Background: For MBC patients with isolated brain progression, current guidelines recommend treatment with CNS-directed therapy and continuation of current systemic therapy, although there are limited data evaluating this strategy. Two Phase 1b trials of tucatinib permitted patients with HER2+ MBC to continue study treatment following CNS-directed therapy in instances of isolated brain metastases (BM) progression. Methods: 2 Phase 1b studies of tucatinib were pooled to identify patients with isolated brain progression (defined as new or progressive BM with stable or responding systemic disease) while on study. In patients treated for isolated brain progression, the median time to any subsequent progression or death was determined. Results: 117 patients were analyzed, 57 in the 004 (tucatinib + T-DM1) and 60 in the 005 (tucatinib +/- trastuzumab +/- capecitabine) trials. 25 patients (21%) with isolated BM were identified and comprised 2 groups: 14 who discontinued study and 11 who continued study treatment following CNS-directed therapy. Median time to isolated brain progression differed between these groups (12.3 months in post-progression treated vs. 6.3 months). The median time to any second event was 8.3 months in the post-progression CNS-treated patients. Patients selected for post-progression treatment had less exposure to pertuzumab, were more frequently treated with the triplet combination, had a longer time from pre-study CNS-directed therapy, had better preserved performance status, and were less likely to have new neurologic adverse events compared to patients not treated post-progression. Conclusions: Patients with isolated BM progression treated post-progression with CNS-directed therapy and continuation of study therapy had a median of 8.3 months to any second event, suggesting a substantial benefit for this treatment strategy. The selection of patients with post-progression treatment appears to be a composite of characteristics both at baseline and at time of brain progression. These results support the further evaluation of this approach to patients with isolated brain progression in the ongoing randomized HER2CLIMB trial. Clinical trial information: NCT01983501 and NCT02025192