NICE announced on 21 December 2016 that pertuzumab, in combination with trastuzumab and chemotherapy, is recommended, within its marketing authorisation, as an option for the neoadjuvant treatment of adults with human epidermal growth factor receptor 2 (HER2)‑positive breast cancer; that is, in patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer at high risk of recurrence. It is recommended only if the company provides pertuzumab with the discount agreed in the patient access scheme.
Pertuzumab is a recombinant monoclonal antibody which targets HER2-positive breast tumours. It interrupts the activation of the HER2 intracellular signalling pathway, leading to cell growth arrest and apoptosis. It is administered by intravenous infusion.
Patients should normally have no more than 4 cycles of neoadjuvant treatment with pertuzumab.
The appraisal committee heard from the clinical experts that there is variation across the NHS in the use of neoadjuvant therapy before surgery in HER2-positive breast cancer. They stated that this may relate to service configuration issues, such as staffing levels and access to HER2 testing, and that this restricted access to neoadjuvant treatment in some parts of the UK. The clinical experts indicated that despite this variation, there is a trend in the NHS towards increasing use of neoadjuvant treatment for HER2-positive breast cancer, following the demonstrated survival benefits of HER2 agents given later in the disease pathway. A reduction in the size of the tumour may make the disease operable when initially it is very extensive, and in other cases allow breast-conserving surgery, thereby reducing the need for more complicated procedures (such as mastectomy and breast reconstruction) and their associated risks.
The company submitted evidence from 2 phase II randomised controlled trials, but were at an early stage of research (phase II) and lacked longer-term efficacy data, had small patient numbers, were open label, and were not powered for key outcomes of interest including progression-free survival and overall survival. The committee concluded that the clinical trial evidence for pertuzumab in the neoadjuvant setting was limited, but in the absence of stronger evidence, results from NeoSphere could be used as the basis of its decision-making, supported by data from TRYPHAENA.
The committee concluded that there was evidence that pertuzumab could improve rates of pathological complete response (pCR) when added to trastuzumab and docetaxel, and that that pCR was more likely than not to have an association with longer-term survival.
The committee noted that patients in the NeoSphere trial were described as having 'operable' disease (defined as tumours over 2 cm in diameter with no lymph nodes or only 1 lymph node involved), and people in this category would have the best prognosis.
The committee considered that there were likely to have been very few UK patients in the trial; there were only 214 patients who had either the intervention or comparator as stated in the scope, across 59 centres, and of these only 2 centres were in the UK. The committee concluded that although there was some uncertainty about the generalisability of the NeoSphere trial to current NHS practice, it was appropriate for decision-making.
The committee discussed the value of pCR as a clinically meaningful indicator of longer-term survival outcomes. It was aware that a number of studies have been done in this area, including the CTNeoBC meta-analysis. At trial-level, CTNeoBC concluded that the evidence that a treatment-related improvement in pCR translated into a treatment-related improvement in survival outcomes was very weak.
The committee was also aware that the evidence review group had reviewed the wider evidence in this area, and had stated that the evidence of a positive treatment effect translating into a positive effect on survival was not convincing.
On balance, although there was uncertainty about the exact relationship, the committee accepted that pCR was more likely than not to have an association with longer-term survival.
The summary of product characteristics includes the following adverse reactions for pertuzumab: decreased appetite, headache, cough, diarrhoea, vomiting, nausea, constipation, rash, pain, oedema, fatigue, asthaenia and left ventricular dysfunction.
The recommended dosage of pertuzumab is an initial loading dose of 840 mg, followed by a maintenance dose of 420 mg every 3 weeks for 3 to 6 cycles.
Pertuzumab costs 2,395 GBP per 420‑mg vial (excluding VAT).