Patterns of progression in patients (pts) with V600 BRAF-mutated melanoma metastatic to the brain treated with dabrafenib (GSK2118436).

Abstract

8558 Background: Dabrafenib has shown efficacy in pts with previously untreated brain metastases (BM) but most will progress. We report the pattern of disease progression (PD) in pts with either previously treated (surgery (Sx), SRS, WBRT) or untreated BM on dabrafenib. Methods: Clinicopathologic parameters were collected on 23 pts enrolled in the brain cohort of the BRF112680 phase I and BRF113929 phase II BM study of dabrafenib at Westmead Hospital between Sept 2009 and June 2011. Pts with RECIST PD but ongoing clinical benefit were allowed to continue dabrafenib. Results: 12 pts (52%) had previously untreated BM and 11 (48%) were previously treated with evidence of progression prior to dabrafenib. Median OS from study entry (8.4 mo, 95% CI 5.0-11.8), diagnosis of first BM (11.0 mo, 95% CI 9.1-13.0), and stage IV diagnosis (17.5 mo, 95% CI 12.1-23.0) were not different between the two groups. Similarly, PFS did not differ between groups. Of the 19 pts who had RECIST PD at datacut, 13 pts had intracranial (IC) PD with no pts progressing in new brain lesions alone (see table). At IC PD, 3/13 underwent SRS/Sx, 5/13 WBRT and 5/13 had no salvage local therapy to BM. 8 pts continued dabrafenib beyond IC PD, median 36 days; range 28-273. All measures of baseline disease burden correlated with worse OS; elevated LDH (HR 1.003, 95% CI 1.0-1.007, P=0.044), increased number (no.) metastatic sites (HR 1.32, 95% CI 0.97-1.81, P=0.08), increased no. of IC lesions (HR 1.04, 95%CI 1.00-1.09, P=0.04), increased no. extracranial (EC) lesions (HR 1.07, 95%CI 1.02-1.12, P<0.01) and increased RECIST sum of diameters (SoD) (HR 1.012, 95% CI 1.003-1.021, P=0.007). High baseline SoD was the only factor that predicted worse RECIST response. Conclusions: Clinical benefit from dabrafenib does not appear to be influenced by prior local therapies to BM. There was no dominant pattern of progression in pts with BM on dabrafenib, but PD due to new lesions alone is rare. Pts with IC PD may benefit from salvage local therapy and continued dabrafenib. [Table: see text]