Jumping higher: is it still possible? The ALTTO trial challenge

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Despite differences in patient population and trial design, including the chemotherapy regimen, timing of trastuzumab initiation and schedule and duration of tras ...
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Jumping higher: is it still possible? The ALTTO trial challenge Expert Rev. Anticancer Ther. 8(12), 1883–1890 (2008)

Gianluca Tomasello, Evandro de Azambuja, Phuong Dinh, Natasa Snoj and Martine Piccart-Gebhart† † Author for correspondence Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles (ULB), 121 Boulevard de Waterloo, 1000, Brussels, Belgium Tel.: +32 2541 3206 Fax: +32 2538 0858 [email protected]

Trastuzumab, a humanized monoclonal antibody directed against HER2, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in the metastatic setting, as well as halving the recurrence rate and improving survival in HER2positive early breast cancer. Lapatinib is an orally active, reversible, small-molecule tyrosine kinase inhibitor that potently inhibits both HER1 and HER2 tyrosine kinase activity. This agent is the most advanced in terms of clinical trials and has been shown to have a favorable safety profile. Owing to the promising activity seen in advanced breast cancer, lapatinib is the ideal candidate for testing in the adjuvant setting. Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) is a four-arm randomized trial designed to compare trastuzumab and lapatinib in women with early-stage HER2-positive breast cancer. Specifically, ALTTO will examine which anti-HER2 agent is more effective and which is their best schedule of administration, namely, what benefit will be derived by taking the drugs separately, in tandem order or in combination. Overall, 8000 patients will be enrolled worldwide. Keywords : adjuvant therapy • ALTTO trial • early breast cancer • HER2-positive • lapatinib • trastuzumab

HER2 belongs to the ErbB family of tyrosine kinase receptors: its overexpression and/or amplification occurs in 20–30% of invasive breast carcinomas and is associated with poor prognosis [1] . The tyrosine kinase domains are activated by both homodimerization and hetero­dimerization, generally induced by ligand binding. In contrast to the extracellular domains of the three other HER receptors, the extra­cellular domain of HER2 can adopt a fixed conformation resembling a ligandactivated state, permitting it to dimerize in the absence of a ligand [2] . In 1989, Slamon et al. correlated HER2 overexpression with adverse clinical outcome, including decreased patient survival and time to relapse [3] . Trastuzumab (Herceptin® ; F HoffmannLaRoche Ltd, Basel, Switzerland; Genentech, Inc., CA, USA), a monoclonal antibody, consists of two antigen-specific sites that bind to the juxtamembrane portion of the extracellular domain of the HER2 receptor and prevent the activation of its intracellular tyrosine kinase [4] . Several possible mechanisms by which trastuzumab might decrease signaling include prevention of HER2 receptor dimerization, increased endocytotic destruction of the receptor, inhibition of shedding of the extra­cellular domain and www.expert-reviews.com

10.1586/14737140.8.12.1883

immune activation [5] . In metastatic breast cancer (MBC), trastuzumab monotherapy can result in response rates ranging from 12 to 34%, with a median duration of 9 months [6,7] . Furthermore, the use of trastuzumab combined with chemotherapy can increase response rate, time to progression and overall survival (OS) [8,9] . In 1998, these important results led to the approval of trastuzumab in MBC. In the adjuvant setting, the combination or sequential use of trastuzumab with different chemo­therapy regimens demonstrated a striking benefit in reducing breast cancer (BC) recurrences, as well as in improving patient survival [10–13] . Despite these impressive results, the reality is that not all patients will derive benefit from trastuzumab therapy, and in those who respond initially, resistance to trastuzumab can often develop, usually within 1 year of treatment initiation. Lapatinib is an oral dual tyrosine kinase inhibitor of HER1 (EGF receptor [EGFR]) and HER2. Dual inhibition of EGFR and HER2 may theoretically provide greater inhibition of downstream signaling and increase anti-tumor activity [10,11] . Clinical data have shown that lapatinib is active in HER2-positive BC as monotherapy and in combination with chemotherapy in patients who

© 2008 Expert Reviews Ltd

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Tomasello, de Azambuja, Dinh, Snoj & Piccart-Gebhart

have failed trastuzumab-based regimens and in trastuzumab-naive patients [12–15] . In fact, the recently published EGF20009 trial, which evaluated the use of single-agent lapatinib in 138 patients with previously untreated HER2-positive locally advanced or mBC, showed promising results [12] . The overall response rate was 24% in the intent-to-treat population, and 31% of patients derived clinical benefit (complete or partial responses and stable disease for ≥ 24 weeks). Although comparisons across trials have to be interpreted with caution, these results obtained with lapatinib are comparable to those obtained for trastuzumab in a similar patient population [7,16] . These data, generated mostly in advanced BC, provide a strong rationale for moving lapatinib to the adjuvant setting. Trastuzumab in the adjuvant setting

In the adjuvant setting, several multicenter, randomized, controlled trials have shown an impressive reduction in the risk of BC recurrence and death when trastuzumab was added to other adjuvant therapies (chemotherapy or endocrine therapy) [17–20] . These striking results were seen across almost all trials despite their different

designs (Table 1) , updated analyses for most of these trials have been presented or published recently. Despite differences in patient population and trial design, including the chemotherapy regimen, timing of trastuzumab initiation and schedule and duration of trastuzumab administration, highly reproducible and impressive results have been produced across most trials. These studies demonstrated a 36–58% reduction in the recurrence rate and a 34–59% reduction in mortality. This degree of benefit in early BC is the largest reported since the introduction of tamoxifen in estrogen receptor (ER)-positive disease. Although these results are impressive, the median follow-up times ranged from 23.5 to 48 months, thus, a much longer follow-up will be needed to evaluate whether this trastuzumab effect persists over time. To date, the only negative adjuvant study was the Protocole Adjuvant dans le Cancer du Sein (PACS)-04 study [21] . Therefore, on the basis of available data and until further results are available from these trials, adjuvant therapy for HER2-positive early BC should consist of 1 year of trastuzumab therapy beginning concurrently with a taxane or subsequent to an adjuvant anthracycline-based therapy.

Table 1. Adjuvant trastuzumab trials: efficacy results. Trial

Patients Patient Treatment regimens (n) characteristics

Primary Median end point follow-up

DFS HR

OS HR

NSABP B-31

2043

Node positive

Intergroup N9831

2766

Node positive

HERA

5102

All except small Any accepted CT alone (observation) (