Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma

Clinical Cancer Research

Dièras

Paul

et al. 2009

599

373

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer.Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy.The primary end point was CNS objective response, defined as z50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6 % of patients. In an exploratory analysis, 21% of patients experienced a z20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a z20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.Brain metastases are diagnosed in approximately one third of women treated with trastuzumab for advanced HER2+ breast cancer (1 -5). The high incidence of HER2+ central nervous system (CNS) disease likely results from the inability of trastuzumab to cross the blood-brain barrier, in combination with a predilection of breast cancers that overexpress HER2 to metastasize to visceral sites, including the brain (6 -9). Despite initial therapy with whole-brain radiotherapy or stereotactic

Section: Discussionmentioning

confidence: 99%

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Clinical Cancer Research

Dièras

Paul

et al. 2009

599

373

“…The low response rate in the brain with temozolomide in patients with metastatic breast cancer illustrates an important point: an agent must have activity against breast cancer if it is going to be effective in treating brain metastases from breast cancer. In contrast, clinical activity in the brain has been reported with capecitabine, an agent that is effective against breast cancer, both in case report format, and recently, in the context of a phase I trial of combined capecitabine and temozolomide (75,79). Despite the promise of targeted therapies, it is likely that cytotoxic agents will retain an important role.…”

Section: New Directionsmentioning

confidence: 99%

Brain Metastases: The HER2 Paradigm

Clinical Cancer Research

Winer²

2007

371

278

Between 100,000 and 170,000 patients with cancer develop central nervous system (CNS) metastases each year in the U.S., of which f20% carry a primary diagnosis of breast cancer. As a consequence of improvements in systemic therapy, which have allowed patients to live longer with advanced cancer, CNS metastases are emerging as an important sanctuary site, and the incidence may be increasing in patients with particular tumor subtypes. Unless there are improvements in the treatment of CNS disease, a growing proportion of patients may be at risk of experiencing both morbidity and mortality as a result of uncontrolled CNS progression, often at a time when their extra-CNS disease is apparently under control. This article reviews changes in the epidemiology and natural history of women with brain metastases from HER2-positive breast cancer over the last decade and presents the therapeutic challenges and opportunities that have arisen in this setting. First, the apparent increase in CNS disease among women with HER2-positive breast cancer, relative to historical controls, is discussed, followed by consideration of potential causes of this observation. Next, the implications of CNS disease, in terms of prognosis and the potential development of preventive strategies are considered. Finally, new developments in systemic approaches to the treatment of CNS disease, including cytotoxic chemotherapy and targeted therapy, are explored.

“…Retrospective case series and case reports have been published, but few chemotherapeutic agents have been prospectively evaluated in the breast cancer population. 4,[8][9][10][11] Lapatinib is a small-molecule inhibitor of epidermal growth factor receptor (EGFR) and HER-2. 12 In heavily pretreated patients, lapatinib achieved an investigator-reported objective response rate of 5% to 8% for systemic metastatic disease.…”

Section: Introductionmentioning

confidence: 99%

Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

Carey

Liu

et al. 2008

JCO

428

251

Purpose-One third of women with advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancer develop brain metastases; a subset progress in the CNS despite standard approaches. Medical therapies for refractory brain metastases are neither well-studied nor Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript established. We evaluated the safety and efficacy of lapatinib, an oral inhibitor of epidermal growth factor receptor (EGFR) and HER-2, in patients with HER-2-positive brain metastases. Results-Thirty-nine patients were enrolled. All patients had developed brain metastases while receiving trastuzumab; 37 had progressed after prior radiation. One patient achieved a PR in the brain by RECIST (objective response rate 2.6%, 95% conditional CI, 0.21% to 26%). Seven patients (18%) were progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional patients with some degree of volumetric reduction in brain tumor burden. The most common adverse events (AEs) were diarrhea (grade 3, 21%) and fatigue (grade 3, 15%). Patients and Methods-Patients Conclusion-The study did not meet the predefined criteria for antitumor activity in highly refractory patients with HER-2-positive brain metastases. Because of the volumetric changes observed in our exploratory analysis, further studies are underway utilizing volumetric changes as a primary end point.