7552 Background: The combination of TMZ and THAL was reported to produce a high response rate (RR) including shrinkage of CNS disease in patients (pts) with metastatic melanoma (Hwu et al JCO 21:3351). We tested the efficacy of a regimen involving TMZ/THAL and WBRT in pts with brain metastases from melanoma. Methods: Pts with melanoma and MRI documented brain metastases received WBRT, 30 Gy in 10 fractions days 1–5 and 8–12; TMZ 75mg/m2/day weeks 1–6; THAL 100 mg po/day weeks 1–4, then escalated by 100 mg/day at weeks 5, 7, and 9 as tolerated to a maximum of 400 mg/day. CNS and systemic tumor response was assessed at wk 10. Pts without CNS or clinically significant systemic progression received additional cycles of TMZ (same dose) and THAL (MTD from cycle 1) at 10 wk intervals. Pts with prior cytotoxic chemotherapy, WBRT or THAL were ineligible. Prior focused RT was permitted for oligometastatic CNS disease. Results: 40 pts (25 M/ 15 F), median age 49 (range 28–81), ECOG PS 0/1 (20/20) were enrolled in the protocol. The majority of pts had brain metastases documented on routine staging head scan. Sites of systemic disease included: lung (28 pts), LN (17), soft tissue (14), liver (14), bone (7), adrenal (6), other (5); number of non-CNS disease sites were: 0 (1 pt), 1 (6), 2 (11), ≥ 3 (18), NA (4). Prior therapy: none (22 pts), IFN (5), vaccine (5), other cytokine (2); 7 pts had received focused RT to isolated CNS lesions (7). 3 pts had CNS responses (1 CR, 2 PR) (RR 7.5%)-all unconfirmed by repeat scan; 7 pts had stable CNS disease at 10 weeks. No pts exhibited a systemic response. Only 4 pts received 2 cycles of therapy and just 1 received 3. Median TTP was 10 wks (range 1–30 wks); median overall survival (OS) was 4 mos (range 0.5 -12 mos). Grade 3–4 side effects included DVT (3 pts), PE (1), myelosuppression (2), CNS events (8), cardiac (3). 18 pts (45%) required admission for side effects (7) and/or symptomatic disease progression. Conclusions: Median OS of pts with brain metastases from melanoma treated with TMZ/THAL and WBRT is comparable to that of other treatments with few clinically meaningful responses. Other treatment approaches are clearly necessary for this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene