Tumor-specific circulating cell-free DNA (cfDNA) BRAF mutations (muts) to predict clinical outcome in patients (pts) treated with the BRAF inhibitor dabrafenib (GSK2118436)

Georgina V. Long, Paolo Antonio Ascierto, Jean Jacques Grob, Omid Hamid, Richard Kefford, Celeste Lebbe, David R. Minor, Antoni Ribas, Dirk Schadendorf, Leslie Anne Fecher, Uwe Trefzer, Nikita Arya, Robert C. Gagnon, Vicki L. Goodman, Anne Siegfried, Jolly Mazumdar, Anne-Marie Martin

Research output: Contribution to journalMeeting abstractpeer-review

Abstract

Background: Tumor specific cfDNA levels in blood increase with tumor burden and decrease following treatment. cfDNA can harbor muts consistent with the tumor. Thus cfDNA could be a useful biomarker of therapeutic response. BREAK-2, an open label, single arm, Phase II study evaluated efficacy, safety and tolerability of dabrafenib in BRAF V600E/K mut+ metastatic melanoma pts. Exploratory objectives of BREAK-2 were to evaluate whether (i) tumor and cfDNA BRAF muts are correlated; (ii) cfDNA levels correlate with baseline tumor burden and (iii) cfDNA muts predict clinical outcome with dabrafenib. Methods: BRAF mut status was established for 92pts using an allele-specific PCR assay in tumor samples. Baseline plasma samples were available for 91/92 pts. cfDNA BRAF mut status was evaluated by Inostics GmBH using the BEAMing technology. Spearman correlation coefficients (R) were used to determine the association between cfDNA fraction (mut DNA molecules > 0.01%) and estimated baseline tumor burden, calculated by the sum of RECIST measurements of target lesions. Logistic regression and Cox proportional hazards models were used to assess the association between cfDNA mut status and objective response rate (ORR) and progression free survival (PFS), respectively. Results: The overall agreement between tumor and cfDNA BRAF V600E and V600K mut status was 83%, and 96% respectively. Higher cfDNA V600E mut fraction was associated with higher baseline tumor burden (R=0.73; p-value < 0.0001; n=60); lower ORR (O.R. = 0.83; 95% CI = 0.72, 0.96; p-value=0.0134; n=46) and shorter PFS (H.R.=1.09; p-value=0.0006; n=46). Median PFS was 27.4 weeks in the overall V600E pt population (n=76) and 20.0 weeks in the cfDNA V600E pt population (n=46). Otherwise, the response endpoints were comparable between the two populations. There was no correlation between V600K mut fraction (n=14) and any efficacy endpoints. Conclusions: cfDNA was useful for detecting BRAF muts in pts treated with dabrafenib and increasing V600E mut fraction was associated with reduced ORR and shorter PFS, suggesting higher amounts of mut cfDNA in V600E mut+ pts predicts poorer clinical outcome.
Original languageEnglish
Pages (from-to)8518-8518
Number of pages1
JournalJournal of Clinical Oncology
Volume30
Issue numberSupplement 15
Publication statusPublished - 20 May 2012
Externally publishedYes
Event48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) - Chicago, United States
Duration: 1 Jun 20126 Jun 2012

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