ICON Clinical Executive, Dr Lee-Ann Jones offers insight into the available data evaluating the appropriate duration of trastuzumab therapy.
The funding of adjuvant trastuzumab has received much attention since its registration and launch in South Africa. Four large phase III trials[i] with more than 10 000 patients, consisting of 52 weeks of adjuvant trastuzumab concomitantly or sequentially with chemotherapy in early breast cancer (stage I to III), have consistently shown a significant reduction in risk of disease recurrence and risk of death.
With such robust data, there is no question about the value of adjuvant trastuzumab. The problem lies with the affordability of the regimen. A 52-week course for an average patient costs approximately R550 000 – a figure that is unsustainable for the majority of funders.
The choice to administer Herceptin for 52 weeks in the clinical trials was, however, not based on any pre-existing evidence. The initial results of a trial using shorter courses of trastuzumab had promising results.
In 2005, the preliminary results of the FinHer trial were presented at the San Antonio Breast Cancer Symposium[ii]. This trial was designed to compare docetaxel to vinorelbine as adjuvant chemotherapy in breast cancer. A total of 1 010 patients were randomised to receive either docetaxel/FEC or vinorelbine/FEC. Of the 1 010 patients, 226 were found to be Her2-positive. The Her2-positive patients were further randomised to receive either docetaxel or vinorelbine, with or without nine weekly trastuzumab infusions. The interim results at 36 months’ follow-up, showed an improvement in recurrence-free survival in the trastuzumab group. Based on these results, many South African breast cancer patients have received the nine-week FinHer regimen.
In 2009, the final result of the FinHer trial was published in the JCO[iii]. At a median follow-up of 62 months, there was no significant difference in distant disease-free survival or overall survival between patients who received trastuzumab (n=116) and those who did not (n=116). Despite these results, the nine-week regimen has been in continual use.
In 2012, the results of two trials confirmed 12-month trastuzumab to be the standard of care. The Phase III PHARE trial, published in The Lancet Oncology[iv], failed to prove non-inferiority of six-month versus 12-month adjuvant trastuzumab on disease-free survival, with all sub-groups favouring 12 months of treatment. The HERA trial released the findings of the one-year versus two-year trastuzumab therapy, revealing no disease-free or overall survival benefit of the two-year treatment.[v]
We eagerly await the results of ongoing trials evaluating the appropriate duration of trastuzumab therapy, as these will further shape our discussions and recommendations. The Persephone trial is an ongoing UK-based trial comparing six months to 12 months of adjuvant trastuzumab. Recruitment is expected to complete in 2016.
[i] Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2- positive breast cancer [supplementary appendix appears online]. N Engl J Med 2005;353:1673-1684. http://www.ncbi.nlm.nih.gov/pubmed/16236738.
Romond EH, Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: final planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831A. Presented at the San Antonio Breast Cancer Symposium in San Antonio, TX; December 4-8, 2012. SABCS Oral presentation #S5-5.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-1672.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. NEngl J Med 2011;365:1273-1283. http://www.ncbi.nlm.nih.gov/pubmed/21991949.
[ii] Joensuu H, Kellokumpu-Lehtinen P, Bono P, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 2006;354:809-820.
[iii] Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol 2009;27:5685-5692.