The results of the PERSEPHONE trial, a phase III randomized, multicentre, non-inferiority clinical trial comparing 6 months of adjuvant trastuzumab to the current standard of 12 months, were presented at ASCO in May this year. Over 4,000 women with HER2-positive, early-stage breast cancer were randomised to 6 vs 12 months of adjuvant trastuzumab. The trial results show that the shorter duration is non-inferior and has a lower incidence of cardiac toxicity 1.
In this trial, patients were stratified by ER status, chemotherapy type, and chemotherapy and trastuzumab duration. The primary endpoint was disease-free survival (DFS). Non-inferiority was defined as ‘no worse than 3%’ below the 12 months assumed 80% 4-yr DFS (5% 1-sided significance, 85% power). The pre-planned definitive DFS analysis required 500 events.
Final analysis at 4.9 years has reported a disease-free survival rate at 4 years of 89.4% with 6 months of therapy and 89.8% with 12 months of therapy. The hazard ratio (HR) non-inferiority limit was set at 1.29. The calculated HR was 1.05 (95% CI 0.88 – 1.25, 95th percentile = 1.22) demonstrating non-inferiority (HR < 1.29) of 6 months trastuzumab as compared with 12 months duration (1-sided p = 0.01). In addition, only 4% of women in the 6-month arm stopped trastuzumab early because of cardiac problems, compared with 8% in the 12-month arm. “The use of trastuzumab has been a major advance for women with HER2-positive breast cancer by increasing the cure rate, but no treatment is free of side effects, and heart damage has always been a concern with this treatment. This new trial shows that a shorter length of treatment can benefit patients just as much as a longer treatment, with less risk of cardiac side effects. This is a win-win for patients with breast cancer who are receiving this common treatment,” said ASCO President Bruce E. Johnson, MD, FASCO.
While we await final publication, we believe this is welcomed news, particularly for patients with limited oncology benefits. The hope is that a shorter duration of trastuzumab will allow more patients to have access to this important medicine. With 6 months of treatment costing half as much as the current standard one year, the issue of patients having to fund a large portion of their treatment or co-payments becomes less of an issue.
With previous trial data indicating the strong probability that shorter duration trastuzumab treatment offered significant clinical benefit, this option was included in the ICON statement on adjuvant trastuzumab included in the 2018 ICON Clinical Treatment Protocols.
ICON STATEMENT ON ADJUVANT / NEOADJUVANT TRASTUZUMAB:
Adjuvant trastuzumab for one year is currently considered standard of care for patients diagnosed with HER2-positive disease, T1bN0M0 or greater.
ICON recognizes that the vast majority of patients with HER2-positive breast cancer in South Africa currently do not have access to anti-HER2 therapy in the adjuvant / neo-adjuvant (or metastatic) settings due to financial constraints.
ICON is also aware that the financial burden associated with cancer treatment (‘financial toxicity’) needs to be part of the conversation with every patient.
For these reasons, the use of less costly options such as biosimilars/clones, alternative formulations, clinical trials and patient access programs are possibilities that should be considered.
Shorter duration trastuzumab may be considered and discussed, particularly in the following situations:
- Financial constraints which limit patient access to one year of trastuzumab
- Patients with an elevated risk of cardio-toxicity
- T1b/T1cN0M0 disease – given the more limited benefit from adjuvant treatment in these patients, the decision to use trastuzumab and chemotherapy should be influenced by considerations of the toxicity of the treatment regimen and discussed with the patient. The National Comprehensive Cancer Network acknowledges that such patients are generally not included in randomized trials of adjuvant therapy.)
Following this new, stronger data, the ICON Clinical Team believes that colleagues need to discuss this option with appropriate patients, taking efficacy, cost and toxicity into consideration.
Earl HM, Hiller L, Vallier A, et al. 6 versus 12 months of adjuvant trastuzumab in patients with HER2 positive early breast cancer: Randomised phase 3 non-inferiority trial with definitive 4-year disease-free survival results (PERSEPHONE). J Clin Oncol 36, 2018 (suppl; abstr 506).