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4507 Background: We have previously reported a > 50% HER2 overexpression in patients (pts) with metastatic urothelial cancer (UC). Methods: Metastatic UC pts were screened for HER2 overexpression. Pts eligible for therapy had: HER2 overexpression by immunohisto-chemistry (IHC) (2+ or 3+) and/or gene amplification by FISH (> 2 by Vysis) and/or elevated serum HER2 >16 ng/ml by OSDI; no prior chemotherapy for metastasis (mets); normal cardiac function, performance status (PS) 0–2; and adequate organ function. HER2 assays were performed centrally. Pts received T 4mg/kg loading dose followed by 2mg/kg on days (D) 1, 8, & 15; P 200 mg/m2 D1; C (AUC 5) on D1; G 800 mg/m2 on D 1& 8. Response and MUGA were assessed Q 3 cycles. Primary end point: toxicity of TPCG. Secondary endpoints: efficacy, survival, time to progression (TTP) and prospective evaluation of HER2 status. Results: 59/109 registered pts (54%) were HER2 positive (+ve) (IHC 51%, FISH 13%, serology 12%). Based on the higher of the IHC score from primary or mets tissue, 27 pts were 2+ and 29 were 3+. HER2 +ve pts had more liver/bone mets (39% vs 22%, p=0.06), more lung mets (32% vs 24%, p=0.40) and more mets sites (47% with ≥ 2 sites vs 28%, p=0.03) than HER2 negative pts. 44/59 HER2 +ve pts (median age 65.5 years, median PS 1, 55% had visceral mets and 32% had prior chemotherapy) were treated with TPCG. The median number of cycles was 6 (range 1–12). The most common grade (G) 3/4 adverse events were neutropenia (77%), thrombocytopenia (64%), anemia (38%), PRBC (25%), fatigue (16%), diarrhea (16%), platelet transfusion (14%), sensory neuropathy (11%), cardiac (all G3, 4.5%) and 3 possibly or definitely therapy-related deaths. There were 32 responses (5 complete and 27 partial, response rate 72.7%), 4 pts had stable disease, 5 not assessable, and 3 with progressive disease. TTP and median survival were 8.5 and 15.2 months, respectively. Conclusions: This is the first trial to prospectively characterize HER2 status in pts with metastatic UC. The combination of TPCG is feasible and is associated with high level of activity. These results warrant validation in a phase III trial. Support: CTEP, 5 P30 CA46592, NO1 CM17101 & Genentech. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech

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