Background: Preclinical studies show that addition of an antiangiogenesis agent improves efficacy of aromatase inhibition in hormone-sensitive breast cancer. Sorafenib is a multitargeted kinase inhibitor of VEGFRs, PDGFRs, FLT3, c-kit, and RAF. In this phase I/II multicenter study, the addition of sorafenib to letrozole as first-line therapy of HR+ MBC was evaluated. We previously reported the phase II dose to be letrozole 2.5 mg daily with sorafenib 400 mg BID. Methods: Eligible patients (pts) were postmenopausal, had measurable or evaluable HR+ MBC, and no prior therapy for metastases. Prior adjuvant tamoxifen (TAM) or aromatase inhibitor (AI) was allowed. The primary endpoint was clinical benefit rate (CBR= PR + SD ≥ 6 mo). The trial planned to enroll 58 pts to detect a CBR of ≥ 67% in a single-stage phase II design (80% power, α = .05). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: 54 pts (median age 54 yrs, range 21-84; median ECOG PS 0, range 0-2) were treated (13 pts in phase I) between 8/2008 – 12/2012 at which time the study closed due to slow accrual. 44% had de novo MBC, 39% pts had prior adjuvant TAM, 11% had prior adjuvant AI, and 2% had both prior TAM and AI. Median no. of cycles was 9 (range 1-62). The median daily dose of sorafenib was 400 mg. Most common gr 1-3 toxicities (%) were hand-foot skin (HFS) reaction (35%), hypertension (33%), rash (26%), diarrhea (19%), joint pains (15%), fatigue (13%), and alopecia (13%). 3 pts had HFS reaction that led to discontinuation of therapy. 5 pts had grade 2-3 rash that led to dose interruption. Of 41 pts evaluable for response, 39% (16 pts) had PRs and 41% (17 pts) had SD ≥ 6 mo. The CBR was 80.5% (95% CI: 65.1 - 90.9%). Median PFS was 20.2 mo (95% CI: 12.4 - 54.5 mo) and median OS was 51.5 mo (lower 95% CI: 44.7 mo). 11 pts continue on study with a median duration of 26 mo (range 14 – 60) and the median daily dose of sorafenib for these pts is also 400 mg. Conclusions: Letrozole combined with sorafenib was active in the treatment of HR+ MBC, and produced durable clinical benefit in a subset of pts as first-line therapy. Treatment benefit was still observed in pts who received lower than the recommended daily dose of sorafenib. Clinical trial information: NCT00634634.