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3003 Background: GW572016 reversibly inhibits ErbB1 and ErbB2 tyrosine kinases, in turn inhibiting downstream tumor growth and survival pathways. Since ErbB2-containing heterodimers elicit potent mitogenic signals, simultaneously interrupting ErbB1 and ErbB2 signaling is an appealing strategy. Methods: Patients with metastatic carcinomas overexpressing ErbB1 and/or ErbB2 were randomized to one of five GW572016 dose cohorts administered orally once daily. Tumor biopsies were obtained prior to (d 0) and 21 days after initiation of therapy, with a panel of tumor biomarkers analyzed by quantitative immunohistochemistry. Clinical response was assessed after 8 weeks of therapy and every 2 months thereafter until termination from study. Results: Thirty-three patients had evaluable d 0 and d 21 tumor biopsies. Partial responses occurred in 4 patients, all with metastatic breast cancer, and 11 experienced stable disease. The frequency of inhibition of phosphorylated-activated forms of ErbB1, ErbB2, Akt, and Erk1/2 as well as decreased cyclin D protein levels within each dose cohort helped identify a biologically active dose range. Whereas inhibition of the aforementioned biomarkers may be necessary for clinical response, it is not sufficient. Increased d 21 TUNEL staining of tumor cells appears linked to subsequent clinical response at 8 weeks. Phospho-Akt inhibition at d 21 appears to be associated with clinical response. Inhibition of p-BAD and survivin, molecules regulating tumor survival also appear to correlate with clinical response. Conclusions: GW572016 is biologically and clinically active in heavily pre-treated patients with a variety of ErbB1 and/or ErbB2 overexpresssing cancers, notably breast cancer. Although inhibition of MAPK-Erk and PI3K-Akt signaling pathways may be necessary for clinical response, it is not sufficient. Elucidating pathways involved in tumor survival may identify patients more likely to respond to GW572016. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Spector et al. (Thu,) studied this question.