Abstract
Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9–47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-012-2126-1) contains supplementary material, which is available to authorized users.
Highlights
Breast cancer is the leading single cause of cancer-related mortality in women worldwide, accounting for more than 450,000 deaths in 2008 (14 % of cancer deaths) [1]
About 15 % of breast cancers are triple-negative breast cancers (TNBC) and, despite being sensitive to systemic chemotherapies, these tumors are, overall, associated with poor outcome compared with other subtypes of breast cancer, with a recurrence rate of 30–40 % presenting as distant metastases [7]
Patients were to be excluded for active infectious disease; gastrointestinal disorders that may interfere with the absorption of the study drug or chronic diarrhea; active/ symptomatic brain metastases; cardiac left ventricular function with resting ejection fraction \50 %; absolute neutrophil count \1,500 cells/mm3; platelet count \100,000 cells/mm3; bilirubin [1.5 mg/dL ([26 lmol/L, SI equivalent) and serum creatinine [1.5 mg/dL ([132 lmol/L, SI unit equivalent); and previous treatment with trastuzumab or EGFR/HER2 inhibitors
Summary
Breast cancer is the leading single cause of cancer-related mortality in women worldwide, accounting for more than 450,000 deaths in 2008 (14 % of cancer deaths) [1]. Breast cancer is not a single disease, but a collection of subtypes based on genotyping and biological properties [2]. The triple-negative breast cancers (TNBC)—so called because they are negative for estrogen receptor (ER), progesterone receptor (PgR), and HER2 [6]—include a large proportion of basal-like tumors. About 15 % of breast cancers are TNBC and, despite being sensitive to systemic chemotherapies, these tumors are, overall, associated with poor outcome compared with other subtypes of breast cancer, with a recurrence rate of 30–40 % presenting as distant metastases [7]. Apart from chemotherapy, TNBC patients have few treatment options as these tumors do not overexpress antigens that would allow for targeted treatment, such as endocrine and anti-HER2 therapy. Overexpression of epidermal growth factor receptor (EGFR/ErbB1) has been
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