|Year : 2014 | Volume
| Issue : 4 | Page : 967-972
Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer
Miguel J Sotelo1, Jose Angel García-Sáenz1, Luis Manso2, Fernando Moreno1, Eva Ciruelos2, Hector R Callata1, Cesar Mendiola2, Santiago Cabezas1, Ismael Ghanem2, Eduardo Díaz-Rubio1
1 Department of Medical Oncology, Hospital Universitario Clínico San Carlos, Spain
2 Hospital Universitario 12 de Octubre, Madrid, Spain
|Date of Web Publication||9-Jan-2015|
Miguel J Sotelo
Department of Medical Oncology, Hospital Universitario Clínico San Carlos, C/ Profesor Martín Lagos s/n, 28040 Madrid
Source of Support: None, Conflict of Interest: None
Background: Dual human epidermal growth factor receptor 2 (HER2) blockade has been preclinically and clinically assessed in HER2-overexpressing metastatic breast cancer (mBC) with encouraging results.
Patients and Methods: This is a descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing mBC from two centers. The primary endpoints were to assess objective response rate (ORR) and toxicity. The secondary endpoints were to assess progression-free survival (PFS) and overall survival.
Results: A total of 23 HER2-positive mBC patients previously treated with trastuzumab received a trastuzumab plus lapatinib based therapy. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%), whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. ORR was 22% (5/23) and 39% (9/23) of patients had stable disease. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, whereas PFS in patients with HT was 2 months. Grade ≥ 3 adverse events were diarrhea (26%) and hand-and-foot syndrome (9%).
Conclusions: These findings suggest that dual HER2 blockade in combination with CT is feasible in pretreated HER2-positive mBC patients.
Keywords: Human epidermal growth factor receptor 2-positive, lapatinib, metastatic breast cancer, pretreated patients, trastuzumab
|How to cite this article:|
Sotelo MJ, García-Sáenz JA, Manso L, Moreno F, Ciruelos E, Callata HR, Mendiola C, Cabezas S, Ghanem I, Díaz-Rubio E. Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer. J Can Res Ther 2014;10:967-72
|How to cite this URL:|
Sotelo MJ, García-Sáenz JA, Manso L, Moreno F, Ciruelos E, Callata HR, Mendiola C, Cabezas S, Ghanem I, Díaz-Rubio E. Lapatinib plus trastuzumab in pretreated human epidermal growth factor receptor 2-positive metastatic breast cancer. J Can Res Ther [serial online] 2014 [cited 2019 Nov 15];10:967-72. Available from: http://www.cancerjournal.net/text.asp?2014/10/4/967/138017
| > Introduction|| |
Breast cancer (BC) is a major public health problem, not only due to its high incidence and prevalence, but also for its mortality.  Metastatic breast cancer (mBC) is incurable in most cases and has a median survival of 18-24 months.  Therefore, treatment is usually palliative during this stage of the disease and it is intended to improve the patient's quality of life and to prolong survival. The use of new hormonal therapies, new cytotoxic agents and the introduction of molecularly targeted drugs and the various therapeutic sequences administered throughout the disease has modified the natural history of mBC.
Overexpression of the human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor occurs in approximately 10-30% of invasive BCs. , HER2 overexpression is associated with reduced overall survival (OS) in mBC. ,
Trastuzumab is a humanized monoclonal antibody which targets the HER2 extracellular domain. A study by Slamon et al. showed that the addition of trastuzumab to chemotherapy (CT) in mBC patients significantly improved response rate and time to disease progression, with a significant reduction in the risk of death.  The addition of trastuzumab to adjuvant CT has resulted in a striking reduction in the risk of relapse and death. ,,
However, the majority of patients who achieve an initial response to trastuzumab-based regimens acquire resistance within 1 year. ,, Elucidating the antitumor mechanisms of trastuzumab and the pathways through which these tumors escape trastuzumab mediated cytotoxicity may improve the survival of these patients. Moreover, new drugs and combinations which allow physicians to overcome this resistance have been assessed. ,
Lapatinib is a small-molecule reversible dual inhibitor of the HER1 and HER2 tyrosine kinase, which directly inhibits the kinase activity of both receptors.  In a phase III trial of patients with progressive, HER2-overexpressing mBC who were previously treated with an anthracycline, a taxane and trastuzumab, lapatinib combined with capecitabine demonstrated a significant increase in the response rate and progression-free survival (PFS). 
Trastuzumab and lapatinib show complementary non-cross-resistant mechanisms of anti-HER2 activity.  Dual HER2 blockade has been preclinically and clinically assessed with encouraging results. ,,, The trastuzumab and lapatinib combination is effective in terms of survival in patients with heavily pretreated HER2-positive mBC. , The same regimen in combination with paclitaxel has also been tested in the neoadjuvant setting in the Neo-ALTTO trial, showing a significant increase in the pathological complete response (pCR) rate.  Similar results were reported in the CHER-LOB trial, where trastuzumab and lapatinib in combination with taxane-anthracycline CT was associated with a higher pCR rate than the lapatinib and trastuzumab arms.  In the same setting, the CALGB 40601 trial aimed to explore the safety and efficacy of dual HER2-targeting with trastuzumab and lapatinib plus paclitaxel, showing a higher pCR rate than that observed with trastuzumab plus paclitaxel, but did not reach statistical significance, probably because the pCR rate in the trastuzumab arm was higher than expected.  Finally, the TBCRC 006 trial assessed the trastuzumab and lapatinib combination in a CT-free regimen (plus hormone therapy in hormone receptor (HR)-positive patients), resulting in a high pCR rate and supporting the hypothesis that selected patients with HER2-positive tumors may not need CT. 
In this retrospective study, we aim to report our experience with lapatinib plus trastuzumab in pretreated HER2-positive mBC.
| > Patients and methods|| |
This is a multicenter retrospective study of patients who were treated with lapatinib-and trastuzumab-based therapy. Patients were recruited from the Oncology Departments of two centers from Madrid, Spain. The study was approved by the local ethic committee. Patients who were alive signed informed consent.
Eligible patients were women ≥18 years of age with histologically confirmed BC. Tumors were required to have HER2 gene amplification as measured by fluorescence in situ hybridization or HER2 overexpression as measured by immunohistochemistry (3+). Patients must have metastatic disease treated with at least one line of trastuzumab-based therapy. All patients must have received lapatinib-and trastuzumab-based therapy at some point of their metastatic disease.
Study end points
The primary endpoints were to assess objective response rate (ORR) and toxicity. The secondary endpoints were to assess PFS and OS.
Trastuzumab was administered intravenously at a dose of 2 mg/kg weekly (after the initial 4 mg/kg loading dose) or 6 mg/kg every 3 weeks (after the initial 8 mg/kg loading dose), according to the recommended scheme of treatment. Lapatinib was administered orally at a daily dose of 1000 or 1250 mg in combination with CT at the physician's discretion, and at a daily dose of 1250 mg daily in combination with hormonotherapy (HT) or with trastuzumab alone. In addition to the lapatinib and trastuzumab combination, the patients received CT or HT at physician`s discretion. Treatment continued until progressive disease (PD) or unacceptable toxicity.
Tumor assessments were conducted at baseline and every 3 months from treatment start to PD or death. Tumor responses were evaluated according to the response evaluation criteria in solid tumors criteria version 1.1. ORR was defined as complete response (CR) or partial response.
Adverse events (AEs) were categorized by the national cancer institute common terminology criteria for adverse events (NCI-CTCAE). The version of the NCI-CTCAE used depended on the year in which each patient was treated. Complete blood counts and serum chemistry were assessed on day 1 of every cycle. Echocardiograms were obtained at treatment start and every 3 months thereafter until PD.
Categorical data were summarized as frequency counts and percents and continuous variables were summarized by using descriptive statistics. ORR was calculated on the basis of the best response until PD based on the physician's judgment. Association between ORR and treatment regimen (dual blockade with CT or HT) was explored by using the Chi-square test. PFS and OS were summarized by using Kaplan-Meier curves. The Log-rank test was used to compare survival in different strata. Patients still responding at the time of this analysis were censored at the time of the last assessment of tumor response. All statistical tests were two-sided and had a 95% confidence interval (CI), with the level of significance established at P < 0.05. The statistical package for the social sciences statistical package, version 19.0, for Windows (SPSS, Chicago, IL, USA), was used for all statistical calculations.
| > Results|| |
From January 2007 to December 2012, clinical data were collected from the medical records of the 23 patients who met the inclusion criteria.
The median age was 53 years (range, 39-89 years). 73% of the patients had an eastern cooperative oncology group performance status ≤1. HRs were positive in 59% of the patients, negative in 36%, and unknown in 5%. 17 women (74%) had visceral metastases; 15 patients (68%) had oligometastatic disease (≤2 metastatic sites). The patients had received a median of 2 prior treatment lines (range, 1-7) for metastatic disease. The characteristics of the patients are summarized in [Table 1].
Thirteen patients (56%) received lapatinib plus trastuzumab in combination with CT; 54% of them received capecitabine, 15% received vinorelbine and 8% received docetaxel. Eight patients (35%) received lapatinib plus trastuzumab in combination with HT; 75% of them received fulvestrant and 25% received letrozole. Of all patients, 2 (9%) received the dual HER2 blockade treatment without any other agent. The lapatinib-and trastuzumab-based regimens are summarized in [Table 2].
The median of follow-up was 11.5 months (range, 0-40 months). The ORR was 22% (there were no CRs) and disease stabilization was observed in 39% of the patients [Table 3]. The median PFS was 4 months (95% CI: 1.7-6.3). At the time of analysis, there were only 7 deaths (70% of cases were censored), therefore the median OS could not be calculated.
In the subgroup analysis, ORR was 31% for patients treated with CT compared with 14% for patients treated with HT. There were no objective responses within patients only treated with lapatinib plus trastuzumab. Median PFS for patients treated with CT was 5 months (95% CI: 1.5-8.5), whereas median PFS for patients treated with HT was only 2 months (95% CI: 0.2-3.8) and 2 months for patients treated only with biological therapy, as shown in [Figure 1]. Median PFS in patients with HR positive and negative was 3 months (95% CI: 1.2-4.8) and 5 months (95% CI: 0.8-9.2) respectively. Moreover, median PFS in patients with <2 prior lines was 5 months (95% CI: 2.4-7.6), while median PFS in patients with ≥2 prior lines was 3 months (95% CI: 1.4-4.6), However, probably due to the small sample size, there were no statistically significant differences in any subanalysis.
|Figure 1: Progression-free survival (PFS). Kaplan-Meier estimates for PFS by subgroups of treatment|
Click here to view
The most common AEs (any grade) were diarrhea (48%), anemia (39%), asthenia (39%) and hand-and-foot syndrome (17%). Seven (30%) of 23 patients had at least one grade 3 or grade 4 AE, the most common of which were diarrhea (26%) and hand-and-foot syndrome (9%). Serious AEs (grade 3 or 4 diarrhea) led to permanent lapatinib discontinuation in 3 patients (13%). There were no reports of symptomatic congestive heart failure. The incidence of cardiotoxicity was 9% (only grade 2), that consisted in a non-symptomatic decrease in left ventricular ejection fraction of 20% or more. The adverse effects are summarized in [Table 4].
| > Discussion|| |
Our retrospective analysis suggests that patients with HER2-positive mBC who progress on a trastuzumab-based therapy might benefit from dual HER2 blockade, with an acceptable safety profile.
Trastuzumab combined with CT increases response rates, time to disease progression and survival in HER2 overexpressed mBC patients.  However, the majority of cancers that initially respond to trastuzumab acquire resistance within 1 year. ,, Elucidating the molecular mechanisms of trastuzumab resistance may improve the survival of these patients. This knowledge allows us to develop novel antiresistance strategies. One of these is dual HER2 blockade, by combining trastuzumab with a HER2 dimeritation inhibitor (pertuzumab) or a tyrosine kinase inhibitor (lapatinib, neratinib or afatinib). ,
In the overall analysis, the ORR was 22%, the disease stabilization rate was 39% and the median PFS was 4 months, which was clinically relevant because this patient population had received a median of 2 prior CT-based regimens (41% of patients received 3 or more prior lines).
In the subgroup analysis, ORR and PFS for patients treated with lapatinib plus trastuzumab in combination with CT were higher than those reported by Blackwell et al. with only dual HER2 blockade. ,
Previous data have shown that continuing trastuzumab after progression can be beneficial due to the ability of trastuzumab to continue to inhibit the still-sensitive aspects of the HER2 signaling network.  Therefore, adding lapatinib to trastuzumab, rather than replacing trastuzumab, might offer a more optimal disruption of the HER2 signaling network. This increased activity is demonstrated in neoadjuvant trials (NeoALTTO, CHER-LOB, CALGB 40601 and TBCRC 006), in which lapatinib plus trastuzumab based therapy is associated with high pCR rates. ,,, Data from these trials support to the idea that targeting HER2-positive tumors with multiple agents to more effectively block the network will produce better results.
On the other hand, adding lapatinib to letrozole significantly prolonged PFS in the first line treatment of mBC patients that co-expresses HR and HER2.  Furthermore, lapatinib in combination with capecitabine, significantly increased ORR and PFS, compared with capecitabine alone, in the second line treatment of patients with HER2-positive mBC.  However, trastuzumab plus lapatinib has shown to significantly improve PFS and OS results, compared with lapatinib alone in pretreated HER2-positive mBC patients. , These data together with those observed in neoadjuvant trials, ,,, allow us to hypothesize that trastuzumab plus lapatinib, in combination with CT could be a therapeutic strategy more effective than lapatinib-based regimens or dual HER2 blockade alone, in this setting.
While trastuzumab-lapatinib in combination with paclitaxel has shown encouraging results in the neoadjuvant setting, the efficacy of this combination in patients with metastatic disease has yet to be confirmed. In this sense, it is currently ongoing a phase III trial evaluating the activity of this combination versus trastuzumab-paclitaxel in patients with HER2-positive mBC (NCT00272987/ClinicalTrials.gov), which surely will give us important information about the efficacy and safety of this regimen.
In the EGF104900 trial, patients with HR positive did not derive an OS benefit from the trastuzumab and lapatinib combination, while patients with HR negative had a significant OS benefit when administered combination therapy. Moreover, patients receiving fewer lines of prior trastuzumab derived a larger OS benefit.  In our analysis, PFS in patients with <2 prior lines was higher than that observed in patients with ≥2 prior lines, and PFS in patients with HR negative was higher than that observed in patients with HR positive. These data suggest that this therapeutic strategy should be considered early in patients with HR negative and HER2-positive mBC, which could be a hypothesis to be evaluated in prospective trials.
In this study, the most common grade 3 or 4 AEs were diarrhea and hand-and-foot syndrome. The incidence of diarrhea was similar to that previously reported with lapatinib and CT. , Therefore, the addition of trastuzumab did not increase the rate of diarrhea secondary to lapatinib. Moreover, the combination of these two agents did not result in greater cardiotoxicity rates than those previously reported for each agent. , These findings are consistent with those observed in a recent meta-analysis, which investigated the risk of cardiac AEs with a combination of anti-HER2 therapies compared with anti-HER2 monotherapy, where there was no increased risk of cardiotoxicity with dual HER2 blockade. 
Our study has some limitations, such as the fact that it is a retrospective analysis, small sample size and the heterogeneous CT regimens. Therefore, definitive conclusions could not be drawn, but it supports an interesting hypothesis.
| > Conclusion|| |
Our findings suggest that lapatinib plus trastuzumab in combination with CT is feasible in pretreated HER2-positive mBC patients. However, further investigation is warranted to demonstrate its superiority over sequential blockade with trastuzumab and lapatinib in this setting.
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[Table 1], [Table 2], [Table 3], [Table 4]