Six versus 12 months’ adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT

Abstract

Background The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives To establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. Design This was a Phase III randomised controlled non-inferiority trial. Setting The setting was 152 NHS hospitals. Participants A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. Intervention Randomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment. Main outcomes The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. Results Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months’ trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months’ trastuzumab, and thus there is a high probability that 6 months’ trastuzumab is cost-effective compared with 12 months’ trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. Limitations The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. Conclusions PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months’ adjuvant trastuzumab is non-inferior to 12 months’. Six months’ treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. Future work Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. Trial registration Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

Non-inferiority trials

“…In the PERSEPHONE study, designed to assess NI of the experimental group (6 months of trastuzumab), the clinically acceptable NI was defined as the 4-year disease-free survival being not worse by an absolute value of 3% than that of the standard group (12 months of trastuzumab), which was estimated to be 80%. [ 2 ] This 3% NI margin was decided before the start of the trial based on consensus from the trial development group that included patient and public involvement groups.…”

“…The PERSEPHONE trial hypothesized that a shorter duration of trastuzumab therapy would be noninferior in terms of survival and offer benefits of being cheaper and having fewer adverse events. [ 2 ] Goyal et al . showed that azithromycin is noninferior to amoxicillin-clavulanic acid for treatment of respiratory exacerbations in children with bronchiectasis with the convenience of once-a-day dosing.…”

“…The PERSEPHONE trial hypothesized that a shorter duration of trastuzumab therapy would be noninferior in terms of survival and offer benefits of being cheaper and having fewer adverse events. [ 2 ]…”

Optimising the Duration of Adjuvant Trastuzumab in Early Breast Cancer in the UK

“…Nine respondents commented at some point in the questionnaire on low risk patients who are receiving paclitaxel for 12 weeks with concurrent trastuzumab continued for 12 months [8]. The number of patients receiving taxane-only chemotherapy within the PERSEPHONE trial is very small (35, 12 month patients and 38, 6 month patients) [11]. Hence, it is impossible to make any recommendations based on such limited data.…”

Ποιότητα Ζωής Ελληνίδων Με Καρκίνο Μαστού

“…Λόγω του σχετικά υψηλού κινδύνου υποτροπής, ακόμη και σε ασθενείς με όγκους N0 <1 cm, θα πρέπει να ληφθεί υπόψη, ιδιαίτερα σε ER-αρνητική νόσο85 .Στις περισσότερες μελέτες, η τραστουζουμάμπη χορηγήθηκε για 1 χρόνο, αν και στη Fin-HER παρόμοια βελτίωση επιτεύχθηκε με μόνο 9 εβδομάδες θεραπείας86 .Δεν εντοπίστηκε επιπρόσθετο όφελος για τη χορήγηση τραστουζουμάμπης διάρκειας 2 ετών στη δοκιμή HERA87 . Σε λίγες μελέτες συγκρίθηκε η βραχύτερη έναντι της συνήθους 12μηνης χορήγησης της τραστουζουμάμπης, αλλά μόνο η μεγαλύτερη δοκιμή Persephone μπόρεσε να δείξει τη μη κατωτερότητα του βραχύτερου 6μηνου σχήματος, αν και αυτό δεν μπορούσε να αποδειχθεί στις άλλες μελέτες88,89 .Επομένως, η συνήθης διάρκεια συνεχίζει να είναι 1 έτος, αν και σε εξαιρετικά επιλεγμένους ασθενείς χαμηλού κινδύνου, οι οποίοι λαμβάνουν χημειοθεραπεία ανθρακυκλίνης/ ταξάνης, μπορεί να συζητηθεί η μείωση της διάρκειας χορήγησης της τραστουζουμάμπης στους 6 μήνες.Η τραστουζουμάμπη είναι συνήθως καλά ανεκτή, αν και μπορεί να προκαλέσει καρδιακή δυσλειτουργία, συνήθως αναστρέψιμη. Η στοιχειώδης καρδιακή λειτουργία (εκφραζόμενη από το κλάσμα εξώθησης αριστερής κοιλίας) είναι απαραίτητη πριν την έναρξη της θεραπείας και απαιτείται περιοδικός έλεγχος της καρδιακής λειτουργίας (συνήθως κάθε 3-4 μήνες) κατά τη διάρκεια της θεραπείας18 .Λόγω της καρδιοτοξικότητάς της, η τραστουζουμάμπη συνήθως δεν πρέπει να χορηγείται μαζί με ανθρακυκλίνη.…”