A search of the literature did not find strong evidence to support the use of weekly paclitaxel with pertuzumab and trastuzumab in the neoadjuvant treatment of early or locally advanced HER2 positive breast cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by a phase II WSG-ADAPT HER2+/HR- trial in women with early or locally advanced breast cancer HER2 positive breast cancer.r
A total of 160 patients with operable cT1-T4c with any clinical nodal status were randomised (5:2) to receive one of the following 2 treatment arms:
Group A: trastuzumab plus pertuzumab x 4 -> surgery -> 12 x paclitaxel weekly plus trastuzumab x 13
Group B: 12 x weekly paclitaxel plus trastuzumab plus pertuzumab -> surgery -> epirubicin/ cyclophosphamide -> trastuzumab x 13
The primary end point was pathological complete response in the breast (pCR). Secondary end points were toxicity and safety, event-free survival (EFS) and overall survival (OS).r
The combination of weekly paclitaxel plus three weekly trastuzumab and pertuzumab has also been used in the metastatic setting for HER-2 positive breast cancer.r
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Nitz et al 2017r |
Yes |
Yes |
- |
Swain et al 2018r |
Yes |
Yes |
Study to evaluate cardiac toxicity of two neoadjuvant anthracycline based chemotherapy regimens followed by taxane (AC + paclitaxel or FEC-D) with pertuzumab and trastuzumab |
Dang et al 2015r |
Yes |
Yes |
Metastatic setting ongoing treatment until disease progression or unacceptable toxicity, 74% and 26% treated in first- and second- line settings respectively |
Phase IIIb trials |
Bachelot et al 2019r |
Yes |
Yes |
Locally recurrent or metastatic setting investigator choice of taxane, ongoing treatment until disease progression or unacceptable toxicity |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v.2 2019 |
Yes |
No doses |
- |
BCCA |
- |
N/A |
- |
- |
CCO |
- |
N/A |
- |
- |
ESMO |
2019 |
Yes |
No doses stated |
In selected higher-risk cases |
Efficacy
The combination of paclitaxel/trastuzumab/pertuzumab demonstrated a significantly higher pCR rate (78.6%) compared to trastuzumab/pertuzumab (24.4%). The observed pCR rate in the paclitaxel/ trastuzumab/pertuzumab group also had significantly improved (90.5%) compared to patients who received trastuzumab/pertuzumab (34.4%).r
Pathological complete response (pCR) rates in the treatment armsr
ypT0/is, ypN0 – observed pCR; ypT0, ypN0 – total pCR
© Ann Oncol 2017
Toxicity
Ten patients experienced serious adverse events (SAEs), five in each arm. Six were judged to be therapy-related, four in paclitaxel-free arm (Group A) and two in paclitaxel arm (Group B). All patients recovered without sequelae. AEs of any grade were reported as 97.6% in paclitaxel/trastuzumab/pertuzumab treated patients and 68.9% in trastuzumab/pertuzumab arm as below.r
Peripheral neuropathy and neutropenia rates were higher in Group B but these were within expected levels.r
Adverse Events |
Arm A*
(T+ P, 90 patients)
|
Arm B*
(T+P+Paclitaxel, 41 patients)
|
p- value** |
Alopecia |
1 (1.1%) |
20 (48.8%) |
<0.001 |
ALT elevation |
3 (3.3%) |
9 (22.0%) |
<0.001 |
Anaemia/ decreased haemoglobin |
0 |
11 (26.8%) |
<0.001 |
Arthralgia |
5 (5.6%) |
4 (9.8%) |
0.46 |
AST elevation |
2 (2.2%) |
7 (17.1%) |
<0.001 |
Cardiac failure |
0 |
1 (2.4%) |
0.53 |
Decreased appetite |
0 |
4 (9.8%) |
0.01 |
Diarrhoea |
26 (28.9%) |
19 (46.3%) |
0.07 |
Dysgeusia |
4 (4.4%) |
5 (12.2%) |
014 |
Epistaxis |
2 (2.2%) |
13 (31.7%) |
<0.001 |
Fatigue |
15 (16.7%) |
15 (36.6%) |
0.01 |
Flushing |
2 (2.2%) |
2 (4.9%) |
0.59 |
Headache |
7 (7.8%) |
5 (12.2%) |
0.52 |
Hypersensitivity |
3 (3.3%) |
4 (9.8%) |
0.2 |
Hypertension |
1 (1.1%) |
2 (4.9%) |
0.23 |
Infusion related reaction |
1 (1.1%) |
0 |
1.0 |
Mucositis |
8 (8.9%) |
12 (29.3%) |
0.01 |
Nasopharyngitis |
2 (2.2%) |
4 (9.8%) |
0.08 |
Nausea |
7 (7.8%) |
10 (24.4%) |
0.01 |
Neutropenia/decreased neutrophil count |
0 |
5 (12.2%) |
0.003 |
Peripheral neuropathy |
4 (4.4%) |
13 (31.7%) |
<0.001 |
Polyneuropathy |
1 (1.1%) |
4 (9.8%) |
0.03 |
Rash |
6 (6.7%) |
7 (17.1%) |
0.11 |
Stomatitis |
7 (7.8%) |
7 (17.1%) |
0.13 |
Torsade de pointes |
0 |
1 (2.4%) |
1.0 |
Vomiting |
2 (2.2%) |
1 (2.4%) |
1.0 |
* Number of patients from a safety population with at least one AE occurrence
** Group A vs. B; flagging device only (no correction for multiple comparison)
In the BERENICE study considering cardiac safety post neoadjuvant anthracycline therapy in paclitaxel and docetaxel cohorts; episodes of NHYA class III or IV heart failure were seen in 1.5% and 0%, declines in LVEF during neoadjuvant treatment were recorded in 6.5% and 2% and which were sustained across 2 or more measures in 1% and 0.5%. The pCR rate (ypT0/is ypN0) was 61.8% in the paclitaxel cohort and 60.7% for the docetaxel cohort.r