Addition of BIBW 2992, an Irreversible Inhibitor of EGFR/HER1 and HER2 Inhibitor, to Treatment Continuation of Letrozole in Estrogen Receptor (ER-) Positive Metastatic Breast Cancer Progressing on Letrozole.
Authors: Gunzer K. , Joly F. , Delozier T. , Ferrero J. , Largillier R. , Gligorov J. , de-Mont-Serrat H. , Uttenreuther-Fischer M. , Solca F. , Bell S. , Stopfer P. , Bousquet G. , Misset J. 
Published: December 2010

Abstract
Background: The mechanisms of acquired hormone-resistance may involve cross-talk between the estrogen receptor (ER) and human epidermal growth factor receptor (HER)1/2 signalling pathways, since inhibition of the latter restores hormone sensitivity in animal models (1). In humans, attempts to restore hormone sensitivity by combining aromatase inhibitors with gefitinib have yielded inconsistent results (2); however, they have proved to be significantly beneficial for the HER2-positive population (EGF30008 trial). BIBW 2992 (Tovok™*) is a novel, oral, irreversible inhibitor of the epidermal growth factor receptor (EGFR)/HER1 and HER2 inhibitor, with preclinical activity in EGFR and HER2 overexpressing herceptin resistant cell lines (SUM 190-PT, SUM 149-PTand MDA-MB 453) and Phase I clinical activity.Methods: A multi-institutional, open-label, single-arm Phase II study with BIBW 2992 added to letrozole upon disease progression on letrozole monotherapy was conducted. Eligibility criteria included post-menopausal patients with proven ER positivity and clinically hormone-sentitive metastatic breast cancer who have progressed under letrozole after prior response to letrozole treatment. Patients had to have a life expectancy of ≥6 months and an Eastern Cooperative Oncology Group performance status of 0–1. By amendment, chemotherapy was allowed prior to BIBW 2992 treatment following progression on letrozole. Patients received 50 mg BIBW 2992 once-daily until disease progression. Tumor assessments are being performed every two treatment courses (one course is 28 days). The primary objective is the rate of non-progression at 16 weeks of therapy. Safety data are also being collected.Results: Thirty patients have been enrolled and 28 patients have been/are being treated in the study. Two patients are still on treatment. Grade 3 skin toxicity was observed at a higher frequency than what would have been anticipated from previous Phase II studies of BIBW 2992. Limited pharmacokinetic (PK) data on BIBW 2992 and letrozole did not indicate any changes in the PK of either drug. The daily dose of BIBW 2992 was reduced from 50 mg to 40 mg, and then to 30 mg. Most frequently observed adverse events to date are diarrhea, acne and mucosal inflammation. The majority of patients included were HER2-negative (19/28). Five of 26 patients evaluable to date reached the study endpoint and were treated with stable disease (SD) for more than 16 weeks. One of these had SD for more than 1 year.Conclusion: Despite the fact that the majority of patients included into this trial were HER2-negative, at present, five of 26 patients have been under continuous therapy with acceptable tolerance and no disease progression between 4 and 12 months. They may represent reversal of acquired hormone resistance. The study is ongoing and we believe that the model deserves further testing. Data will be updated.1. Osborne et al. Clin Cancer Res 2005;11(Suppl):865S–870S2. Smith et al. J Clin Oncol 2007;25:3816–3822*Trade name not FDA approved.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4098.