Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FD02 
Mechanism of action

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

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

Clinical efficacy and safety

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


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

Metastatic breast cancer

Perjeta in combination with trastuzumab and docetaxel
CLEOPATRA (WO20698) is a multicentre, randomised, double-blind, placebo-controlled phase III clinical trial conducted in 808 patients with HER2-positive metastatic or locally recurrent unresectable breast cancer.
Patients with clinically important cardiac risk factors were not included (see section 4.4). Due to the exclusion of patients with brain metastases no data are available on Perjeta activity on brain metastases.
There is very limited data available in patients with unresectable locally recurrent disease. Patients were randomised 1:1 to receive placebo + trastuzumab + docetaxel or Perjeta + trastuzumab + docetaxel.

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

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

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

The efficacy results from the CLEOPATRA study are summarised in Table 3. A statistically significant improvement in IRF-assessed PFS was demonstrated in the Perjeta-treated group compared with the placebo- treated group. The results for investigator-assessed PFS were similar to those observed for IRF-assessed PFS.


Table 3 Summary of efficacy from CLEOPATRA study

Parameter                                 Placebo+            Perjeta+        HR             p-value trastuzumab         trastuzumab    (95% CI)
+ docetaxel         + docetaxel n=406                n=402
Progression-Free Survival
(independent review) – primary endpoint*
 no. of patients with an event            242 (59%)          191 (47.5%)        0.62          <0.0001 Median months                              12.4                18.5        [0.51;0.75] Overall Survival - secondary endpoint**
 no. of patients with an event           221 (54.4%)         168 (41.8%)        0.68          0.0002 Median months                              40.8                56.5        [0.56;0.84] Objective Response Rate
(ORR)^ - secondary endpoint no. of patients with measurable disease                                     336                  343       Difference        0.0011 Responders***                           233 (69.3%)         275 (80.2%)     in ORR: 95% CI for ORR                          [64.1; 74.2]        [75.6; 84.3]     10.8% Complete response (CR)                   14 (4.2%)           19 (5.5%)     [4.2,17.5] Partial Response (PR)                   219 (65.2%)         256 (74.6%) Stable disease (SD)                     70 (20.8%)           50 (14.6%) Progressive disease (PD)                 28 (8.3%)           13 (3.8 %) Duration of Response †^ n=                                           233                275
Median weeks                                 54.1               87.6
95% CI for Median                          [46;64]            [71;106] * Primary progression-free survival analysis, cutoff date 13th May 2011.
** Event-driven final overall survival analysis, cutoff date 11th February 2014.
*** Patients with best overall response of confirmed CR or PR by RECIST.
† Evaluated in patients with Best Overall Response of CR or PR.
^ Objective response rate and duration of response are based on IRF-assessed tumour assessments.

Consistent results were observed across pre-specified patient subgroups including the subgroups based on stratification factors of geographic region and prior adjuvant/neoadjuvant therapy or de novo metastatic breast cancer (see Figure 1). A post hoc exploratory analysis revealed that for patients who had received prior trastuzumab (n = 88), the hazard ratio for IRF-assessed PFS was 0.62 (95% CI 0.35, 1.07), compared with 0.60 (95% CI 0.43, 0.83) for patients who had received prior therapy which did not include trastuzumab (n = 288).


Figure 1    IRF-assessed PFS by patient subgroup



The event-driven final analysis of OS was performed when 389 patients had died (221 in the placebo-treated group and 168 in the Perjeta-treated group). The statistically significant OS benefit in favour of the Perjeta- treated group, previously observed at an interim analysis of OS (performed one year after the primary analysis), was maintained (HR 0.68, p = 0.0002 log-rank test). The median time to death was 40.8 months in the placebo-treated group and 56.5 months in the Perjeta-treated group (see Table 3, Figure 2).

A descriptive analysis of OS performed at the end of the study when 515 patients had died (280 in the placebo-treated group and 235 in the Perjeta-treated group) showed that the statistically significant OS benefit in favour of the Perjeta-treated group was maintained over time after a median follow-up of 99 months (HR 0.69, p < 0.0001 log-rank test; median time to death 40.8 months [placebo-treated group] versus 57.1 months [Perjeta-treated group]). Landmark survival estimates at 8 years were 37% in the Perjeta-treated group and 23% in the placebo-treated group.


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



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


No statistically significant differences were found between the two treatment groups in Health Related Quality of Life as assessed by FACT-B TOI-PFB scores.

Additional supportive clinical trial information

BO17929 - single-arm trial in metastatic breast cancer
BO17929 was a phase II, non-randomised study in patients with metastatic breast cancer whose tumours had progressed during treatment with trastuzumab. Treatment with Perjeta and trastuzumab resulted in a response rate of 24.2%, with a further 25.8% of patients experiencing stabilisation of disease lasting at least 6 months, indicating that Perjeta is active following progression on trastuzumab.

Early Breast Cancer

Neoadjuvant Treatment
In the neoadjuvant setting, locally advanced and inflammatory breast cancers are considered as high-risk irrespective of hormone receptor status. In early stage breast cancer, tumor size, grade, hormone receptor status and lymph node metastases should be taken into account in the risk assessment.

The indication in the neoadjuvant treatment of breast cancer is based on demonstration of an improvement in pathological complete response rate, and trends to improvement in disease-free survival that nevertheless do not establish or precisely measure a benefit with regard to long-term outcomes, such as overall survival or disease-free survival.

NEOSPHERE (WO20697)

NEOSPHERE is a phase II, multicentre, multinational randomised controlled trial with Perjeta and was conducted in 417 adult female patients with newly diagnosed, early, inflammatory or locally advanced HER2-positive breast cancer (T2-4d; primary tumour > 2cm in diameter) who had not received prior trastuzumab, chemotherapy or radiotherapy. Patients with metastases, bilateral breast cancer, clinically important cardiac risk factors (see section 4.4) or LVEF < 55% were not included. The majority of patients were less than 65 years old.


Patients were randomised to receive one of the following neoadjuvant regimens for 4 cycles prior to surgery: 
•   Trastuzumab plus docetaxel
•   Perjeta plus trastuzumab and docetaxel
•   Perjeta plus trastuzumab
•   Perjeta plus docetaxel.

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

Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every three weeks.
Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every three weeks.
Docetaxel was given intravenously at an initial dose of 75 mg/ m2 followed by 75 mg/ m2 or 100 mg/ m2 (if tolerated) every 3 weeks. Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m2), epirubicin (90 mg/m2), cyclophosphamide (600 mg/m2) (FEC) given intravenously every three weeks, and trastuzumab administered intravenously every three weeks to complete one year of therapy. Patients who only received Perjeta plus trastuzumab prior to surgery subsequently received both FEC and docetaxel post surgery.

The primary endpoint of the study was pathological complete response (pCR) rate in the breast (ypT0/is).
Secondary efficacy endpoints were clinical response rate, breast conserving surgery rate (T2-3 tumours only), disease-free survival (DFS), and PFS. Additional exploratory pCR rates included nodal status (ypT0/isN0 and ypT0N0).

Demographics were well balanced (median age was 49-50 years, the majority were caucasian (71%)) and all patients were female. Overall 7% of patients had inflammatory breast cancer, 32% had locally advanced breast cancer and 61% had operable breast cancer. Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as ER positive and/or PgR positive).

The efficacy results are presented in Table 4. A statistically significant improvement in pCR rate (ypT0/is) was observed in patients receiving Perjeta plus trastuzumab and docetaxel compared to patients receiving trastuzumab and docetaxel (45.8% vs 29.0%, p value = 0.0141). A consistent pattern of results was observed regardless of pCR definition. The difference in pCR rate is considered likely to translate into a clinically meaningful difference in long term outcomes and is supported by positive trends in PFS (HR 0.69, 95% CI 0.34, 1.40) and DFS (HR 0.60, 95% CI 0.28, 1.27).

The pCR rates as well as the magnitude of benefit with Perjeta (Perjeta plus trastuzumab and docetaxel compared to patients receiving trastuzumab and docetaxel) were lower in the subgroup of patients with hormone receptor-positive tumours (difference of 6% in pCR in the breast) than in patients with hormone receptor-negative tumours (difference of 26.4% in pCR in the breast).
pCR rates were similar in patients with operable versus locally advanced disease. There were too few patients with inflammatory breast cancer to draw any firm conclusions but the pCR rate was higher in patients who received Perjeta plus trastuzumab and docetaxel.

TRYPHAENA (BO22280)

TRYPHAENA is a multicentre, randomised phase II clinical trial conducted in 225 adult female patients with HER2-positive locally advanced, operable, or inflammatory breast cancer (T2-4d; primary tumour > 2cm in diameter) who had not received prior trastuzumab, chemotherapy or radiotherapy. Patients with metastases, bilateral breast cancer, clinically important cardiac risk factors (see section 4.4) or LVEF < 55% were not included. The majority of patients were less than 65 years old. Patients were randomised to receive one of three neoadjuvant regimens prior to surgery as follows:

•   3 cycles of FEC followed by 3 cycles of docetaxel, all given concurrently with Perjeta and trastuzumab
•   3 cycles of FEC alone followed by 3 cycles of docetaxel, with trastuzumab and Perjeta given concurrently
•   6 cycles of TCH in combination with Perjeta.

Randomisation was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and /or PgR positivity.
Pertuzumab was given intravenously at an initial dose of 840 mg, followed by 420 mg every three weeks.
Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every three weeks.
FEC (5-fluorouracil [500 mg/m2], epirubicin [100 mg/m2], cyclophosphamide [600 mg/m2]) were given intravenously every three weeks for 3 cycles. Docetaxel was given as an initial dose of 75 mg/m2 IV infusion every three weeks with the option to escalate to 100 mg/m2 at the investigator’s discretion if the initial dose was well tolerated. However, in the group treated with Perjeta in combination with TCH, docetaxel was given intravenously at 75 mg/m2 (no escalation was permitted) and carboplatin (AUC 6) was given intravenously every three weeks. Following surgery all patients received trastuzumab to complete one year of therapy.

The primary endpoint of this study was cardiac safety during the neoadjuvant treatment period of the study.
Secondary efficacy endpoints were pCR rate in the breast (ypT0/is), DFS, PFS and OS.

Demographics were well balanced between arms (median age was 49-50 years, the majority were Caucasian [77%]) and all patients were female. Overall 6% of patients had inflammatory breast cancer, 25% had locally advanced breast cancer and 69% had operable breast cancer. Approximately half the patients in each treatment group had ER-positive and/or PgR-positive disease.

Compared with published data for similar regimens without pertuzumab, high pCR rates were observed in all 3 treatment arms (see Table 4). A consistent pattern of results was observed regardless of pCR definition used. The pCR rates were lower in the subgroup of patients with hormone receptor-positive tumours (range 46.2% to 50.0%) than in patients with hormone receptor-negative tumours (range 65.0% to 83.8%).
 pCR rates were similar in patients with operable and locally advanced disease. There were too few patients with inflammatory breast cancer to draw any firm conclusions.


Table 4       NEOSPHERE (WO20697) and TRYPHAENA (BO22280): Overview of efficacy (Intent to Treat Population)

NEOSPHERE (WO20697)                                       TRYPHAENA (BO22280) Perjeta+
Trastuzumab
FEC
Perjeta+                                                    +
Trastuzuma                                                                           Perjeta+ Trastuzumab   Perjeta+                   Perjeta           FEC                              Perjeta b                                                                             Trastuzumab Parameter +Docetaxel       +     Trastuzumab                 +Docetaxel        Perjeta+                           +TCH +
Docetaxel     N=107                      N=96          Trastuzumab                           N=77 N=107                                                                             Docetaxel N=107                                                      +
N=75
Docetaxel
N=73 pCR rate in the breast
31 (29.0%)      49 (45.8%)      18 (16.8%)     23 (24.0%)       45 (61.6%)      43 (57.3%)        51 (66.2%) (ypT0/is)
[20.6; 38.5]    [36.1; 55.7]   [10.3; 25.3]    [15.8; 33.7]     [49.5; 72.8]    [45.4; 68.7]      [54.6; 76.6] n (%)
[95% CI]1
Difference in pCR                         +16.8 %         -12.2 %         -21.8 % rates2                                                                            NA              NA                NA [3.5; 30.1]    [-23.8; -0.5]   [-35.1; -8.5]
[95% CI]3 p-value
0.0141          0.0198          0.0030
(with
(vs.         (vs.          (vs Perjeta+
Simes corr.                                                                       NA              NA                NA Trastuzumab+ Trastuzumab+ Trastuzumab for CMH
Docetaxel)   Docetaxel)  +Docetaxel) test)4 pCR rate in the breast and lymph node        23 (21.5%)        42 (39.3%)      12 (11.2%)     17 (17.7%)       41 (56.2%)      41 (54.7%)        49 (63.6%) (ypT0/is    [14.1; 30.5]      [30.3; 49.2]    [5.9; 18.8]    [10.7; 26.8]     [44.1; 67.8]    [42.7; 66.2]      [51.9; 74.3] N0) n (%)
[95% CI] ypT0 N0
13 (12.1%)      35 (32.7%)       6 (5.6%)      13 (13.2%)       37 (50.7%)      34 (45.3%)        40 (51.9%) n (%)
[6.6; 19.9]     [24.0; 42.5]    [2.1; 11.8]     [7.4; 22.0]     [38.7; 62.6]    [33.8; 57.3]      [40.3; 63.5] [95% CI]
Clinical
79 (79.8%)     89 (88.1%)      69 (67.6%)       65 (71.4%)      67 (91.8%)       71 (94.7%)        69 (89.6%) Response5
FEC: 5-fluorouracil, epirubicin, cyclophosphamide; TCH: docetaxel, carboplatin and trastuzumab, CMH: Cochran– Mantel–Haenszel
1. 95% CI for one sample binomial using Pearson-Clopper method.
2. Treatment Perjeta+Trastuzumab+Docetaxel and Perjeta+Trastuzumab are compared to Trastuzumab+ Docetaxel while Perjeta+Docetaxel is compared to Perjeta+Trastuzumab+Docetaxel.
3. Approximate 95% CI for difference of two response rates using Hauck-Anderson method.
4. p-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.
5. Clinical response represents patients with a best overall response of CR or PR during the neoadjuvant period (in the primary breast lesion).

BERENICE (WO29217)

BERENICE is a non-randomized, open-label, multicentre, multinational, Phase II trial conducted in 401 patients with HER2-positive locally advanced, inflammatory, or early-stage breast cancer (with primary tumours  2cm in diameter or node-positive disease).


The BERENICE study included two parallel groups of patients. Patients considered suitable for neoadjuvant treatment with trastuzumab plus anthracycline/taxane-based chemotherapy were allocated to receive one of the two following regimens prior to surgery as follows:

•   Cohort A - 4 cycles of two weekly dose-dense doxorubicin and cyclophosphamide followed by 4 cycles of Perjeta in combination with trastuzumab and paclitaxel.
•   Cohort B - 4 cycles of FEC followed by 4 cycles of Perjeta in combination with trastuzumab and docetaxel.

Following surgery all patients received Perjeta and trastuzumab intravenously every 3 weeks to complete 1 year of therapy.

The primary endpoint of the BERENICE trial is cardiac safety in the neoadjuvant period of the trial. The primary endpoint of cardiac safety, i.e. the incidence of NYHA Class III/IV LVD and LVEF declines, was consistent with previous data in the neoadjuvant setting (see section 4.4. and 4.8).

Adjuvant Treatment

In the adjuvant setting, based on data from the APHINITY study, HER2-positive early breast cancer patients at high risk of recurrence are defined as those with lymph node-positive or hormone receptor-negative disease.

APHINITY (BO25126)

APHINITY is a multicentre, randomised, double-blind, placebo-controlled Phase III trial conducted in 4804 patients with HER2-positive early breast cancer who had their primary tumour excised prior to randomisation. Patients were then randomised to receive Perjeta or placebo, in combination with adjuvant trastuzumab and chemotherapy. Investigators selected one of the following anthracycline-based or non- anthracycline-based chemotherapy regimens for individual patients:

•   3 or 4 cycles of FEC or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), followed by 3 or 4 cycles of docetaxel or 12 cycles of weekly paclitaxel
•   4 cycles of AC or epirubicin and cyclophosphamide (EC), followed by 3 or 4 cycles of docetaxel or 12 cycles of weekly paclitaxel
•   6 cycles of docetaxel in combination with carboplatin

Pertuzumab and trastuzumab were administered intravenously (see section 4.2) every 3 weeks starting on Day 1 of the first taxane-containing cycle, for a total of 52 weeks (up to 18 cycles) or until recurrence, withdrawal of consent or unmanageable toxicity. Standard doses of 5-fluorouracil, epirubicin, doxorubicin, cyclophosphamide, docetaxel, paclitaxel and carboplatin were administered. After completion of chemotherapy, patients received radiotherapy and/or hormone therapy as per local clinical standard.

The primary endpoint of the study was invasive disease-free survival (IDFS), defined as the time from randomisation to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. Secondary efficacy endpoints were IDFS including second primary non-breast cancer, overall survival (OS), disease-free survival (DFS), recurrence-free interval (RFI) and distant recurrence-free interval (DRFI).


Demographics were well balanced between the two treatment arms. The median age was 51 years, and over 99% of patients were female. The majority of patients had node-positive (63%) and/or hormone receptor- positive disease (64%), and were Caucasian (71%).

After a median follow-up of 45.4 months, the APHINITY study showed a 19% (hazard ratio [HR] = 0.81; 95% CI 0.66, 1.00 p-value 0.0446) reduction in risk of recurrence or death in patients randomised to receive Perjeta compared with patients randomised to receive placebo.

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

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

Table 5      Overall Efficacy: ITT Population
Placebo +
Perjeta + trastuzumab trastuzumab +
+ Chemotherapy        Chemotherapy
N=2400                N=2404
Primary Endpoint
Invasive Disease Free Survival (IDFS) *
Number (%) of patients with event                            171 (7.1%)                           210 (8.7%) HR [95% CI]                                                                  0.81 [0.66, 1.00] p-value (Log-Rank test, stratified1)                                              0.0446 3 year event-free rate2 [95% CI]                             94.1 [93.1, 95.0]               93.2 [92.2, 94.3] Secondary Endpoints1
IDFS including second primary non-breast cancer*
Number (%) of patients with event                            189 (7.9%)                           230 (9.6%) HR [95% CI]                                                                  0.82 [0.68, 0.99] p-value (Log-Rank test, stratified1)                                              0.0430 3 year event-free rate2 [95% CI]                             93.5 [92.5, 94.5]               92.5 [91.4, 93.6] Disease Free Survival (DFS)*
Number (%) of patients with event                            192 (8.0%)                           236 (9.8%) HR [95% CI]                                                                  0.81 [0.67, 0.98] p-value (Log-Rank test, stratified1)                                              0.0327 3 year event-free rate2 [95% CI]                             93.4 [92.4, 94.4]               92.3 [91.2, 93.4] Overall Survival (OS)**
Number (%) of patients with event                            168 (7.0%)                                202 (8.4%) HR [95% CI]                                                                    0.83 [0.68, 1.02] 

Key to abbreviations (Table 5): HR: Hazard Ratio; CI: Confidence Interval * Primary Invasive Disease Free Survival analysis, cutoff date 19th December 2016.
** Data from 3rd interim analysis for overall survival, cutoff date 10th January 2022.1. All analyses stratified by nodal status, protocol version, central hormone receptor status, and adjuvant chemotherapy regimen.
2. 3-year event-free rate derived from Kaplan-Meier estimates.


Figure 3        Kaplan-Meier Curve of Invasive Disease Free Survival 


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

The estimate of IDFS at 4-years was 92.3% in the Perjeta-treated group versus 90.6% in the placebo-treated group. At the time of the estimate the median follow-up was 45.4 months.

Results of Subgroup Analysis

At the time of the primary analysis, the benefits of Perjeta were more apparent in subgroups of patients a high risk of recurrence: patients with node-positive or hormone receptor-negative disease (see table 6).


Table 6 Efficacy results in subgroups by nodal status and hormone receptor status1 
Number of IDFS events/Total N (%)                         Unstratified HR Perjeta +               Placebo +                    (95% CI)
Population                        trastuzumab +           trastuzumab + chemotherapy            chemotherapy
Nodal status
Positive                              139/1503                      181/1502                      0.77 (9.2%)                        (12.1%)                  (0.62, 0.96)
Negative                           32/897                         29/902                      1.13 (3.6%)                         (3.2%)                  (0.68, 1.86)
Hormone receptor status
Negative                              71/864                         91/858                      0.76 (8.2%)                        (10.6%)                  (0.56, 1.04)
Positive                          100/1536                      119/1546                      0.86 (6.5%)                         (7.7%)                  (0.66, 1.13)
1
Prespecified subgroup analyses without adjusting for multiple comparisons, therefore, results are considered descriptive.

Estimates of IDFS rates in the lymph node- positive subgroup were 92.0% versus 90.2% at 3 years and 89.9% vs. 86.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively. In the lymph node- negative subgroup, estimates of IDFS rates were 97.5% versus 98.4% at 3 years and 96.2% versus 96.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively. In the hormone receptor-negative subgroup, estimates of IDFS rates were 92.8% versus 91.2% at 3 years and 91.0% versus 88.7% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively. In the hormone receptor-positive subgroup estimates of IDFS rates were 94.8% versus 94.4% at 3 years and 93.0% versus 91.6% at 4 years in Perjeta-treated patients versus placebo-treated patients, respectively.

Patient Reported Outcomes (PRO)

Secondary endpoints included the assessment of patient-reported global health status, role and physical function, and treatment symptoms using the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires. In the analyses of patient-reported outcomes, a 10-point difference was considered clinically meaningful.

Patients’ physical function, global health status and diarrhoea scores showed a clinically meaningful change during chemotherapy in both treatment arms. The mean decrease from baseline at that time for physical function was -10.7 (95% CI-11.4, -10.0) in the Perjeta arm and -10.6 (95% CI -11.4, -9.9) in the placebo arm; global health status was -11.2 (95% CI -12.2, -10.2) in the Perjeta arm and -10.2 (95% CI -11.1,-9.2) in the placebo arm. Change in diarrhoea symptoms increased to +22.3 (95% CI 21.0, 23.6) in the Perjeta arm versus +9.2 (95% CI 8.2, 10.2) in the placebo arm.

Thereafter in both arms physical function and global health status scores returned to baseline levels during targeted treatment. Diarrhoea symptoms returned to baseline after HER2 therapy in the Perjeta-arm. The addition of Perjeta to trastuzumab plus chemotherapy did not affect patients’ overall role function over the course of the study.

Immunogenicity

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

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

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

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

Absorption

Perjeta is administered as an intravenous infusion.
Distribution

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

Biotransformation

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

Elimination

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

Pertuzumab displayed linear pharmacokinetics within the recommended dose range.

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

Renal impairment

No dedicated renal impairment trial for Perjeta has been conducted. Based on the results of the population pharmacokinetic analysis, pertuzumab exposure in patients with mild (creatinine clearance [CLcr] 60 to 90 ml/min, N=200) and moderate renal impairment (CLcr 30 to 60 ml/min, N=71) was similar to that in patients with normal renal function (CLcr greater than 90 ml/min, N=200). No relationship between CLcr and pertuzumab exposure was observed over the range of CLcr (27 to 244 ml/min).

Other special populations

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

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