Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common ADRs (≥ 30 %) reported in patients treated with Phesgo or intravenous pertuzumab in 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 or intravenous 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 intravenous pertuzumab 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 and the intravenous pertuzumab in combination with trastuzumab treatment arm. The following adverse drug reactions were reported with a higher frequency (≥ 5 %) with Phesgo compared to intravenous pertuzumab in combination with trastuzumab: alopecia 79 % vs 73 %, myalgia 27.0 % vs 20.6 %, and dyspnea 12.1 % vs 6 %.

Tabulated list of adverse reactions

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 and most common adverse drug reactions (ADRs) varied depending on whether pertuzumab in combination 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 of pertuzumab in combination with trastuzumab and chemotherapy in the below mentioned pivotal clinical trials (n= 3834) and in the post-marketing setting. As pertuzumab is used in combination with trastuzumab and chemotherapy, it is difficult to ascertain the causal relationship of an adverse reaction to 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 as monotherapy.

•     CLEOPATRA, in which pertuzumab was given in combination with trastuzumab and docetaxel to patients with metastatic breast cancer (n= 453)
•      NEOSPHERE (n= 309) and TRYPHAENA (n= 218), in which neoadjuvant pertuzumab was given 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 and anthracycline-based or non-anthracycline-based, taxane-containing chemotherapy to patients with 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) and subsequently 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 pivotal clinical trials^, ^^, and in the post-marketing setting†

N = 3834^                       N = 243^^

Pertuzumab+trastuzumab Phesgo with               Phesgo monotherapy chemotherapy
ADR                  Frequency category         Frequency category    Frequency category (MedDRA Preferred
Term)
System Organ Class

Blood    and     lymphatic system 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 
Cardiac disorders

Left ventricular              Common                     Uncommon              Uncommon dysfunction**

Cardiac failure**             Common                     Uncommon              Common 
Eye disorders

Lacrimation increased         Very common                Common                Uncommon 
Gastrointestinal disorders

Diarrhea                      Very common                Very common           Very common 
Nausea                        Very common                Very common           Common 
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 

N = 3834^                    N = 243^^
Pertuzumab+trastuzumab Phesgo with          Phesgo monotherapy chemotherapy

General disorders and administration site conditions

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 
Immune system disorders

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 
Infections and infestations

Nasopharyngitis               Very common             Common              Common 
Upper respiratory tract       Common                  Common              Common infection

Paronychia                    Common                  Common              Common 
Metabolism and nutrition disorders

Decreased appetite            Very common             Very common         Common 
Tumour lysis syndrome†        Rare                    Not known           Not known 


N = 3834^                    N = 243^^

Pertuzumab+trastuzumab Phesgo with         Phesgo monotherapy chemotherapy
Musculoskeletal and connective tissue disorders

Arthralgia                    Very common            Very common         Very common 
Myalgia                       Very common            Very common         Common 
Pain in extremity             Very common            Common              Common 
Nervous system disorders

Dysgeusia                     Very common            Very common         Common 
Headache                      Very common            Very common         Common 
Peripheral sensory            Very common            Very common         Common neuropathy

Neuropathy peripheral         Very common            Very common         Common 
Dizziness                     Very common            Common              Common 
Paraesthesia                  Very common            Common              Common 
Psychiatric disorders

Insomnia                      Very common            Very common         Common 
Respiratory, thoracic and mediastinal 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 monotherapy chemotherapy

Skin and subcutaneous tissue 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 
Vascular disorders

Hot flush                           Very common                      Common                      Very common ^
Shows pooled data from the overall treatment period in CLEOPATRA (data cut off 11 February 2014; median number of cycles of pertuzumab was 24); and from the neoadjuvant treatment period in NEOSPHERE (median number of cycles of pertuzumab was 4, across all treatment arms) and TRYPHAENA (median number of cycles of pertuzumab was 3-6 across treatment arms); from the treatment period of APHINITY (median number of cycles 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 was 18)
* 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 reflect the 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 reactions section.
°° No events of Interstitial lung disease were reported in the FeDeriCa study but these events have been observed with trastuzumab.
°°°Observed with Phesgo only (subcutaneous administration related). The higher frequency observed in the adjuvant 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.

Description of selected adverse reactions

Left ventricular dysfunction
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 treated patients vs 0% of intravenous pertuzumab and trastuzumab-treated patients during neoadjuvant phase (when concomitantly administered with chemotherapy). Of the patients who experienced symptomatic heart failure, none of the Phesgo-treated patients had recovered at the data cut-off and one patient was withdrawn from Phesgo due to an event of symptomatic heart failure. The incidences of symptomatic heart failure with a LVEF decline of at least 10 % points from baseline and to < 50 % were similar in 
the adjuvant (when Phesgo was administered alone) and in the follow-up phases. Asymptomatic or mildly 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 were reported in 0.4% of intravenous pertuzumab and trastuzumab-treated patients during the neoadjuvant phase (see sections 4.2 and 4.4). There was no report of asymptomatic or mildly symptomatic (NYHA class II) declines in LVEF of at least 10 % points from baseline and to < 50 % (confirmed by secondary LVEF) in both arms in the adjuvant phase. In the follow up phase, 1.6 % of Phesgo treated patients and 3.6 % of intravenous pertuzumab and trastuzumab-treated patients had this type of cardiac event.

Pertuzumab intravenous in combination with trastuzumab and chemotherapy 
In the pivotal trial CLEOPATRA, the incidence of LVD during study treatment was higher in the placebo-treated group than the pertuzumab-treated group (8.6 % and 6.6 %, respectively). The incidence 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 as neoadjuvant treatment, the incidence of LVD (during the overall treatment period) was higher in the pertuzumab, trastuzumab and docetaxel-treated group (7.5 %) compared to the trastuzumab and docetaxel-treated group (1.9 %). There was one case of symptomatic LVD in the pertuzumab and trastuzumab-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 group treated with pertuzumab plus trastuzumab and docetaxel following FEC; and 6.6 % in the group treated with pertuzumab in combination with TCH (docetaxel, carboplatin and trastuzumab). The incidence of symptomatic LVD (congestive heart failure) was 1.3 % in the group treated with pertuzumab plus trastuzumab and docetaxel following FEC (this excludes a patient who experienced symptomatic LVD during FEC treatment prior to receiving pertuzumab plus trastuzumab and docetaxel) and also 1.3 % in the group treated with pertuzumab in combination with TCH. No patients in the group treated with pertuzumab plus trastuzumab and FEC followed by pertuzumab 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 dose dense doxorubicin and cyclophosphamide (AC) followed by pertuzumab plus trastuzumab and paclitaxel and none of the patients (0 %) experienced symptomatic LVD in the group treated with FEC followed by pertuzumab 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 dose dense AC followed by pertuzumab plus trastuzumab and paclitaxel and 3.5 % in the group 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 LVEF decline of at least 10 % points from baseline and to < 50 % was < 1 % (0.6 % of pertuzumab-treated patients vs 0.3 % of placebo-treated patients). Of the patients who experienced symptomatic heart failure, 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 the events were reported in anthracycline-treated patients. Asymptomatic or mildly symptomatic (NYHA class 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 systemic reaction reported within 24 hours of Phesgo or intravenous pertuzumab in combination with trastuzumab administration (see sections 4.2 and 4.4).

Injection-related reactions were reported in 0.4 % of Phesgo treated patients and infusion related reactions were reported in 10.7 % of intravenous pertuzumab and trastuzumab-treated patients in the neoadjuvant 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 and trastuzumab-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 Phesgo administration, were reported in 6.9 %, and in 12.9% of Phesgo treated patients in the neoadjuvant phase and the adjuvant phase, respectively, and were all grade 1 or 2 events. Most of the local injection 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 as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. In the pivotal trial CLEOPATRA, the initial dose of pertuzumab was given the day before trastuzumab and docetaxel to allow for the examination of pertuzumab associated reactions. On the first day when only pertuzumab was administered, the overall frequency of infusion-related reactions was 9.8 % in the placebo-treated group and 13.2 % in the pertuzumab-treated group, with the majority of reactions being mild or moderate. The most common 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 most common infusion related reactions (≥ 1.0 %) in the pertuzumab-treated group were fatigue, drug hypersensitivity, dysgeusia, hypersensitivity, myalgia, and vomiting (see section 4.4).

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

Hypersensitivity reactions/anaphylaxis

Phesgo
In the pivotal trial FEDERICA, the overall frequency of hypersensitivity/anaphylaxis reported events related to HER2-targeted therapy was 1.2 % in the Phesgo-treated patients vs. 0.8 % in the intravenous pertuzumab and trastuzumab-treated patients, of which none were NCI-CTCAE (version 4.0) grade 3-4 (see section 4.4). One patient experienced a hypersensitivity/anaphylaxis event during or 
immediately 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 pertuzumab and 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 and trastuzumab-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 investigator reported hypersensitivity/anaphylaxis events during the entire treatment period was 9.3 % in the placebo-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 in the pertuzumab-treated group experienced events described as anaphylaxis by the investigator (see section 4.4).

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

In the neoadjuvant and adjuvant trials, hypersensitivity/anaphylaxis events were consistent with those observed in CLEOPATRA. In NEOSPHERE, two patients in the pertuzumab and docetaxel-treated group experienced anaphylaxis. In both the TRYPHAENA and APHINITY trials, the overall frequency 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.

Febrile neutropenia

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 the neoadjuvant 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 also higher (13.7 %) during the neoadjuvant phase. During the adjuvant phase, no events of febrile neutropenia (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 at least one leucopenic event (63.0 % of patients in the pertuzumab-treated group and 58.3 % of patients in the placebo-treated group), of which the majority were neutropenic events (see section 4.4). Febrile neutropenia 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 the first cycle of therapy and declined steadily thereafter. An increased incidence of febrile neutropenia was observed among Asian patients in both treatment groups compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher 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 and docetaxel experienced febrile neutropenia compared with 7.5 % of patients treated with trastuzumab and docetaxel. In the TRYPHAENA trial, febrile neutropenia occurred in 17.1 % of patients treated with neoadjuvant pertuzumab + TCH, and 9.3 % of patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel following FEC. In TRYPHAENA, the incidence of febrile neutropenia was higher in patients who received six cycles of pertuzumab compared with patients who received three cycles of pertuzumab, independent of the chemotherapy given. As in the CLEOPATRA trial, a higher incidence of neutropenia and febrile neutropenia was observed among Asian patients compared with other patients in both neoadjuvant trials. In NEOSPHERE, 8.3 % of Asian patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel experienced febrile neutropenia compared with 4.0 % of Asian patients treated with neoadjuvant trastuzumab and docetaxel.

In the APHINITY trial, febrile neutropenia occurred in 12.1 % of pertuzumab-treated patients and 11.1 % of placebo-treated patients. As in the CLEOPATRA, TRYPHAENA, and NEOSPHERE trials, a higher incidence of febrile neutropenia was observed among pertuzumab-treated Asian patients compared with other races in the APHINITY trial (15.9 % of pertuzumab-treated patients and 9.9 % of placebo-treated patients).

Diarrhoea

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 ≥ 3 diarrhoea was reported in 6.6 % of patients in the Phesgo arm vs. 4.0 % in the intravenous pertuzumab and trastuzumab arm (see section 4.4).

During the adjuvant phase, diarrhoea occurred in 17.7 % of Phesgo-treated patients and 20.6 % of intravenous pertuzumab and trastuzumab-treated patients. Grade ≥ 3 diarrhoea was reported in 0 % of patients 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 % of pertuzumab-treated patients and 48.7 % of placebo-treated patients (see section 4.4). Most events were mild 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-treated patients. The median duration of the longest episode was 18 days in pertuzumab-treated patients and 8 days 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 neoadjuvant pertuzumab, 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 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 in severity.

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 % of patients 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 the targeted 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 chemotherapy cessation, affecting 18.1 % of patients in the pertuzumab arm vs. 9.2 % of patients in the placebo arm in the post-chemotherapy targeted therapy period.


Rash
Phesgo

In the pivotal trial FEDERICA rash occurred in 10.7 % of Phesgo-treated patients and 15.5 % of intravenous pertuzumab and trastuzumab-treated patients during the neoadjuvant phase. During the adjuvant phase, rash occurred in 8.2 % of Phesgo-treated patients and 8.7 % of intravenous pertuzumab 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 in severity, occurred in the first two cycles, and responded to standard therapies, such as topical or oral treatment 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 docetaxel following FEC. The incidence of rash was higher in patients who received six cycles of pertuzumab compared with patients who received three cycles of pertuzumab, independent of the chemotherapy given.

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

Laboratory abnormalities

Phesgo
In the pivotal trial FEDERICA, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was balanced in the two treatment groups (13.6 % of Phesgo -treated patients and 13.9 % of intravenous pertuzumab and trastuzumab-treated patients) during the neoadjuvant phase and were significantly lower during the adjuvant phase (0.8% of Phesgo -treated patients and 0 % of intravenous pertuzumab and trastuzumab-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 Grade 3-4 neutropenia was balanced in the two treatment groups (86.3 % of pertuzumab-treated patients and 86.6 % 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 % in patients treated with neoadjuvant pertuzumab, trastuzumab and docetaxel compared with 84.5 % in patients 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 was 85.3 % in patients treated with neoadjuvant pertuzumab+ TCH and 77.0 % in patients treated with neoadjuvant 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 % in patients treated with pertuzumab, trastuzumab and chemotherapy compared with 39.1 % in patients 

treated with placebo, trastuzumab and chemotherapy, including 28.3 % and 26.5 % Grade 4 neutropenia, respectively.

Immunogenicity

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

In the FEDERICA study, the incidence of treatment-emergent anti-pertuzumab and anti-trastuzumab antibodies was 10.6 % (26/245) and 0.4 % (1/245), respectively, in patients treated with intravenous pertuzumab 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-vorhyaluronidase alfa antibodies was 12.9 % (31/241), 2.1 % (5/241), and 6.3 % (15/238), respectively, in patients treated with Phesgo. Among these patients, neutralizing anti-pertuzumab antibodies were detected in two 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 and trastuzumab and Phesgo subcutaneous (Arm A) and vice versa (Arm B) with a primary objective to evaluate 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) was 77.5 % (62/80 patients) compared to Cycles 4-6 (subcutaneous treatment) which was 72.5 % (58/80 patients). Among the patients in Arm B, the incidence of AEs during Cycles 1-3 (subcutaneous treatment) was 77.5 % (62/80 patients) compared to Cycles 4-6 (intravenous treatment) which was 63.8 % (51/80 patients), mainly due to higher incidence of local injection site reactions (all grade 1 or 2) during Phesgo administration. Pre-switching rates (Cycles 1-3) for serious adverse events, grade 3 adverse events and treatment discontinuations due to adverse events were low (< 6 %) and similar to post-switching rates (Cycles 4-6).

No grade 4 or grade 5 adverse events were reported.

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

However, in the pivotal pertuzumab clinical trials with intravenous pertuzumab in combination with trastuzumab, decreased appetite, anaemia, weight decreased, asthenia, dysgeusia, neuropathy peripheral, 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 intravenous pertuzumab and trastuzumab. Post-marketing data shows no differences in safety of pertuzumab in combination with trastuzumab in patients ≥ 65 and < 65 years of age.



Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form sideeffects.health.gov.il/