For the third time since 2013, the German Institute for Quality and Efficiency in Health Care (IQWiG) examined in an early benefit assessment the added benefit of the drug pertuzumab in the treatment of HER2-positive breast cancer. The monoclonal antibody is always used in combination with trastuzumab and chemotherapy. Whereas the first two benefit assessments dealt with the treatment of advanced breast cancer and with neoadjuvant treatment, i.e. treatment administered before surgery, this assessment dealt with the advantages and disadvantages in adjuvant, i.e. supportive treatment of early breast cancer at high risk of recurrence.
The conclusion: For patients under 65 years of age, the combination therapy of pertuzumab, trastuzumab, a taxane, and, if applicable, an anthracycline is not better than the appropriate comparator therapy. There is even a hint of lesser benefit for patients aged 65 or older. A notable positive aspect was the methodologically solid validation of the surrogate outcome "disease-free survival" and the long follow-up observation period for symptoms and health-related quality of life.
APHINITY study showed no significant survival advantage
In its dossier, the drug manufacturer cited a single randomized controlled trial, from which it derived an added benefit of pertuzumab: A majority of the just over 4800 patients in the ongoing APHINITY study concurred with the approval of the drug. All patients had their primary tumours surgically removed before the start of the study. They were then randomly allocated in a 1:1 ratio to the arm with pertuzumab, trastuzumab and chemotherapy, or to the comparator arm with placebo, trastuzumab and chemotherapy. Trastuzumab and pertuzumab are monoclonal antibodies that aim to reduce the risk of recurrence by blocking the epidermal growth factor receptor HER2/neu, which is overexpressed in the cancer cells.
No statistically significant difference was shown between the treatment groups for the patient-relevant outcome "overall survival". There was an indication of an added benefit of the pertuzumab combination in the morbidity outcome "recurrence", but hints of lesser benefit for some symptoms. In the outcome category "health-related quality of life", there were hints of an added benefit in two of nine areas, but also a hint of lesser benefit in one area. In addition, there were some indications of lesser benefit in the category of side effects, e.g. in form of more frequent serious adverse events.
In summary, the negative aspects outweighed the advantages of the new combination; there was even lesser benefit in comparison with the appropriate comparator therapy for patients over 65 years of age.
Up to two years of follow-up
In contrast to very advanced metastatic breast cancer, the treatment goal of early breast cancer is to cure the disease: Many patients still have a long life ahead of them. Many studies in the early benefit assessment hardly allow assessing whether deterioration of a symptom or of health-related quality of life, for example, are of a temporary nature as the data are only recorded during treatment. The present study with its long follow-up observation period for symptoms and quality of life (up to two years after the end of treatment), however, measured these outcomes both during treatment and at some interval after the end of treatment. This kind of study design allows to differentiate between temporary advantages or disadvantages of a treatment and long-term effects.
Methodologically exemplary surrogate validation
Due to the relatively long life expectancy of patients with early breast cancer, a significant advantage in overall survival was not expected to be shown during the study. The manufacturer therefore interpreted the so-called disease-free survival (such as the frequency of recurrences) as surrogate parameter for this outcome and derived an added benefit from it. This was based on the assumption that a positive treatment effect on such a substitute outcome also has a favourable effect on the actually relevant outcome. As it is by no means certain that this is the case, surrogates need to be thoroughly validated. The manufacturer conducted a validation study, where it collected data on disease-free survival and overall survival from other comparable studies and first investigated the strength of the correlation between these two entities.
These other studies differed from the APHINITY study, particularly regarding their comparator therapies. The surrogate validation is still conclusive because these studies also included patients with early breast cancer receiving adjuvant treatment with monoclonal antibodies, and hence the patient populations, the drug class, and the lines of treatment were the same. The correlation determined between disease-free survival and overall survival was of medium strength. Hence the researchers then established the so-called surrogate threshold effect (STE). The STE is the minimum effect on the surrogate that has to be shown to consider an effect on the clinical outcome to still be proven in case of medium correlation.
Effect too small for transferability to overall survival
Conclusions on overall survival based on disease-free survival would only be possible if the treatment effect on the surrogate in the APHINITY study was fully above this threshold. This was not the case, however.
Beate Wieseler, Head of IQWiG's Drug Assessment Department notes: "The effect on the surrogate outcome was not large enough. Hence it is not certain that there is an effect on the patients' overall survival, which is the outcome of actual interest." According to Beate Wieseler, the surrogate validation did not change the assessment result in this assessment. "It does show, however, that the correlation-based validation methods we proposed in our 2010 report on surrogate outcomes, are practicable", she adds.
G-BA decides on the extent of added benefit
The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G-BA). After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.