perjeta-treated group, previously observed at an interim analysis of OS (performed one year afterthe primary analysis), was maintained (HR 0.68, p = 0.0002 log-rank test). The median time to deathwas 40.8 months in the placebo-treated group and 56.5 months in the Perjeta-treated group (see

Table 3, Figure 2).

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 Perjeta-treated group) showed that the statistically significant OSbenefit in favour of the Perjeta-treated group was maintained over time after a median follow-up of 99months (HR 0.69, p < 0.0001 log-rank test; median time to death 40.8 months [placebo-treated group]versus 57.1 months [Perjeta-treated group]). Landmark survival estimates at 8 years were 37% in the

Perjeta-treated group and 23% in the placebo-treated group.

Figure 2 Kaplan-Meier Curve of Event-Driven Overall Survival

HR= hazard ratio; CI= confidence interval; Pla= placebo; Ptz= pertuzumab (Perjeta); T= trastuzumab (Herceptin); 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.

Additional supportive clinical trial information

BO17929 - single-arm trial in metastatic breast cancer

BO17929 was a phase II, non-randomised study in patients with metastatic breast cancer whosetumours had progressed during treatment with trastuzumab. Treatment with Perjeta and trastuzumabresulted in a response rate of 24.2%, with a further 25.8% of patients experiencing stabilisation ofdisease lasting at least 6 months, indicating that Perjeta is active following progression ontrastuzumab.

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, tumor 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 that nevertheless do not establish or precisely measure a benefit with regard to long-termoutcomes, such as overall survival or disease-free survival.

NEOSPHERE (WO20697)

NEOSPHERE is a phase II, multicentre, multinational randomised controlled trial with Perjeta andwas conducted in 417 adult female patients with newly diagnosed, early, inflammatory or locallyadvanced HER2-positive breast cancer (T2-4d; primary tumour > 2cm 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

* Perjeta plus trastuzumab and docetaxel

* Perjeta plus trastuzumab

* Perjeta plus docetaxel.

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

ER 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/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 Perjeta plus trastuzumab prior to surgerysubsequently 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), disease-free survival (DFS), and PFS. Additional exploratory pCR rates includednodal 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 4. A statistically significant improvement in pCR rate(ypT0/is) was observed in patients receiving Perjeta plus trastuzumab and docetaxel compared topatients receiving trastuzumab and docetaxel (45.8% vs 29.0%, p value = 0.0141). A consistent patternof results was observed regardless of pCR definition. The difference in pCR rate is considered likely totranslate into a clinically meaningful difference in long term outcomes and is supported by positivetrends in PFS (HR 0.69, 95% CI 0.34; 1.40) and DFS (HR 0.60, 95% CI 0.28; 1.27).

The pCR rates as well as the magnitude of benefit with Perjeta (Perjeta plus trastuzumab and docetaxelcompared to patients receiving trastuzumab and docetaxel) were lower in the subgroup of patients withhormone receptor-positive tumours (difference of 6% in pCR in the breast) than in patients withhormone 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 Perjeta 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 > 2cm 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 Perjeta andtrastuzumab

* 3 cycles of FEC alone followed by 3 cycles of docetaxel, with trastuzumab and Perjeta givenconcurrently

* 6 cycles of TCH in combination with Perjeta.

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/kg everythree weeks. FEC (5-fluorouracil [500 mg/m2], epirubicin [100 mg/m2], cyclophosphamide [600mg/m2]) were given intravenously every three weeks for 3 cycles. Docetaxel was given as an initialdose of 75 mg/m2 IV infusion every three weeks with the option to escalate to 100 mg/m2 at theinvestigator’s discretion if the initial dose was well tolerated. However, in the group treated with

Perjeta in combination with TCH, docetaxel was given intravenously at 75 mg/m2 (no escalation waspermitted) and carboplatin (AUC 6) was given intravenously every three weeks. Following surgery allpatients 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 4). 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 4 NEOSPHERE (WO20697) and TRYPHAENA (BO22280): Overview of efficacy(Intent to Treat Population)

NEOSPHERE (WO20697) TRYPHAENA (BO22280)

Perjeta+

Trastuzuma FEC

Perjeta+ b+

Trastuzum Trastuzumab Perjeta+ Perjeta FEC Perjeta+ Perjetaab

Parameter Trastuzumab+Docetaxel + Trastuzumab +Docetaxel Perjeta+ + +TCH

N=107 Docetaxel N=107 N=96 Trastuzumab+ Docetaxel N=77

N=107

Docetaxel N=75

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

Difference inpCR rates2 +16.8 % -12.2 % -21.8 %

NA NA NA[95% CI]3 [3.5; 30.1] [-23.8; -0.5] [-35.1; -8.5]p-value (with 0.0141 0.0198 0.0030

Simes corr. (vs. (vs. (vs Perjeta+for CMH NA NA NA

Trastuzumab+ Trastuzumab+ Trastuzumabtest)4 Docetaxel) Docetaxel) +Docetaxel)pCR rate inthe breast andlymph node 23 (21.5%) 42 (39.3%) 12 (11.2%) 17 (17.7%) 41 (56.2%) 41 (54.7%) 49 (63.6%)(ypT0/is N0) [14.1; 30.5] [30.3; 49.2] [5.9; 18.8] [10.7; 26.8] [44.1; 67.8] [42.7; 66.2] [51.9; 74.3]n (%)[95% CI]ypT0 N013 (12.1%) 35 (32.7%) 6 (5.6%) 13 (13.2%) 37 (50.7%) 34 (45.3%) 40 (51.9%)n (%)[6.6; 19.9] [24.0; 42.5] [2.1; 11.8] [7.4; 22.0] [38.7; 62.6] [33.8; 57.3] [40.3; 63.5][95% CI]

Clinical5 79 (79.8%) 89 (88.1%) 69 (67.6%) 65 (71.4%) 67 (91.8%) 71 (94.7%) 69 (89.6%)

Response

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 Perjeta+Trastuzumab+Docetaxel and Perjeta+Trastuzumab are compared to Trastuzumab+

Docetaxel while Perjeta+Docetaxel is compared to Perjeta+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 > 2cm 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 Perjeta in combination with trastuzumab and paclitaxel.

* Cohort B - 4 cycles of FEC followed by 4 cycles of Perjeta in combination with trastuzumaband docetaxel.

Following surgery all patients received Perjeta 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 section 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 Perjeta 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, overall survival (OS), disease-freesurvival (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% (hazard ratio [HR] =0.81; 95% CI 0.66, 1.00 p-value 0.0446) reduction in risk of recurrence or death in patientsrandomised to receive Perjeta compared with patients randomised to receive placebo.

After a median follow-up of 101.2 months (8.4 years), at the third OS interim analysis, the number ofdeaths in patients randomised to the Perjeta arm was 168 deaths [7.0%] compared with 202 deaths[8.4%] in the placebo arm; HR=0.83, 95% CI [0.68; 1.02].

The efficacy results from the APHINITY trial are summarised in Table 5 and in Figure 3.

Table 5 Overall Efficacy: ITT Population

Perjeta + trastuzumab + Placebo + 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-breast cancer*

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)**

Number (%) of patients with event 205 (8.5%) 247 (10.3%)

HR [95% CI] 0.83 [0.69; 1.00]p-value (Log-Rank test, stratified1) 0.044110 year event-free rate2 [95% CI] 91.55 [90.38; 92.71] 89.79 [88.53; 91.06]

Key to abbreviations (Table 5): HR: Hazard Ratio; CI: Confidence Interval

* Primary Invasive Disease Free Survival analysis, cutoff date 19th December 2016.

** Data from final analysis for overall survival, cutoff date 28th November 2024; p-value boundary 0.04961. All analyses stratified by nodal status, protocol version, central hormone receptor status, and adjuvantchemotherapy regimen.2. 3-year event-free rate and 10 year event-free rate derived from Kaplan-Meier estimates.

Figure 3 Kaplan-Meier Curve of Invasive Disease Free Survival

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

The estimate of IDFS at 4-years was 92.3% in the Perjeta-treated group versus 90.6% in the placebo-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 Perjeta were more apparent in subgroups of patientsa high risk of recurrence: patients with node-positive or hormone receptor-negative disease (seetable 6).

Table 6 Efficacy results in subgroups by nodal status and hormone receptor status1

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

Perjeta + 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 years and89.9% vs. 86.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively. Inthe lymph node- negative subgroup, estimates of IDFS rates were 97.5% versus 98.4% at 3 years and96.2% versus 96.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively.

In the hormone receptor-negative subgroup, estimates of IDFS rates were 92.8% versus 91.2% at 3years and 91.0% versus 88.7% at 4 years in Perjeta-treated patients versus placebo-treated patients,respectively. In the hormone receptor-positive subgroup estimates of IDFS rates were 94.8% versus94.4% at 3 years and 93.0% versus 91.6% at 4 years in Perjeta-treated patients versus placebo-treatedpatients, respectively.

Patient Reported Outcomes (PRO)

Secondary endpoints included the assessment of patient-reported global health status, role and physicalfunction, 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 Perjeta arm and -10.6 (95% CI -11.4; -9.9) inthe placebo arm; global health status was -11.2 (95% CI -12.2; -10.2) in the Perjeta arm and -10.2(95% CI -11.1;-9.2) in the placebo arm. Change in diarrhoea symptoms increased to +22.3 (95% CI21.0; 23.6) in the Perjeta arm versus +9.2 (95% CI 8.2; 10.2) in the placebo 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 the Perjeta-arm. The addition of Perjeta to trastuzumab plus chemotherapy did not affect patients’ overall rolefunction over the course of the study.

Patients in the pivotal trial CLEOPATRA were tested at multiple time-points for anti-drug antibodies(ADA) to Perjeta. 3.3% (13/389 patients) of Perjeta-treated patients and 6.7% (25/372 patients) ofplacebo-treated patients tested positive for ADA. In BERENICE, 4.1% (16/392) of the patients treatedwith Perjeta tested positive for ADA. None of these patients experiencedanaphylactic/hypersensitivity reactions that were clearly related to ADA.

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

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

A population pharmacokinetic analysis was performed with data from 481 patients across differentclinical trials (phase I, II and III) with various types of advanced malignancies who had received

Perjeta as a single agent or in combination at pertuzumab doses ranging from 2 to 25 mg/kgadministered every 3 weeks as a 30-60 minutes intravenous infusion.

Perjeta is administered as an intravenous infusion.

Across all clinical studies, the volume of distribution of the central (Vc) and the peripheral (Vp)compartment in the typical patient, was 3.11 litres and 2.46 litres, respectively.

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

The median clearance (CL) of pertuzumab was 0.235 litres/day and the median half-life was 18 days.

Pertuzumab displayed linear pharmacokinetics within the recommended dose range.

Based on the population pharmacokinetic analysis, no significant difference was observed in thepharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175).

No dedicated renal impairment trial for Perjeta has been conducted. Based on the results of thepopulation pharmacokinetic analysis, pertuzumab exposure in patients with mild (creatinine clearance[CLcr] 60 to 90 ml/min, N=200) and moderate renal impairment (CLcr 30 to 60 ml/min, N=71) wassimilar to that in patients with normal renal function (CLcr greater than 90 ml/min, N=200). Norelationship between CLcr and pertuzumab exposure was observed over the range of CLcr (27 to244 ml/min).

The population PK analysis suggested no PK differences based on age, gender and ethnicity (Japaneseversus non-Japanese). Baseline albumin and lean body weight were the most significant covariatesinfluencing CL. CL decreased in patients with higher baseline albumin concentrations and increased inpatients with greater lean body weight. However sensitivity analyses performed at the recommendeddose and schedule of Perjeta showed that at the extreme values of these two covariates, there was nosignificant impact on the ability to achieve target steady-state concentrations identified in preclinicaltumour xenograft models. Therefore, there is no need to adjust the dosage of pertuzumab based onthese covariates.

The PK results of pertuzumab in the NEOSPHERE and APHINITY studies were consistent with thepredictions from the previous population PK model. No differences in pertuzumab PK were observedin patients with early breast cancer compared to patients with metastatic breast cancer.

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 study.

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 of10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greaterthan the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from

GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases inembryo-foetal death between GD25 to GD70. The incidences of embryo-foetal loss were 33, 50, and85% for pregnant female monkeys treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg,respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesareansection on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopicevidence of renal hypoplasia consistent with delayed renal development were identified in allpertuzumab 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.

In cynomolgus monkeys, weekly intravenous administration of pertuzumab at doses up to150 mg/kg/dose was generally well tolerated. With doses of 15 mg/kg and higher, intermittent mildtreatment-associated diarrhoea was noted. In a subset of monkeys, chronic dosing (7 to 26 weeklydoses) resulted in episodes of severe secretory diarrhoea. The diarrhoea was managed (with theexception of euthanasia of one animal, 50 mg/kg/dose) with supportive care including intravenousfluid replacement therapy.

Histidine

Glacial acetic acid

Sucrose

Polysorbate 20 (E432)

Water for injections

Glucose (5%) solution should not be used to dilute Perjeta since it is chemically and physicallyunstable in such solutions.

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

Unopened vial2 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 30°C and up to 30 daysat 2°C to 8°C protected from light.

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

Store in a refrigerator (2°C-8°C).

Do not freeze.

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

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

Vial (Type I glass) with a stopper (butyl rubber) containing 14 ml of solution.

Pack of 1 vial.

Perjeta does not contain any antimicrobial preservative. Therefore, care must be taken to ensure thesterility of the prepared solution for infusion and should be prepared by a healthcare professional incontrolled and validated aseptic conditions (see section 6.3).

Perjeta is for single use only.

The vial must not be shaken. 14 ml of Perjeta concentrate should be withdrawn from the vial using asterile needle and syringe and diluted into a 250 ml PVC or non-PVC polyolefin infusion bag ofsodium chloride 9 mg/ml (0.9%), or alternatively 4.5 mg/ml (0.45%), solution for infusion. Afterdilution, one ml of solution should contain approximately 3.02 mg of pertuzumab (840 mg/278 ml) forthe initial dose where two vials are required and approximately 1.59 mg of pertuzumab(420 mg/264 ml) for the maintenance dose where one vial is required.

The bag should be gently inverted to mix the solution in order to avoid foaming.

Parenteral medicinal products should be inspected visually for particulates and discolouration prior toadministration. If particulates or discoloration are observed, the solution should not be used. Once theinfusion is prepared it should be administered immediately (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Perjeta is compatible with polyvinylchloride (PVC) or non-PVC polyolefin bags includingpolyethylene.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/13/813/001

Date of first authorisation: 4th March 2013

Date of latest renewal: 8th December 2017

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

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