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Clinical Trial
. 2013 Sep 1;19(17):4868-78.
doi: 10.1158/1078-0432.CCR-13-0827. Epub 2013 Jul 5.

Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436)

Katherine L Nathanson  1 , Anne-Marie Martin, Bradley Wubbenhorst, Joel Greshock, Richard Letrero, Kurt D'Andrea, Steven O'Day, Jeffrey R Infante, Gerald S Falchook, Hendrik-Tobias Arkenau, Michael Millward, Michael P Brown, Anna Pavlick, Michael A Davies, Bo Ma, Robert Gagnon, Martin Curtis, Peter F Lebowitz, Richard Kefford, Georgina V Long
Affiliations
Clinical Trial

Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436)

Katherine L Nathanson et al. Clin Cancer Res. .

Abstract

Purpose: Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.

Experimental design: Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.

Results: All baseline patient samples had BRAF(V600E/K) confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1-24.3) vs. 32.1 weeks (95% CI, 24.1-33), P=0.059]. Higher copy number of CCND1 (P=0.009) and lower copy number of CDKN2A (P=0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.

Conclusions: Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients.

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Conflict of interest statement

Conflicts of interest: KLN, SO’D and H-TA have received research funding from GlaxoSmithKline; A-MM, JG, RG, BM and MC are employees of, and have stock ownership of, GlaxoSmithKline; BW, RL, KD’A and AP have no conflicts of interest to declare; JRI has acted as an uncompensated consultant or advisor for GlaxoSmithKline; GSF has received research funding and other remuneration from GlaxoSmithKline; MM has acted as a compensated consultant or advisor for GlaxoSmithKline; MPB has acted as a compensated consultant or advisor for, and has received research funding from, GlaxoSmithKline; MAD has served on advisory boards for GlaxoSmithKline, Genentech and Novartis, and has received research funding from GlaxoSmithKline, Genentech, AstraZeneca, Merck, Myriad and Oncothyreon; PFL was an employee of GlaxoSmithKline; RK has acted as a compensated consultant or advisor for GlaxoSmithKline; GVL has acted as a compensated consultant or advisor for GlaxoSmithKline, Roche, Novartis, Amgen and Bristol-Myers Squibb, and has received honoraria from Roche.

Figures

Figure 1
Figure 1. Association with PTEN genetic status with response and progression free survival upon treatment with dabrafenib
A. Waterfall plot. One patient with stable disease was not included because tumor percent change was unknown. B. Median PFS in patients with tumors with mutations or deletions of PTEN (red line) vs. all others (black line).
Figure 2
Figure 2. array based Comparative Genomic Hybridization analysis of melanoma samples
Figure 3
Figure 3. Association between gene copy number and outcome
For visualization of the association between copy number and outcome, the samples were divided by median copy number and Kaplan-Meier curves for PFS were generated A. CCND1 B. CDKN2A C. BRAF copy gain and correlation with PFS, response and time of sample collection (A – archival; P – pre-treatment; S – on-treatment; G – progression)
See this image and copyright information in PMC

References

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