Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Decreases in LVEF have been reported with medicinal products that block HER2 activity, including pertuzumab and trastuzumab. The incidence of symptomatic left ventricular systolic dysfunction (LVD [congestive heart failure]) was higher in patients treated with pertuzumab in combination with trastuzumab and chemotherapy compared to trastuzumab and chemotherapy. In the adjuvant setting, the majority of cases of symptomatic heart failure reported were in patients who received anthracycline-based chemotherapy (see section 4.8). Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines based on studies with intravenous pertuzumab in combination with trastuzumab and chemotherapy.
Patients with history of serious cardiac illness or medical conditions, history of ventricular dysrhythmias or risk factors for ventricular dysrhythmias were excluded from the (neo-)adjuvant EBC pivotal trial FEDERICA with Phesgo.
Phesgo has not been studied in patients with: a pretreatment LVEF value of <55% (EBC) or <50% (MBC); a prior history of congestive heart failure (CHF); conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to >360 mg/m² of doxorubicin or its equivalent. In addition, pertuzumab in combination with trastuzumab and chemotherapy has not been studied in patients with decreases in LVEF <50% during prior trastuzumab adjuvant therapy.
Assess LVEF prior to initiation of Phesgo and at regular intervals during treatment (e.g. once during neoadjuvant treatment and every 12 weeks in the adjuvant and metastatic setting) to ensure that LVEF is within normal limits. If the LVEF has declined as indicated in section 4.2 and has not improved, or has declined further at the subsequent assessment, discontinuation of Phesgo should be strongly considered, unless the benefits for the individual patient are deemed to outweigh the risks.
Cardiac risk should be carefully considered and balanced against the medical need of the individual patient before use of Phesgo with an anthracycline. Based on the pharmacological actions of HER2-targeted agents and anthracyclines, the risk of cardiac toxicity might be expected to be higher with concomitant use of Phesgo and anthracyclines than with sequential use.
Sequential use of Phesgo (in combination with a taxane) has been evaluated following the doxorubicin component of two anthracycline-based regimens in the FEDERICA study while sequential use of intravenous pertuzumab (in combination with trastuzumab and a taxane) has been evaluated following the epirubicin or doxorubicin component of many anthracycline-based regimens in the APHINITY and BERENICE studies. Only limited safety data are available on concurrent use of intravenous pertuzumab in combination with trastuzumab and an anthracycline. In the TRYPHAENA study, intravenous pertuzumab in combination with trastuzumab was given concurrently with epirubicin, as part 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 same regimen but with pertuzumab administered sequentially (following FEC chemotherapy).
Phesgo has been associated with injection-related reactions (see section 4.8). Injection-related reactions were defined as any systemic reaction with symptoms such as fever, chills, headache, likely due to a release of cytokines occurring within 24 hour of administration of Phesgo. Close observation of the patient during and for 30 minutes after administration of the loading dose and during and for 15 minutes following the administration of the maintenance dose of Phesgo is recommended. If a significant injection-related reaction occurs, the injection should be slowed down or paused and appropriate medical therapies should be administered. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be considered in patients with severe injection-related reactions. This clinical assessment should be based on the severity of the preceding reaction and response to administered treatment for the adverse reaction (see section 4.2). Although fatal outcomes resulting from injection-related reactions have not been observed with Phesgo, caution should be exercised, as fatal infusion related-reactions have been associated with intravenous pertuzumab in combination with intravenous trastuzumab and chemotherapy.
Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity reactions, including anaphylaxis and events with fatal outcomes, have been observed with pertuzumab in combination with trastuzumab and chemotherapy (see section 4.8). The majority of anaphylactic reactions occurred within the first 6-8 cycles of treatment when pertuzumab and trastuzumab were given in combination with chemotherapy. Medicinal products to treat such reactions, as well as emergency equipment, should be available for immediate use. Phesgo must be permanently discontinued in case of NCI-CTCAE Grade 4 hypersensitivity reactions (anaphylaxis), bronchospasm or acute respiratory distress syndrome (see section 4.2). Phesgo is contraindicated in patients with known hypersensitivity to pertuzumab, trastuzumab or to any of its excipients (see section 4.3).
Patients treated with Phesgo in combination with a taxane are at increased risk of febrile neutropenia.
Patients treated with intravenous pertuzumab in combination with trastuzumab and docetaxel are at increased risk of febrile neutropenia compared with patients treated with placebo, trastuzumab and docetaxel, especially during the first 3 cycles of treatment (see section 4.8). In the CLEOPATRA trial in metastatic breast cancer, nadir neutrophil counts were similar in pertuzumab-treated and placebotreated patients. The higher incidence of febrile neutropenia in pertuzumab-treated patients was associated with the higher incidence of mucositis and diarrhoea in these patients. Symptomatic treatment for mucositis and diarrhoea should be considered. No events of febrile neutropenia were reported after cessation of docetaxel.
Phesgo may elicit severe diarrhoea. Diarrhoea is most frequent during concurrent administration with taxane therapy. Elderly patients (≥65 years) have a higher risk of diarrhoea compared with younger patients (<65 years). Treat diarrhoea according to standard practice and guidelines. Early intervention with loperamide, fluids and electrolyte replacement should be considered, particularly in elderly patients, and in case of severe or prolonged diarrhoea. Interruption of treatment with Phesgo should be considered if no improvement in the patient’s condition is achieved. When the diarrhoea is under control treatment with Phesgo may be reinstated.
Severe pulmonary events have been reported with the use of trastuzumab in the post-marketing setting. These events have occasionally been fatal. In addition, cases of interstitial lung disease including lung infiltrates, acute respiratory distress syndrome, pneumonia, pneumonitis, pleural effusion, respiratory distress, acute pulmonary oedema and respiratory insufficiency have been reported. Risk factors associated with interstitial lung disease include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. These events may occur as part of an infusion-related reaction or with a delayed onset. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk of pulmonary events. Therefore, these patients should not be treated with Phesgo. Caution should be exercised for pneumonitis, especially in patients being treated concomitantly with taxanes.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
No formal drug interaction studies have been performed.
No PK interactions were observed between pertuzumab and trastuzumab, or between 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 a drug-drug interaction has been shown between pertuzumab and trastuzumab or between pertuzumab and docetaxel. This absence of drug-drug interaction was confirmed by PK 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 of any PK interaction between pertuzumab and any of these agents. The PK of pertuzumab in these studies was comparable to those observed in single-agent studies.
No formal drug interaction studies have been performed. Clinically significant interactions between trastuzumab and the concomitant medicinal products used in clinical trials have not been observed.
PK data from studies BO15935 and M77004 in women with HER2-positive metastatic breast cancer suggested that exposure to paclitaxel and doxorubicin (and their major metabolites 6-α hydroxylpaclitaxel, POH, and doxorubicinol, DOL) was not altered in the presence of trastuzumab (8 mg/kg or 4 mg/kg intravenous loading dose followed by 6 mg/kg q3w or 2 mg/kg q1w intravenous, respectively). However, trastuzumab may elevate the overall exposure of one doxorubicin metabolite, (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite were unclear.
Data from study JP16003, a single-arm study of trastuzumab (4 mg/kg intravenous loading dose and 2 mg/kg intravenous weekly) and docetaxel (60 mg/m² intravenous) in Japanese women with HER2-positive metastatic breast cancer, suggested that concomitant administration of trastuzumab had no effect on the single dose pharmacokinetics of docetaxel. Study JP19959 was a substudy of BO18255 (ToGA) performed in male and female Japanese patients with advanced gastric cancer to study the pharmacokinetics of capecitabine and cisplatin when used with or without trastuzumab. The results of this substudy suggested that the exposure to the bioactive metabolites (e.g. 5-FU) of capecitabine was not affected by concurrent use of cisplatin or by concurrent use of cisplatin plus trastuzumab. However, capecitabine itself showed higher concentrations and a longer half-life when combined with trastuzumab. The data also suggested that the pharmacokinetics of cisplatin were not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus trastuzumab.
PK data from Study H4613g/GO01305 in patients with metastatic or locally advanced inoperable HER2-positive cancer suggested that trastuzumab had no impact on the PK of carboplatin.
By comparison of simulated serum trastuzumab concentrations after trastuzumab monotherapy (4 mg/kg loading/2 mg/kg q1w intravenous) and observed serum concentrations in Japanese women with HER2-positive metastatic breast cancer (study JP16003) no evidence of a PK effect of concurrent administration of docetaxel on the pharmacokinetics of trastuzumab was found. Comparison of PK results from two Phase II studies (BO15935 and M77004) and one Phase III study (H0648g) in which patients were treated concomitantly with trastuzumab and paclitaxel and two Phase II studies in which trastuzumab was administered as monotherapy (W016229 and MO16982), in women with HER2-positive MBC indicates that individual and mean trastuzumab trough serum concentrations varied within and across studies but there was no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of trastuzumab.
Comparison of trastuzumab PK data from Study M77004 in which women with HER2-positive metastatic breast cancer were treated concomitantly with trastuzumab, paclitaxel and doxorubicin to trastuzumab PK data in studies where trastuzumab was administered as monotherapy (H0649g) or in combination with anthracycline plus cyclophosphamide or paclitaxel (Study H0648g), suggested no effect of doxorubicin and paclitaxel on the pharmacokinetics of trastuzumab. Pharmacokinetic data from Study H4613g/GO01305 suggested that carboplatin had no impact on the PK of trastuzumab.
The administration of concomitant anastrozole did not appear to influence the pharmacokinetics of trastuzumab.
Women of childbearing potential should use effective contraception while receiving Phesgo and for 7 months following the last dose.
In animal studies pertuzumab has shown reproductive toxicity. There is only a limited amount of data from the use of pertuzumab in pregnant women.
From animal studies, it is not known whether trastuzumab can affect reproductive capacity (see section 5.3). However, in the post-marketing setting, cases of foetal renal growth and/or function impairment in association with oligohydramnios, some of which resulted in fatal pulmonary hypoplasia of the foetus, have been reported in pregnant women receiving trastuzumab.
Based on the aforementioned animal studies and post-marketing data, Phesgo should therefore be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. Women who become pregnant should be advised of the possibility of harm to the foetus. If a pregnant woman is treated with Phesgo, or if a patient becomes pregnant while receiving Phesgo or within 7 months following the last dose of Phesgo, close monitoring by a multidisciplinary team is desirable.
As human IgG is secreted into human milk and the potential for absorption and harm to the infant is unknown, women should not breast-feed during Phesgo therapy and for at least 7 months following the last dose.
No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of pertuzumab for up to six-month duration in cynomolgus monkeys (see section 5.3).
Reproduction studies conducted in cynomolgus monkeys with trastuzumab revealed no evidence of impaired fertility in female cynomolgus monkeys (see section 5.3).
Phesgo has minor influence on the ability to drive and use machines (see section 4.8). Patients experiencing injection-related reactions or dizziness (see section 4.4) should be advised not to drive and use machines until symptoms abate.
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 (14.9% vs. 0.4%).
The safety of pertuzumab in combination with trastuzumab has been evaluated in 3834 patients with HER2-positive breast cancer s in the pivotal trials CLEOPATRA, NEOSPHERE, TRYPHAENA APHINITY and FEDERICA. It was generally consistent across studies, although the incidence and most common adverse drug reaction (ADRs) varied depending on whether pertuzumab in combination with trastuzumab were administered with or without concomitant anti-neoplastic agents.
Table 2 presents 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 ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency:
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†:
| System organ class | Very Common | Common | Uncommon | Rare |
|---|---|---|---|---|
| Infections and infestations | Nasopharyngitis | Paronychia Upper respiratory tract infection | ||
| Blood and lymphatic system disorders | Febrile neutropenia* Neutropenia Leucopenia Anaemia | |||
| Immune system disorders | Infusion reaction°°,* | Hypersensitivity°,* Drug hypersensitivity°,* | Anaphylactic reaction°,* | Cytokine release syndrome°° |
| Metabolism and nutrition disorders | Decreased appetite | Tumour lysis syndrome† | ||
| Psychiatric disorders | Insomnia | |||
| Nervous system disorders | Neuropathy peripheral Headache Dysgeusia Peripheral sensory neuropathy Dizziness Paraesthesia | |||
| Eye disorders | Lacrimation increased | |||
| Cardiac disorders | Left ventricular dysfunction** | Cardiac failure congestive** | ||
| Vascular disorders | Hot flush | |||
| Respiratory, thoracic and mediastinal disorders | Cough Epistaxis Dyspnoea | Interstitial lung disease Pleural effusion | ||
| Gastrointestinal disorders | Diarrhoea Vomiting Stomatitis Nausea Constipation Dyspepsia Abdominal pain | |||
| Skin and subcutaneous tissue disorders | Alopecia Rash Nail disorder Pruritus Dry skin | |||
| Musculoskeletal and connective tissue disorders | Myalgia Arthralgia Pain in extremity | |||
| General disorders and administration site conditions | Mucosal inflammation Oedema peripheral Pyrexia Fatigue Asthenia Injection site reaction°°° | Chills Pain Oedema |
^ Table 2 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 treatment period of FEDERICA (median number of cycles of Phesgo was 7).
* 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.
° Hypersensitivity/anaphylactic reaction is based on a group of terms.
°° Infusion reaction includes a range of different terms within a time window, defined as any systemic events reported as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or within 24 hours of the infusion.
°°° Observed with Phesgo only (subcutaneous administration related)
† ADRs reported in the post marketing setting
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 1.2% of Phesgo treated patients vs 0.8% of intravenous pertuzumab and trastuzumab-treated patients. 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. 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 reported in 0.8% of Phesgo-treated patients and 4% of intravenous pertuzumab and trastuzumab-treated patients, of whom one of the Phesgo-treated patients had recovered at the data cut-off and two patients were withdrawn from Phesgo (see sections 4.2 and 4.4).
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 placebotreated 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 pertuzumabtreated patients and 80.6% of placebo-treated patients had recovered at the data cutoff.
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 0.8% of Phesgo treated patients and infusion related reactions were reported in 10.7% 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, pyrexia or vomiting.
Injection site reactions were defined as any local reaction reported within 24 hours of Phesgo administration were reported in 14.9% of Phesgo treated patients 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.
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.
In the pivotal trial FEDERICA, the overall frequency of hypersensitivity/anaphylaxis reported events related to HER2-targeted therapy was 1.6% in the Phesgo-treated patients vs. 1.2% 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).
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 NCICTCAE Grade 3-4.
In the pivotal trial FEDERICA, febrile neutropenia occurred in 6.5% of Phesgo-treated patients and 5.6% of intravenous pertuzumab and trastuzumab-treated patients.
As in intravenous pertuzumab and trastuzumab pivotal trials, a higher incidence of febrile neutropenia 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%).
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).
In the pivotal trial FEDERICA diarrhoea occurred in 61.7% of Phesgo-treated patients and 59.1% of intravenous pertuzumab and trastuzumab-treated patients. Grade ≥3 diarrhoea was reported in 7.3% of patients in the Phesgo arm vs. 5.2% in the intravenous pertuzumab and trastuzumab 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 and taxane chemotherapy period (57.7% of patients in the Phesgo-treated arm vs. 53.6% of patients in the intravenous pertuzumab and trastuzumabtreated arm)-(see section 4.4).
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 NCICTCAE 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 antidiarrhoeal 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.
In the pivotal trial FEDERICA rash occurred in 18.1% of Phesgo-treated patients and 21.8% of intravenous pertuzumab and trastuzumab-treated patients. The majority of rash events were Grade 1 or 2.
In the pivotal trial CLEOPATRA in metastatic breast cancer, rash occurred in 51.7% of pertuzumabtreated 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.
In the pivotal trial FEDERICA, the incidence of NCI-CTCAE v.4 Grade 3-4 neutropenia was balanced in the two treatment groups (14.5% of Phesgo-treated patients and 13.9% of intravenous pertuzumab and trastuzumab-treated patients).
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.
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 6.1% (15/245) 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 two patients.
The incidence of anti-pertuzumab and anti-trastuzumab antibodies detected at any time point (including baseline) was 10.3% (26/252) and 1.2% (3/252), respectively, in patients treated with intravenous pertuzumab and trastuzumab. Among these patients, neutralizing anti-pertuzumab antibodies were detected in three patients.
The incidence of treatment-emergent anti-pertuzumab, anti-trastuzumab, and anti-vorhyaluronidase alfa antibodies was 8.3% (20/241), 1.7% (4/241), and 3.8% (9/238), 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 incidence of anti-pertuzumab, anti-trastuzumab, and anti-vorhyaluronidase alfa antibodies detected at any time point (including baseline) was 12.1% (30/248), 3.2% (8/248), and 9% (22/245), respectively, in patients treated with Phesgo. Among these patients, neutralizing anti-pertuzumab antibodies were detected in three patients, neutralizing anti-trastuzumab antibodies were detected in one patient, and neutralizing anti-vorhyaluronidase alfa antibodies were detected in one patient.
The clinical relevance of the development of anti-pertuzumab, anti-trastuzumab or antivorhyaluronidase alfa antibodies after treatment with Phesgo is unknown.
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.
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Phesgo is a ready to use solution which should not be mixed or diluted with other products.
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