Dataset Information

Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer.

ABSTRACT:

Background

Preclinical data indicate that dual HER2 inhibition overcomes trastuzumab resistance and that use of an HER2 inhibitor with an anti-angiogenic agent may augment responses.

Patients and methods

We conducted a dose-escalation, phase I study of a combination of trastuzumab, lapatinib and bevacizumab. The subset of patients with metastatic breast cancer was analyzed for safety and response.

Results

Twenty-six patients with metastatic breast cancer (median = 7 prior systemic therapies) (all with prior trastuzumab; 23 with prior lapatinib; one with prior bevacizumab) received treatment on a range of dose levels. The most common treatment-related grade 2 or higher toxicities were diarrhea (n = 11, 42%) and skin rash (n = 2, 8%). The recommended phase 2 dose was determined to be the full Food and Drug Administration (FDA) approved doses for all the three agents (trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance dose, intravenously every 3 weeks; lapatinib 1250 mg daily, bevacizumab 15 mg/kg intravenously every 3 weeks). The overall rate of stable disease (SD) ≥6 months and partial or complete remission (PR/CR) was 50% (five patients with SD ≥6 months; seven PRs (including one unconfirmed); one CR). The rate of SD ≥6 months/PR/CR was not compromised in patients who had previously received study drugs, those with brain metastases, and patients treated at lower dose levels.

Conclusions

The combination of trastuzumab, lapatinib and bevacizumab was well-tolerated at maximally approved doses of each drug, and its activity in heavily pretreated patients with metastatic breast cancer suggests that it warrants further investigation.

Clintrialsgov id

NCT00543504.

SUBMITTER: Falchook GS

PROVIDER: S-EPMC3841018 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer.

Falchook G S GS Moulder S L SL Wheler J J JJ Jiang Y Y Bastida C C CC Kurzrock R R

Annals of oncology : official journal of the European Society for Medical Oncology 20131024 12

<h4>Background</h4>Preclinical data indicate that dual HER2 inhibition overcomes trastuzumab resistance and that use of an HER2 inhibitor with an anti-angiogenic agent may augment responses.<h4>Patients and methods</h4>We conducted a dose-escalation, phase I study of a combination of trastuzumab, lapatinib and bevacizumab. The subset of patients with metastatic breast cancer was analyzed for safety and response.<h4>Results</h4>Twenty-six patients with metastatic breast cancer (median = 7 prior s ...[more]

PMID: 24158411

Similar Datasets

Project description:BackgroundTrastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy.MethodsFifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy.ResultsThe median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53%-72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (± 6 weeks) of trastuzumab-based therapy.ConclusionThe incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab-based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen.Implications for practiceDual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network.

Dataset Information

Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer.

Background

Patients and methods

Results

Conclusions

Clintrialsgov id

Publications

Dual HER2 inhibition in combination with anti-VEGF treatment is active in heavily pretreated HER2-positive breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets