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2008 Background: Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure in pts with brain tumours. Preliminary data suggest that low-dose RT may disrupt the BBB, and could facilitate increased drug delivery into brain tumours. CamBMT1 is a phase 1b/2 pre-operative window-of-opportunity trial designed to test if the delivery of afatinib into brain mets might be enhanced by targeted, low dose-RT. Methods: Pts with operable brain mets from breast or lung origin were treated with afatinib for 11 days prior to surgery on day 12. Pts also received a single fraction of targeted RT on day 10 (pts in either 2Gy or 4Gy arm). In phase 1b, afatinib dose (20, 30, or 40mg QD) was escalated in each arm using an accelerated titration design. Primary endpoint: steady-state afatinib concentration in resected brain mets, compared with plasma. Secondary endpoints: safety and tolerability. Results: 10 pts were treated (4 breast, 6 lung), with no dose-limiting toxicities seen, thus completing recruitment to phase 1b. Treatment was generally well tolerated. Median afatinib concentrations on day 12 were: plasma 22.7ng/mL (range 9.94-179); and tumour 405ng/g (range 120-1129). Conclusions: It was feasible to conduct a window-of-opportunity study of afatinib plus RT in pts with operable brain mets. The recommended phase 2 dose of afatinib was 40mg QD for both 2Gy and 4Gy arms. Afatinib concentrations in resected tumour were on average >15-fold higher than those in plasma. Phase 2 of CamBMT1 is now underway in multiple UK sites, and randomises patients into 3 treatment arms (n=20 per arm): 1. afatinib 40mg QD; 2. afatinib 40mg QD + 2Gy# RT; 3. afatinib 40mg QD + 4Gy# RT. Clinical trial information: NCT02768337. [Table: see text]