ArticlesLapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response
Introduction
Overexpression or amplification of HER2 occurs in roughly 15% of breast cancers, and is associated with poor prognosis.1 Anti-HER2 drugs such as the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are widely used for the treatment of HER2-positive breast cancer; trastuzumab is approved for use in the metastatic and adjuvant settings, whereas lapatinib is approved in the metastatic setting only.2, 3, 4, 5, 6
Previously, we reported findings from the phase 3, randomised NeoALTTO study,7 which showed that dual anti-HER2 inhibition with lapatinib and trastuzumab combined with weekly paclitaxel significantly increased the proportion of patients achieving pathological complete response in the combination group compared with trastuzumab (78 [51·3%] of 152 patients [95% CI 43·1–59·5] vs 44 [29·5%] of 149 patients [22·4–37·5], respectively, p=0·0001). Lapatinib alone did not increase rates of pathological complete response compared with trastuzumab (38 of 154 patients [24·7%, 18·1–32·3], p=0·34). In a meta-analysis8 funded by the US Food and Drug Administration (FDA) of 11 955 patients, achievement of pathological complete response after neoadjuvant therapy was significantly associated with improved event-free survival (hazard ratio [HR] 0·39 [95% CI 0·31–0·50]) and overall survival (HR 0·34 [0·24–0·47]), irrespective of hormone receptor status.8
Here, we report the prespecified secondary outcomes of event-free and overall survival from NeoALTTO, and the association between achievement of locoregional pathological complete response (ypT0/is ypN0) and survival outcomes.
Section snippets
Study design and participants
Study design and patient eligibility has been reported previously.7 Briefly, 455 women were randomly assigned between Jan 5, 2008, and May 27, 2010, to one of the three parallel treatment groups: oral lapatinib, intravenous trastuzumab, or lapatinib plus trastuzumab. Key eligibility criteria included histologically confirmed HER2-positive early breast cancer,9 tumour size greater than 2 cm, adequate hepatic, renal, cardiac, and bone marrow function at baseline, and left ventricular ejection
Results
Of the 455 patients enrolled, 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group (figure 1). Patients' demographic characteristics, sex, geographical location, and medical history have been previously described.7
This report presents a pre-specified analysis at 3 years after the last woman had surgery for breast cancer. The median follow-up was 3·77 years (IQR 3·50–4·22) and the median survival follow-up was
Discussion
The NeoALTTO trial was not powered to detect significant differences in survival outcomes. Our findings showed that women with pathological complete response after neoadjuvant anti-HER2 therapies had significantly better event-free and overall survival than did women without pathological complete response. Women treated with lapatinib plus trastuzumab who achieved pathological complete response had improved 3-year event-free survival, and significantly lower risk of an event, than did those
References (28)
- et al.
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial
Lancet
(2012) - et al.
Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates
J Clin Epidemiol
(1995) - et al.
Importance of events per independent variable in proportional hazards analysis. I. Background, goals, and general strategy
J Clin Epidemiol
(1995) - et al.
Neoadjuvant and adjuvant trastuzumab in patients with HER2- positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort
Lancet Oncol
(2014) - et al.
Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer
Ann Oncol
(2013) - et al.
Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial
Lancet Oncol
(2013) - et al.
Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial
Lancet Oncol
(2012) - et al.
Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene
Science
(1987) - et al.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
N Engl J Med
(2001) - et al.
Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer
N Engl J Med
(2005)