Overexpression of the human epidermal growth factor receptor 2 (HER2) oncogene occurs in 25 to 30% of all breast cancers,1 and is associated with enhanced cell proliferation and survival, increased risk of disease progression and reduced progression-free and overall survival compared with other breast cancers.2 In the 1990s, the development of targeted therapies that block the HER2 signalling pathway represented a major breakthrough in breast cancer therapy. Trastuzumab (Herceptin®), is a humanized monoclonal antibody that blocks the activity of HER2. In a pivotal clinical trial, trastuzumab was found to improve time to disease progression, response rate, response duration and overall survival.1 As a result, chemotherapy followed by trastuzumab treatment has become the standard of care for patients with HER-positive breast cancer. However, many patients either do not experience a response to first-line trastuzumab, monotherapy3 or their disease progresses during treatment.4
Lapatinib (Tyverb®) is a dual inhibitor of epidermal growth factor receptor (EGFR) and
HER2 tyrosine kinases and is indicated for use in combination with capecitabine for the
treatment of HER2-positive metastatic breast cancer that has progressed with standard
treatment.5 Since trastuzumab acts at the surface of cancer cells while lapatinib
penetrates inside the cell to disable HER2 (Figure 1), it was hypothesised that the nonoverlapping
mechanism of action between lapatinib and trastuzumab would overcome
the primary and acquired resistance to the agents by dual blockade. In 2012, a Phase III
study found that the addition of lapatinib to trastuzumab therapy showed improvements
in all clinical endpoints and conferred an overall survival advantage of 4.5 months in 291
women with HER2-positive metastatic breast cancer whose disease progressed during
prior trastuzumab-based therapies,6,7 as well as improving health-related quality of life.8
Additional subgroup analysis revealed that patients receiving fewer trastuzumab
treatments derived the greatest overall survival benefit, suggesting that dual HER2
blockade should occur early in the treatment.
Following these data, clinical studies have investigated the combination of lapatinib and
trastuzumab in different clinical settings. The NeoALTTO (Neoadjuvant Lapatinib and/or
Trastuzumab Treatment Optimisation) study found that the addition of lapatinib plus
trastuzumab to chemotherapy improved clinical outcomes in the neoadjuvant setting. 9
However, in the phase III ALTTO trial, which evaluated 8,381 patients with completely
excised invasive nonmetastatic HER2-positive breast cancer, the combination failed to
demonstrate a statistically significant improvement in disease-free survival compared to
In 2015, a Phase II study found that early use of lapatinib plus trastuzumab was active in
87 women with metastatic breast cancer,11 leading to a resurgence of interest in the
combined therapy. In March 2016, a late-breaking abstract at the 10th European Breast
Cancer Conference presented the results from a UK multicentre clinical trial, EPHOS-B
(Effect of perioperative anti-HER2 therapy on early breast cancer study – biological
phase).12 The study comprised two parts: in part 1, 130 newly diagnosed women with
HER-positive breast cancer were randomised to receive pre-operative trastuzumab only,
lapatinib only or no pre-operative treatment for 11 days after diagnosis and before
surgery (control group). In part 2, following evidence from other trials of the effectiveness
of this combination, 127 women were randomised to the control group (n=29),
trastuzumab only (n=32), or the combination of lapatinib and trastuzumab (n=66). During
both parts of the trial, the women continued to receive standard treatment after surgery.
Samples of tumour tissue were taken from the first biopsy and again during surgery, and
analysed by immunohistochemistry. The primary endpoint was the change in the level of
Ki67 protein, a cellular marker of proliferation, or a rise in apoptosis of 30% or more from
the time of the first biopsy. The women were categorised as either having pathological
complete response (pCR) if no active cancer cells could be found, or minimal residual
disease (MRD) if the tumour was less than 5mm in diameter, or other.
After 11 days, the primary end pint was met by 76%, 43% and 7% of patients in the
combined, trastuzumab and control groups respectively. In addition 11% of the
combined treatment group had pCR and 17% had MRD. For women randomised to
receive only trastuzumab, 0% had pCR and 3% had MRD and no patients had either
pCR or MRD in the control group. The researchers commented: “The early reduction or
absence of invasive disease in approximately quarter of patients after only 11 days’
preoperative combination HER2 therapy identifies cancers addicted to the HER2
These impressive data have suggest that it is possible to personalise preoperative anti
HER2 therapy, and that women can be treated with a dual blockade approach, without
the need for chemotherapy. Furthermore, the rapid response time means that nonresponders
can be identified early and referred for alternative treatment. However, longterm
data are needed to determine whether these early responses result in improved
Note for design, when redrawing this figure, please omit all the boxes with drug names in
them, together with their arrows, except for trastuzumab and lapatinib, and just have the
first box containing lapatinib with two arrows going to the targets. Also, instead of the
words proteosomal degradation and its associated drawing, please insert the box below.
I (Kat) can scan and send a hand-amended version if needed.
Induction of apoptosis
Decreased cell proliferation
Decreased VEGF production
1. Slamon DJ, Leyland-Jones B, Shak S, et al., Use of chemotherapy plus a monoclonal
antibody against HER2 for metastatic breast cancer that overexpresses HER2, N Engl J
2. Slamon DJ, Clark GM, Wong SG, et al., Human breast cancer: correlation of relapse
and survival with amplification of the HER-2/neu oncogene, Science, 1987;235:177-82.
3. Vogel CL, Cobleigh MA, Tripathy D, et al., Efficacy and safety of trastuzumab as a
single agent in first-line treatment of HER2-overexpressing metastatic breast cancer, J
Clin Oncol, 2002;20:719-26.
4. Montemurro F, Donadio M, Clavarezza M, et al., Outcome of patients with HER2-
positive advanced breast cancer progressing during trastuzumab-based therapy,
5. Medina PJ, Goodin S, Lapatinib: a dual inhibitor of human epidermal growth factor
receptor tyrosine kinases, Clin Ther, 2008;30:1426-47.
6. Blackwell KL, Burstein HJ, Storniolo AM, et al., 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;30:2585-92.
7. Blackwell KL, Burstein HJ, Storniolo AM, et al., Randomized study of Lapatinib alone
or in combination with trastuzumab in women with ErbB2-positive, trastuzumabrefractory
metastatic breast cancer, J Clin Oncol, 2010;28:1124-30.
8. Wu Y, Amonkar MM, Sherrill BH, et al., Impact of lapatinib plus trastuzumab versus
single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+
metastatic breast cancer, Ann Oncol, 2011;22:2582-90.
9. Baselga J, Bradbury I, Eidtmann H, et al., Lapatinib with trastuzumab for HER2-
positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase
3 trial, Lancet, 2012;379:633-40.
10. Piccart-Gebhart MJ, Holmes, A.P., Baselga, J. et al., 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:Suppl; abstr LBA4.
11. Lin NU, Guo, H., Yap, J.T. et al, Phase II Study of Lapatinib in Combination With
Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive
Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early
[18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003) J Clin
12. Bundred N, Cameron, D.m Armstrong, A, et al, Effects of perioperative lapatinib and
trastuzumab, alone and in combination, in early HER2+ breast cancer – the UK EPHOSB
trial (CRUK/08/002), presented at the 10th European Breast Cancer Conference, 9-11
March 2016, Amsterdam, the Netherlands. Abstract 6LBA.