- •First phase III study of adjuvant dual HER2 blockade for HER2+ breast cancer.
- •8381 patients with stage I-III HER2+ breast cancer, followed for at least 5 years.
- •Compared chemotherapy + trastuzumab versus chemotherapy + 3 lapatinib-containing arms.
- •Lapatinib associated with increased non-cardiac.
- •Chemotherapy + lapatinib/trastuzumab not superior to chemotherapy + trastuzumab.
To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial.
Patients and methods
8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac).
At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74–1.00) for L+T versus T and 0.93 (95% CI, 0.81–1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70–1.06) for L+T versus T and 0.88 (95% CI, 0.71–1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64–1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69–1.00; 6-yr DFS% = 83% versus79%)] subgroups.
T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer.
clinicaltrials.gov Identifier NCT00490139.
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- Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.N Engl J Med. 2005; 353: 1673-1684
- Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.J Clin Oncol. 2014; 32: 3744-3752
- Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.N Engl J Med. 2005; 353: 1659-1672
- Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.Lancet Oncol. 2011; 12: 236-244
- 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.Lancet. 2013; 382: 1021-1028
- Adjuvant trastuzumab in HER2-positive breast cancer.N Engl J Med. 2011; 365: 1273-1283
- Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.J Clin Oncol. 2005; 23: 5305-5313
- Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer.J Clin Oncol. 2008; 26: 2999-3005
- Lapatinib plus capecitabine for HER2-positive advanced breast cancer.N Engl J Med. 2006; 355: 2733-2743
- Lapatinib or trastuzumab plus taxane therapy for human epidermal growth factor receptor 2-positive advanced breast cancer: final results of NCIC CTG MA.31.J Clin Oncol. 2015; 33: 1574-1583
- Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study.J Clin Oncol. 2012; 30: 2585-2592
- Lapatinib 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.Lancet Oncol. 2014; 15: 1137-1146
- First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC).J Clin Oncol. 2014; 32
- Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.J Clin Oncol. 2016; 34: 1034-1042
- NCI common terminology criteria for adverse events (CTCAE) files.2018
- Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481
- The natural duration of cancer.Rep Publ Health Med Subj. 1926; 33: 1-26
- Regression models and life-tables.J R Stat Soc Series B Stat Methodol. 1972; 34: 187-220
- Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.Lancet. 2012; 379: 633-640
- 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; 13: 25-32
- Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study.J Clin Oncol. 2012; 30: 1989-1995
- Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006.J Clin Oncol. 2013; 31: 1726-1731
- 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; 14: 1183-1192
- Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).Ann Oncol. 2013; 24: 2278-2284
- Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.N Engl J Med. 2012; 366: 109-119
- Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.N Engl J Med. 2015; 372: 724-734
- Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial.Ann Oncol. 2019; 30: 1507-1513
- Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.N Engl J Med. 2017; 377: 122-131
- GS1-04. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 years' follow-up.J Clin Oncol. 2021 Feb 4; (JCO2001204)https://doi.org/10.1200/JCO.20.01204
- Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2017; 18: 1688-1700
- Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer for the phase III ExteNET trial.Clin Breast Canc. 2021; 21 (80-91e7)
- Adaptive randomization of neratinib in early breast cancer.N Engl J Med. 2016; 375: 11-22
- Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial.J Clin Oncol. 2020 Sep; 38: 3138-3149
Published online: March 22, 2021
Accepted: January 24, 2021
Received in revised form: January 14, 2021
Received: October 26, 2020
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