Five trials assessed lapatinib and trastuzumab (L+T) combined with paclitaxel-containing chemotherapy regimens. They showed high pathological complete response rates, but at the cost of toxicity. This trial assesses L+T combined with docetaxel. The use of docetaxel rather than paclitaxel does not avoid much of the toxicity. Regarding efficacy our results are very consistent with NSABP-B41 trial.
Keywords: breast cancer, HER2, lapatinib, neoadjuvant chemotherapy, trastuzumab, pathological response
Abstract
Background
Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab.
Patients and methods
Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies.
Results
From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%).
Frequency (%) of the most common grade 3–4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8.
Conclusions
This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity.
ClinicalTrials.gov
introduction
Trastuzumab (Herceptin), a monoclonal humanised anti- human epidermal growth factor receptor 2 (HER2) antibody targets the HER2 protein with high affinity. When administered in combination with chemotherapy, it prolongs overall survival in patients with either metastatic disease [1], or early breast cancer when compared with chemotherapy alone [2, 3]. When administered together with chemotherapy in the neoadjuvant setting, trastuzumab significantly increases both pathological complete response (pCR) rate [4, 5] and event-free survival [5]. However, despite the efficacy of trastuzumab, almost all patients with metastatic disease and some with early breast cancer will experience disease relapse. Additional anti-HER2 therapies that target HER2 through different mechanisms of action have been developed to address this clinical challenge. Lapatinib is an oral dual tyrosine kinase inhibitor with demonstrated clinical activity in women with HER2-positive metastatic breast cancer that developed resistance during trastuzumab treatment when used as monotherapy [6, 7], combined with trastuzumab [8] or with capecitabine in heavily pre-treated patients [9].
In the neoadjuvant setting, ∼20–30% of patients will relapse within 3 years despite receiving trastuzumab [5, 10]. Thus, the question as to whether dual anti-HER2 blockade would be a more effective therapy has been the subject of a number of randomised clinical trials. One such study combined trastuzumab with pertuzumab [11], and five trials evaluated dual anti-HER2 blockade with lapatinib and trastuzumab in combination with chemotherapy [12–16]. All these studies used pCR as a surrogate for treatment efficacy, and demonstrated an increased percentage of patients achieving pCR for the use of double anti-HER2 therapy compared with single-agent HER2 therapy, in combination with chemotherapy. This increase was statistically significant in two trials [11, 12] and numerically superior in the other four [13–16]. However, in lapatinib studies, dual HER2 blockade was associated with a higher toxicity than trastuzumab combined with chemotherapy. For example in the NeoALTTO trial, treatment was stopped or not delivered as planned in up to 39.5% of patients [12]. Of note, all the backbone chemotherapy regimens in the studies testing lapatinib used paclitaxel.
Having completed a phase I study which confirmed that docetaxel could be combined with lapatinib 1000 mg/m2 [17], when given without preceding anthracyclines (in contrast to GeparQuinto, in which anthracyclines plus lapatinib were given upfront [18]), we embarked on this randomised phase II study to explore the efficacy of docetaxel and lapatinib in the neoadjuvant setting, hypothesising that the toxicity observed in neoadjuvant trials with dual anti-HER2 blockade with lapatinib and trastuzumab might be due to a specific pharmacokinetic interaction between paclitaxel and lapatinib (with or without trastuzumab) [19]. The aim was to assess the toxicity and activity of the combination of docetaxel with either lapatinib or trastuzumab or with the dual HER2 blockade, followed by anthracycline-based chemotherapy, given as neoadjuvant treatment to patients with HER2-positive breast cancer, using pCR as a surrogate for treatment efficacy.
patients and methods
study design, eligibility, and treatment
This was a non-comparative randomised multicentre phase IIb study in which patients with locally advanced, inflammatory or large operable HER2-positive primary breast cancer were randomly assigned to receive chemotherapy plus lapatinib, chemotherapy plus trastuzumab, or chemotherapy plus combined trastuzumab and lapatinib. In June 2012, accrual in the lapatinib arm was closed for futility after the publication of several reports suggesting that lapatinib monotherapy plus chemotherapy was either less effective or not inferior to but more toxic than chemotherapy plus trastuzumab (for more details see the supplementary Appendix, available at Annals of Oncology online).
Main eligibility criteria and patients' randomisation assignments are described in the supplementary Appendix, available at Annals of Oncology online. Before registration, all patients provided written informed consent for the clinical trial and for research on tumour and blood samples.
All patients were scheduled to receive six cycles of i.v. chemotherapy every 3 weeks: three cycles of docetaxel 100 mg/m2, day 1 followed by three cycles of fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 (FEC) day 1. Patients were randomised (1 : 1 : 1) to receive during the first three cycles either concomitant lapatinib [1000 mg orally (p.o.) daily], concomitant trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or concomitant trastuzumab plus lapatinib at the same dose. The use of growth factors was strongly recommended during the concomitant administration of lapatinib and docetaxel or lapatinib and trastuzumab and docetaxel.
Patients whose disease progressed during neoadjuvant treatment went off study and treatment was left to the discretion of the investigator.
Toxic effects were graded according to the National Cancer Institute Common Terminology Criteria (NCI-CTC) version 3.0. In case of haematological or non-haematological grade 3 or 4 toxicity related to study agents, therapy was interrupted and dose reductions were implemented as described in the full protocol.
Left ventricular ejection fraction (LVEF) was evaluated before study entry and repeated at the end of cycle 4 and at the completion of treatment. The decision to administer or to delay lapatinib or trastuzumab according to interval LVEF assessments was based on the algorithm provided in the full protocol.
The choice between breast conserving surgery or a mastectomy was left to the investigator according to each centre's policy. Patients received post-surgery trastuzumab every 3 weeks, at a dose of 6 mg/kg, for 1 year in the three arms. Post-operative endocrine and radiation therapy were to be given according to local guidelines.
objectives
The primary end point was pCR in the breast defined as complete disappearance of invasive cancer in the primary tumour with the exception of very few scattered invasive tumour cells (the presence of ductal carcinoma in situ was allowed).
The secondary end points were safety and tolerability of the combination according to CTCAE 3.0, response rate according to RECIST version 1.0 [20] in patients with measurable disease, and rate of breast conserving surgery.
Exploratory analyses include pCR rates in the breast and nodes, pCR rates in the breast and in the breast and nodes by steroid hormone receptors status (positive or negative).
Patients enrolled in the original lapatinib monotherapy arm that was discontinued will be analysed as a separate group in the final analysis.
pathology assessment
Tumours were defined as hormone receptor positive or negative by local pathologists. No central review of HER2 status was carried out. We did not register the list of the actual cut-offs used for estrogen receptor, progesterone receptor, and HER2.
Pathological response was assessed by local pathologists after completion of the neoadjuvant chemotherapy. In addition, a central clinical two-reader (CM and HB) review of histopathology reports from post-treatment surgical specimens was carried out as previously described [21]. The latter is reported in the manuscript.
statistical analysis
This phase II study had a one-stage Fleming design for each of the lapatinib-containing experimental arms, with the trastuzumab and chemotherapy arm acting as a reference. The type I error was 10%. For a null hypothesis of a 40% pCR rate and an alternative hypothesis of a 60% pCR rate, 50 eligible patients needed to be treated in each arm to have a 92.5% power. An experimental arm was deemed interesting for further research if at least 25 pCR of 50 treated eligible patients were observed. This decision rule corresponded to rejecting the null hypothesis.
When the lapatinib monotherapy arm was closed prematurely, the statistical plan was not altered for the two remaining arms, as a formal comparison of the two arms was not foreseen. Inference on the pCR rate is reported as a 2-sided 80% Pearson–Clopper interval. The reported P value corresponds to the one-sided test (significance level = 10%) for H0: pCR rate = 40% versus HA: pCR rate ≥40% based on the binomial distribution (exact).
The analysis populations are detailed in the supplementary Appendix, available at Annals of Oncology online.
protocol review
This study was conducted in accordance with the Declaration of Helsinki and the European Guidelines on Good Clinical Practice. The protocol underwent independent peer review and approval by the EORTC Protocol Review Committee. The trial was approved by national and local ethics committees in all participating centres. The full protocol can be assessed at http://www.cancer.gov/clinicaltrials/EORTC-10054.
results
patient and tumour characteristics
From October 2010 to January 2013, 128 patients were enrolled at 14 centres. Of these patients, 23 were randomly assigned to the lapatinib group before closure, 53 to the trastuzumab group, and 52 to the combination (lapatinib plus trastuzumab) group. Patients and tumour characteristics are summarised in Table 1. The majority of patients had large operable breast cancers (74%, 79%, and 77% in lapatinib, trastuzumab, and combination arms, respectively) and clinical involvement of lymph nodes (70%, 68%, and 62%, respectively). Six patients were excluded from the efficacy population: five because of a major violation of an eligibility criterion (metastatic disease in one, over 70 years old in one, HER2-negative tumour after reassessment at the treating centre in three), two of which did not start the allocated treatment (supplementary Figure S1, available at Annals of Oncology online). Additionally, one patient refused to start the allocated treatment.
Table 1.
Patient and tumour characteristics
| Lapatinib group | Trastuzumab group | Combination group | |
|---|---|---|---|
| N (%) | N (%) | N (%) | |
| Number of patients | 23 | 53 | 52 |
| Age (years) | |||
| Median (range) | 49.9 (27.3–68.5) | 47 (25.3–68.9) | 49.4 (27.3–70.8) |
| ≤40 | 6 (26.1) | 13 (24.5) | 10 (19.2) |
| 41–50 | 7 (30.4) | 20 (37.7) | 17 (32.7) |
| 51–60 | 5 (21.7) | 12 (22.6) | 13 (25.0) |
| 61–70 | 5 (21.7) | 8 (15.1) | 11 (21.2) |
| 71–80 | 0 (0.0) | 0 (0.0) | 1 (1.9) |
| Tumour category | |||
| Locally advanced or inflammatory | 6 (26.1) | 11 (20.8) | 11 (21.2) |
| Large operable | 17 (73.9) | 42 (79.2) | 41 (78.8) |
| Clinical tumour status | |||
| T0 | 0 (0.0) | 0 (0.0) | 1 (1.9)a |
| T1 | 1 (4.3) | 0 (0.0) | 0 (0.0) |
| T2 | 11 (47.8) | 24 (45.3) | 28 (53.8) |
| T3 | 8 (34.8) | 19 (35.8) | 13 (25.0) |
| T4 | 3 (13.0) | 10 (18.9) | 9 (17.3) |
| Missing | 0 (0.0) | 0 (0.0) | 1 (1.9)b |
| Clinical nodal status | |||
| N0 | 7 (30.4) | 17 (32.1) | 19 (36.5) |
| N1 | 13 (56.5) | 32 (60.4) | 29 (55.8) |
| N2 | 2 (8.7) | 3 (5.7) | 3 (5.8) |
| N3 | 1 (4.3) | 1 (1.9) | 1 (1.9) |
| M stage | |||
| M0 | 23 (100.0) | 52 (98.1) | 52 (100.0) |
| M1 | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Mx | 0 (0.0) | 1 (1.9) | 0 (0.0) |
| Bilateral breast cancer | |||
| No | 23 (100.0) | 52 (98.1) | 52 (100.0) |
| Yes | 0 (0.0) | 1 (1.9) | 0 (0.0) |
| Hormone receptor status | |||
| Negative | 8 (34.8) | 26 (49.1) | 26 (50) |
| Positive | 15 (65.2) | 27 (50.9) | 25 (48.1) |
| Missing | 0 (0.0) | 0 (0.0) | 1 (1.9) |
The nodal status for the one patient with tumour status T0 was N2.
Data are missing for one ineligible patient in the combination group.
D, docetaxel; L, lapatinib; T, trastuzumab; FEC, fluorouracil, epirubicin, cyclophosphamide.
toxicity and compliance with treatment
Patients randomised to the two lapatinib-containing groups presented more grade 3 and 4 adverse events than those in the trastuzumab group (Table 2). Patients in the combination group had more grade 3 diarrhoea (18%) and hepatic (8%) toxicities. No patient developed symptoms of congestive heart failure. Data regarding cardiac investigations are summarised in supplementary Table S1, available at Annals of Oncology online.
Table 2.
Grade 3 and 4 adverse events during treatmenta
| Lapatinib group N = 22, N (%) |
Trastuzumab group N = 53, N (%) |
Combination group N = 50, N (%) |
||||
|---|---|---|---|---|---|---|
| Grade 3 | Grade 4 | Grade 3 | Grade 4 | Grade 3 | Grade 4 | |
| Adverse event in >1% of patients | ||||||
| Neutropenia | 3 (13.6) | 7 (31.8) | 7 (13.2) | 15 (28.3) | 4 (8.0) | 19 (38.0) |
| Febrile neutropenia | 3 (13.6) | 2 (9.1) | 8 (15.1) | 0 | 4 (8.0) | 1 (2.0) |
| Diarrhoea | 2 (9.1) | 0 | 1 (1.9) | 0 | 9 (18.0) | 0 |
| Infection other | 2 (9.1) | 0 | 2 (3.8) | 0 | 4 (8.0) | 0 |
| Hepaticb | 0 | 0 | 0 (0.0) | 1 (1.9) | 4 (8.0) | 0 |
| Skin disorderc | 0 | 0 | 2 (3.8) | 0 | 3 (4.0) | 0 |
| Other | 0 | 0 | 2 (3.8) | 0 | 3 (6.0) | 0 |
| Fatigue | 2 (9.1) | 0 | 2 (3.8) | 0 | 0 (0.0) | 0 |
| Nausea | 2 (9.1) | 0 | 2 (3.8) | 0 | 0 | 0 |
| Paind | 0 | 0 | 1 (1.9) | 0 | 2 (4.0) | 0 |
| Allergic reaction/hypersensitivity | 0 | 0 | 1 (1.9) | 0 | 1 (2.0) | 0 |
| Anaemia | 0 | 0 | 1 (1.9) | 0 | 1 (2.0) | 0 |
| Adverse event in ≤1% of patients | ||||||
| Hypocalcaemia | 0 | 0 | 0 (0.0) | 1 (1.9) | 0 | 0 |
| Anorexia | 0 | 0 | 1 (1.9) | 0 | 0 | 0 |
| Constipation | 0 | 0 | 0 | 0 | 1 (2.0) | 0 |
| Dehydration | 1 (4.5) | 0 | 0 | 0 | 0 | 0 |
| Mucositis/stomatitis | 0 | 0 | 0 | 0 | 1 (2.0) | 0 |
| Vomiting | 0 | 0 | 0 | 0 | 1 (2.0) | 0 |
| Gastrointestinal other | 0 | 0 | 0 | 0 | 1 (2.0) | 0 |
| Neurology other | 0 | 0 | 1 (1.9) | 0 | 0 | 0 |
| Dyspnoea | 1 (4.5) | 0 | 0 | 0 | 0 | 0 |
Takes into account all assessments post-baseline until 5 weeks after the stop of allocated protocol treatment.
Hepatic: worst grade of elevated SGPT, elevated SGOT and hyperbilirubinemia.
Dermatology/skin: worst grade of alopecia, bruising, dry skin, nail changes, rash hand–foot skin reaction, urticarial, rash/desquamation, other dermatology/skin.
Pain: worst grade of abdomen NOS, joint, muscle, head/headache, chest/thorax NOS, other pain.
The neoadjuvant therapy was completed as planned per protocol in 95.5% of patients in the lapatinib group, 90.6% in the trastuzumab group and 74% in the combination group (supplementary Table S2, available at Annals of Oncology online). The main reason for interrupting treatment was toxicity in all three groups.
pathological response
The percentage of the 122 assessable patients with a pCR in the breast, and a pCR in the breast and nodes was numerically highest in the combination group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%, respectively), and lowest in the lapatinib monotherapy group (46% and 36%, respectively) (Figure 1 and supplementary Table S3, available at Annals of Oncology online). The rate of pCR was slightly higher in patients with ER-negative tumours (55% versus 53% and 53% versus 48% by both definitions).
Figure 1.
Pathological complete response (pCR) in the overall efficacy population and in the hormone receptor-positive and -negative tumour groups. (A) Breast pCR definition. (B) Breast and nodes pCR definition.
response and surgery
For the 99 patients assessable for response in the trastuzumab and combination groups, objective response rates were 94% (46/49) (57% complete responses, 37% partial responses) and 88% (36/41) (58% complete responses, 29% partial responses), respectively (supplementary Table S4, available at Annals of Oncology online).
Details on surgery of primary tumour and of the axilla are summarised in supplementary Table S5, available at Annals of Oncology online, available online.
discussion
This study was originally designed to test the hypothesis that docetaxel could be effectively and safely combined with lapatinib, with or without trastuzumab, as part of a standard approach to the neoadjuvant chemotherapy of HER2-positive breast cancer. That aim was met: the data suggest that the dual anti-HER2 combination is likely to be more effective, although the additional anti-cancer effect comes with an increase in toxicity. The lapatinib-only arm was closed in 2012 for futility based on a growing volume of data emerging in the metastatic setting [22], neoadjuvant [12–16, 18], and adjuvant settings, all of which indicated that lapatinib was likely to be clinically inferior to the standard trastuzumab arm: so these data will not be discussed further. Our study demonstrates a numerically greater rate of complete pathological responses in favour of double anti-HER2 blockade with an absolute 8.5% difference using the ypT0/is pCR definition chosen initially as our primary objective and a 4.4% difference, respectively, using the ypT0/isypN0 pCR definition chosen as an exploratory analysis after publication of the meta-analysis of the Food and Drug Administration in 2014 [23]. While from a strictly statistical view point, these data allow a rejection of the null hypothesis with the combination arm, from a clinical perspective this modest increase in pCR comes with additional toxicity such that it may not be particularly clinically useful.
It is helpful to perhaps put these results in perspective with other datasets relating to this question. We are aware of five other neoadjuvant trials testing the dual HER2 blockade concept with lapatinib and trastuzumab in the neoadjuvant setting [12–16], and using pCR as the efficacy measure (supplementary Table S6, available at Annals of Oncology online). They have many differences: overall design (phase II or phase III), duration of anti-HER2 therapies, backbone therapies, and certainly a molecular heterogeneity between sub-groups (even within the HER2-positive group). These trials could be divided into those with a ‘pragmatic’ design, giving a standard neoadjuvant treatment with the addition (or not) of lapatinib to conventional anthracycline/taxanes-based neoadjuvant chemotherapy, and those with a ‘translational research’ design, usually giving only the taxanes component of the chemotherapy before surgery, such as NeoALTTO and CALGB 40601 trials [12, 15]. Our study belongs to the first category and results are very consistent with the NSABP-B41 trial, which included over 500 patients [16]. Using the definition of pCR in both breast and axillary lymph nodes, the average percentage of patients who achieved a pCR in the trastuzumab group and in the combination groups for the four studies in this category (including the EORTC 10054 trial) are 43%, 47%, and 59% for the lapatinib, trastuzumab, and combination arms, respectively. The difference in the design of the NeoALTTO and the CALGB trials (translational research design) on one hand [12, 15], and the CHER-LOB, LPT109096, NSABP, and EORTC trials (pragmatic design) on the other [13, 14, 16], may explain these higher pCR rates. In the latter, patients were all exposed to, not only the taxanes and anti-HER2 therapy, but also to anthracyclines, which are known to be active in HER2-positive tumours.
The data on neoadjuvant pCR rates can be compared with the results of the large adjuvant study ALTTO, whose two co-primary disease-free survival end points were presented at the 2014 ASCO meeting [24]. Sequential trastuzumab followed by lapatinib had a similar hazard ratio (HR) compared with trastuzumab [0.93; 97.5% confidence interval (CI) 0.76–1.13; non-inferiority P = 0.044]. Combined anti-HER2 had a numerically better HR compared with trastuzumab (0.84; 97.5% CI 0.70–1.02; P = 0.048), but since there were two experimental arms, did not reach the level of significance (2.5%) required to be considered statistically significantly different from the trastuzumab monotherapy arm. Thus, the data available on ALTTO are consistent with the pCR rates above: while monotherapy lapatinib appears to be not non-inferior, the combination arm is superior but by a lesser degree than anticipated.
In NeoALTTO and NSABP-B41 trials, ∼40% of patients in the combination group (double HER2 blockade) discontinued neoadjuvant protocol therapy [12, 16] mainly due to toxicity (21.7% and 28%, respectively). Unfortunately, our results suggest that the use of docetaxel rather than paclitaxel may not reduce toxicity: in the combination group, 26% did not complete the protocol therapy as planned and 18% of patients presented at least one episode of grade 3 diarrhoea.
In conclusion, this phase II study demonstrates that the use of docetaxel rather than paclitaxel combined with the dual anti-HER2 combination of lapatinib and trastuzumab does not avoid much of the excess toxicity. Despite this toxicity, the pCR rate was higher in those patients given the anti-HER2 combination therapy consistent with other studies.
funding
This work was supported by the US National Cancer Institute (grants 2U10 CA11488-31 through 5U10 CA011488-40, Bethesda, MD, USA); Fonds Cancer (FOCA) from Belgium; Cancer Research UK and the French Ligue Nationale Contre le Cancer (donations through the EORTC Charitable Trust); GlaxoSmithKline contributed to this study with an Educational Grant to EORTC Headquarters and by providing lapatinib (Tyverb®). The sponsor of the trial (EORTC) designed and coordinated the trial. The funding sources of the study had no role in the design of the study; collection, analysis, or interpretation of the data; or in the writing of this report.
disclosure
DC is conducting research funded by GSK as well as Roche and has received honoraria from GSK and Roche. Other authors have declared no conflicts of interest. Disclaimer: this publication content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute or the European Commission.
Supplementary Material
acknowledgements
We thank the patients, doctors, data managers, and nurses involved in the EORTC 10054 study for their generous participation. We also thank the data managers from the EORTC (Nicolas Dif, Edith Bastiaens); the Fondation pour la lutte contre le cancer et pour des recherches medico-biologiques and SIRIC BRIO (Site de Recherche Intégrée sur le Cancer–Bordeaux Recherche Intégrée Oncologie) [Grant INCa-DGOS-Inserm 6046] for financial support; Jone Iriondo, Institut Bergonié, for assistance in preparation and submission of the manuscript.
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