A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 07/2012; 134(3):1149-59. DOI: 10.1007/s10549-012-2126-1
Source: PubMed


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 (≥B) for ≥4 treatment courses in triple-negative (≥ohort 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 receptorpositive breast cancer (≥ohort 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 C4 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. © The Author(s) 2012. This article is published with open access at

Download full-text


Available from: Jacques De Greve
  • Source
    • "EGFR is expressed in the epithelium; it helps maintain mucosal integrity and promote mucosal repair in the gut and maintains the protective barrier of the skin.56,57 Therefore, the most common treatment-related adverse events of EGFR-TKIs in general, and afatinib in particular, are gastrointestinal (GI) and cutaneous side effects, specifically diarrhea and rash.22,55 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.
    Preview · Article · Mar 2013 · OncoTargets and Therapy
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dual anti-HER2 blockade with trastuzumab/pertuzumab or trastuzumab/lapatinib in combination with anthracycline/taxane-based chemotherapy can reach pCR rates of up to 60% in HER2-positive breast cancer. The DAFNE phase II study (NCT015591477) investigated a dual blockade with the irreversible pan-HER inhibitor afatinib and trastuzumab in this setting. Participants with untreated, centrally HER2-positive breast cancer were treated for 6 weeks with afatinib (20mg/day) and trastuzumab ((8)6mg/kg/3weeks) alone; followed by 12 weeks treatment with paclitaxel (80mg/m²/1week), trastuzumab and afatinib; followed by 12 weeks with epirubicin (90mg/m²/3weeks), cyclophosphamide (600mg/m²/3weeks), and trastuzumab before surgery. Primary objective was pCR rate defined as ypT0/is ypN0. We expected a pCR rate of 70%; 65 patients were needed to exclude a rate of ≤55%. pCR rate was 49.2% (90% CI: 38.5; 60.1) in 65 treated patients. Patients with hormone-receptor-negative (N=19) or -positive (N=46) tumors showed pCR rates of 63.2% and 43.5%, respectively (P=0.153). Patients with (N=9) or without (N=56) lymphocyte predominant breast cancer (LPBC) showed pCR rates of 100% and 41.1%, respectively (P<0.001). PCR rate was not different in patients with or without PIK3CA tumor mutations (P=0.363). Clinical responses were seen in 96.3% of 54 evaluable patients; and breast conserving surgery was possible in 59.4% of 62 assessable patients. Most frequent non-hematological grade 3-4 toxicities were diarrhea (7.7%), increased creatinine (4.6%), and infection (4.6%). One patient developed symptomatic congestive heart failure. Neoadjuvant treatment with afatinib, trastuzumab and chemotherapy showed acceptable tolerability and a pCR rate comparable to that of other anti-HER2 doublets but below challenging expectations. Copyright © 2015, American Association for Cancer Research.
    No preview · Article · Dec 2012 · Cancer Research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: We evaluated the ability of the PET imaging agent (89)Zr-trastuzumab to delineate HER2-positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor afatinib. Methods: Using (89)Zr-trastuzumab, (18)F-FDG, or 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT PET), we imaged HER2-positive NCI-N87 and HER2-negative MKN74 gastric cancer xenografts in mice. Next, we examined the pharmacodynamic effects of afatinib in NCI-N87 xenografts using (89)Zr-trastuzumab and (18)F-FDG PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies. Results: Although (18)F-FDG uptake in NCI-N87 tumors did not change, a decrease in (89)Zr-trastuzumab uptake was observed in the afatinib-treated versus control groups (3.0 ± 0.0 percentage injected dose per gram (%ID/g) vs. 21.0 ± 3.4 %ID/g, respectively; P < 0.05). (89)Zr-trastuzumab PET results corresponded with tumor reduction, apoptosis, and downregulation of HER2 observed on treatment with afatinib. Downregulation of total HER2, phosphorylated (p)-HER2, and p-EGFR occurred within 24 h of the first dose of afatinib, with a sustained effect over 21 d of treatment. Conclusion: Afatinib demonstrated antitumor activity in HER2-positive gastric cancer in vivo. (89)Zr-trastuzumab PET specifically delineated HER2-positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib.
    Full-text · Article · Apr 2013 · Journal of Nuclear Medicine
Show more