A search of the literature did not find any strong phase III evidence to support the use of this regimen in the neoadjuvant setting. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the randomised open-label phase II Neosphere trial in women with locally advanced, inflammatory or early HER-2 positive breast cancer.rr
A total of 417 patients with operable, locally advanced or inflammatory breast cancer with tumours greater than 2 cm were randomised (1:1:1:1) to receive one of the following 4 treatment arms:
Group A: Docetaxel plus trastuzumab x 4 -> surgery -> FEC x 3 -> trastuzumab x 13
Group B: Docetaxel plus trastuzumab plus pertuzumab x 4 -> surgery -> FEC x 3 -> trastuzumab x 13
Group C: Trastuzumab plus pertuzumab x 4 -> surgery -> docetaxel x 4 -> FEC x 3 -> trastuzumab x 13
Group D: Docetaxel plus pertuzumab x 4 -> surgery -> FEC x 3 -> trastuzumab x 17
The primary end point was pathological complete response in the breast (pCR). (NB: pCR as a valid surrogate endpoint for long-term clinical benefit, such as disease-free survival (DFS) and overall survival (OS), is still an area of contention). Secondary objectives included progression-free survival, disease free survival and safety.
The combination of docetaxel, pertuzumab and trastuzumab has also been used extensively in the metastatic setting for HER-2 positive breast cancer.
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trial |
Gianni et al. 2016r |
Yes |
Yes |
- |
Guidelines |
Date published/revised |
Supports use |
Is the dose and regiment consistent with the protocol |
Comments |
NCCN |
Breast V2.2017r |
Yes |
Yes |
Given before or after FEC or after AC |
CCO |
- |
N/A |
- |
- |
BCCA |
- |
N/A |
- |
- |
ESMO |
2015r |
Yes |
No doses |
Acceptable neoadjuvant option in selected higher risk cases |
Efficacy
The combination of trastuzumab/pertuzumab/docetaxel had a significantly improved pCR rate (45.8%) compared to patients who received docetaxel/trastuzumab (29%) (p=0.0141), as demonstrated below.r
© Lancet Oncol 2012
5-year progression-free survival (PFS) rates were 81% for group A, 86% for group B, 73% for group C and 73% for group D (see below). Disease-free survival (DFS) results were consistent with the PFS results 81% for group A, 84% for group B, 80% for group C and 75% for group D.r
5 year PFS
© Lancet Oncol 2016
Patients who achieved pCR (across all groups) had longer progression-free survival compared with patients who did not (85% vs 76%, HR 0.54, 95% CI 0.29 - 1.00).r
Toxicity
The incidence of serious adverse events during overall treatment was balanced across all groups. Neutropenia and febrile neutropenia were reported most frequently.
Treatment-related toxicity
Grade 3/4r |
Group A
Docetaxel/trastuzumab
n = 107 |
Group B
Docetaxel/pertuzumab/trastuzumab
n = 107 |
Group C
Pertuzumab/trastuzumab
n = 108 |
Group D
Docetaxel/pertuzumab
n = 94 |
Neutropenia |
57% |
48% |
1% |
55% |
Febrile neutropenia |
7% |
8% |
0 |
7% |
Leucopenia |
12% |
5% |
0 |
7% |
Diarrhoea |
4% |
6% |
0 |
4% |
Asthenia |
0 |
2% |
0 |
2% |
Granulocytopenia |
1% |
1% |
0 |
2% |
Rash |
2% |
2% |
0 |
1% |
Menstruation irregular |
1% |
1% |
0 |
4% |
Drug hypersensitivity |
0 |
1% |
2% |
0 |
ALT increase |
3% |
1% |
0 |
1% |
Congestive heart failure |
0 |
0 |
1% |
0 |
Fulminant hepatitis |
0 |
1% |
0 |
0 |