Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer

Abstract

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 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.

Patients and methods: Patients had HER-2-positive breast cancer, progressive brain metastases, prior trastuzumab treatment, and at least one measurable metastatic brain lesion. Patients received lapatinib 750 mg orally twice a day. Tumor response was assessed by magnetic resonance imaging every 8 weeks. The primary end point was objective response (complete response [CR] plus partial response [PR]) in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included objective response in non-CNS sites, time to progression, overall survival, and toxicity.

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%).

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.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although 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 Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Nancy U. Lin, GlaxoSmithKline (C); Lisa A. Carey, Genentech (U), GlaxoSmithKline (U), Pfizer (U), Bristol Meyers Squib (U); John W. Henson, GlaxoSmithKline (C); Elizabeth Kasparian, GlaxoSmithKline (C); Eric P. Winer, Genentech (C), GlaxoSmithKline (C) Stock Ownership: None Honoraria: Minetta C. Liu, GlaxoSmithKline; Elizabeth Kasparian, GlaxoSmithKline Research Funding: Nancy U. Lin, GlaxoSmithKline; Lisa A. Carey, Genentech, GlaxoSmithKline, Bristol Meyers Squib; Minetta C. Liu, GlaxoSmithKline; Eric P. Winer, Genentech, GlaxoSmithKline Expert Testimony: None Other Remuneration: None

Figures

Fig 1

Partial regression of CNS metastases after 16 weeks of lapatinib treatment. Representative image of patient with biopsy-proven CNS metastasis (A) before initiation of lapatinib and (B) after 16 weeks of lapatinib treatment demonstrating durable partial regression.

Fig 2

(A) Proportion of patients without progression. Progression in either CNS or non-CNS sites is counted as progressive disease. Dashed lines indicate the upper and lower bounds of the 95% CI. (B) Overall survival for all 39 patients, from time of study entry. Dashed lines indicate the upper and lower bounds of the 95% CI.

Fig 3

Best volumetric change in sum of CNS target lesions with lapatinib. Each bar represents an individual patient with at least a baseline and week 8 magnetic resonance imaging scan (n = 34). Pale yellow bars indicate patients with 10% to 30% volumetric reduction. Yellow bars indicate patients with at least 30% volumetric reduction. The arrow denotes the patient who achieved a partial response in the CNS by Response Evaluation Criteria in Solid Tumors. (*) Concomitant increase in corticosteroid dose at the time of the restaging scan.