Pertuzumab

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

Studies in animals have shown reproductive toxicity.

Pertuzumab is not recommended during pregnancy and in women of childbearing potential not using contraception.

Because human IgG is secreted in human milk and the potential for absorption and harm to the infant is unknown, a decision should be made to discontinue breast-feeding or to discontinue treatment, taking into account the benefit of breast-feeding for the child and the benefit of pertuzumab therapy for the woman.

Contraception

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

Fertility

No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab. In repeated dose toxicity studies in cynomolgus monkeys, no definitive conclusions could be drawn on the adverse effect on male reproductive organs. No adverse reactions were observed in sexually mature female cynomolgus monkeys exposed to pertuzumab.

On the basis of reported adverse reactions, pertuzumab has no or negligible influence on the ability to drive or use machines. Patients experiencing infusion reactions should be advised not to drive and use machines until symptoms abate.

Summary of the safety profile

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

List of adverse reactions

The following list summarizes the ADRs from the pertuzumab-treated groups of the following pivotal clinical trials:

• CLEOPATRA, in which pertuzumab was given in combination with docetaxel and trastuzumab 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)

In addition, ADRs reported in the post-marketing setting are included in the following table. As pertuzumab was used with trastuzumab and chemotherapy in these trials, it is difficult to ascertain the causal relationship of an adverse event to a particular medicinal product.

The ADRs are listed below by MedDRA system organ class (SOC) and categories of frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

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

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

Summary of ADRs in patients treated with pertuzumab in clinical trials^{^}, and in the Post-marketing setting^†:

^ list shows pooled data from the overall treatment period in CLEOPATRA (data cutoff 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) and from the treatment period of APHINITY (median number of cycles of pertuzumab was 18).
* ADRs with a fatal outcome have been reported.
** For the overall treatment period across the 4 studies. The incidence of left ventricular dysfunction and 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, see “Description of selected adverse reactions” below.
^† ADRs reported in the post marketing setting

Description of selected adverse reactions

Left ventricular dysfunction (LVD)

In the pivotal trial CLEOPATRA in metastatic breast cancer, the incidence of LVD during study treatment was higher in the placebo-treated group than in 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).

In the neoadjuvant trial NEOSPHERE, in which patients received 4 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.

Infusion reactions

An infusion 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 reactions was 9.8% in the placebo-treated group and 13.2% in the pertuzumab-treated group, with the majority of infusion reactions being mild or moderate. The most common infusion 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 reactions in the pertuzumab-treated group (≥ 1.0%) were fatigue, dysgeusia, drug hypersensitivity, myalgia and vomiting.

In neoadjuvant and adjuvant trials, pertuzumab was administered on the same day as other study treatments in all cycles. Infusion 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 at the cycles when pertuzumab was given on the same day as trastuzumab and docetaxel, with the majority of reactions being mild or moderate in severity.

Hypersensitivity reactions / anaphylaxis

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.

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

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. 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

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. 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 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

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 event 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

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.