Phesgo Adverse Reactions

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 (14.9% vs. 0.4%).
Tabulated list of adverse reactions: The safety of pertuzumab in combination with trastuzumab has been evaluated in 3344 patients with HER2-positive breast cancer in the pivotal trials CLEOPATRA, NEOSPHERE, TRYPHAENA and APHINITY. 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.
The safety of Phesgo has been evaluated in 248 patients with HER2-positive early breast cancer in the pivotal trial FEDERICA.
Table 8 presents ADRs that have been reported in association with the use of intravenous pertuzumab in combination with trastuzumab and chemotherapy in the mentioned pivotal clinical trials (n=3344) and in the post-marketing setting as follows. Additionally, an ADR specific to the Phesgo route of administration that has been reported in the FEDERICA study, is included in Table 8.
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=248) or intravenous pertuzumab and trastuzumab (n=252) was given in combination with chemotherapy to patients with early breast cancer.
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 as follows 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. (See Table 8.)

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Description of selected adverse reactions: Left ventricular dysfunction: Phesgo in combination with chemotherapy: 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 Dosage & Administration and Precautions).
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 Precautions).
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 combination with chemotherapy: 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 Dosage & Administration and Precautions).
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.
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 Precautions).
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 combination with chemotherapy: 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 Precautions). 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 Dosage & Administration and Precautions).
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 Precautions).
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 combination with chemotherapy: 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%).
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 Precautions). 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 combination with chemotherapy: 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 trastuzumab-treated arm)-(see Precautions).
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 Precautions). 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 combination with chemotherapy: 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.
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 combination with chemotherapy: 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).
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 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 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 Pharmacology: Pharmacodynamics under Actions 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 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.