Abstract
3047 Background. ErbB1 or ErbB2 overexpression predicts for a poor clinical outcome in certain epithelial malignancies. GW572016, a reversible inhibitor of ErbB1/ErbB2 tyrosine kinases, induces tumor cell growth arrest and/or apoptosis. Methods. 64 patients (pts) (22 colon, 6 lung, 5 adenocarcinoma of unknown primary (AUP), 5 H&N, 5 renal, 4 breast, 3 ovarian, and 14 other) were treated with GW572016 once (qd) or twice (bid) daily in a dose escalation scheme. Thirty-nine pts were administered 175-1800 mg qd and 25 pts administered either 500, 750, or 900 mg bid. Pts were evaluated monthly and treated until disease progression or intolerable side effects. Clinical response was determined every 8 wks (RECIST). Results. One CR (sustained for 16+ mos) was observed in an ErbB1 overexpressing head and neck squamous cell carcinoma. Twenty-two pts with various tumors, most overexpressing either ErbB1 or ErbB2, experienced SD with a median duration of 4 mos (range 1–13+ months). Patients continuing therapy for > 4 mos were administered GW572016 at doses ≥ 1200 mg/day. Of the 22 SD pts, 2 with non-small cell lung cancer and AUP metastatic to lung, both progressing on previous Iressa therapy, remained on GW572016 for 12+ and 8+ mos, respectively. Transient grade 1–2 rash, diarrhea, nausea/vomiting, fatigue, and anorexia were the most frequent AEs in all cohorts. There were no cases of interstitial pneumonitis. We also investigated whether serum VEGF levels represent an easily accessible pharmacodynamic endpoint for GW572016 therapy since VEGF is regulated in part by ErbB receptor signaling. Days 0 and 14 serum VEGF levels were assessed with VEGF inhibition observed in 30 patients (median % inhibition-23%). Conclusion.QD administration of GW572016 is well tolerated with evidence of clinical activity in this heavily pre-treated population. Serum VEGF may be a potential biomarker for GW572016 activity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline Bristol-Myers Squibb; GlaxoSmithKline GlaxoSmithKline
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