Neurological benefit of BRAF-inhibition and MEK-inhibition in patients with brain metastases from BRAF-mutated melanoma

Background

Patients (pts) with brain metastases (BM) from melanoma have a median survival of 2 to 6 months after whole brain radiotherapy. Targeted therapy (TT) improves OS in pts with BRAF-mutated metastatic melanoma. In this retrospective analysis we investigated response, neurological benefit and survival in pts with BM from BRAF-mutated melanoma treated with TT.

Methods

We analysed 147 pts diagnosed with BM from BRAF-mutated melanoma between 2010 and 2016 treated at the Netherlands Cancer Institute. Pts either received vemurafenib, dabrafenib, or the combination of vemurafenib/cobimetinib or dabrafenib/trametinib. Neurological symptoms were scored before treatment and every 4 weeks until cessation of therapy. Response was assessed with MRI brain and CT thorax/abdomen after 8 weeks. Kaplan-Meier analyses were used to estimate PFS and OS.

Results

Median OS of all pts was 6.6 months (mo) (95%CI 5.7–7.4). Median intracranial PFS of all pts was 4.2 mo (95%CI 3.3–5.2). Sixty-three pts (43%) had symptomatic BM (sBM) before start of TT and had a median intracranial PFS of 3.7 mo (95%CI 2.7–4.7). The intracranial radiological response rate (RRR: stable disease/partial or complete response) was 63% versus extracranial 68%. Twenty-nine pts with sBM showed a clinical neurological response (46%), 13 were stable (21%), 16 progressive (25%) and 5 were not evaluable (8%). Pts with improving or stable neurological symptoms had a significantly better OS compared to pts with worsening symptoms; 8.8 vs 4.4 mo (p

Conclusions

Intracranial response parallels systemic response in pts with brain-metastasized melanoma treated with TT. TT improves neurological symptoms in about half of the pts with sBM from BRAF-mutated melanoma.

Clinical trial identification

Legal entity responsible for the study

Netherlands Cancer Institute

Funding

Netherlands Cancer Institute

Disclosure

C. Blank: Advisory role for Novartis, Roche/Genentech, MSD, GlaxoSmithKline, Bristol Myers Squibb, Pfizer and Lilly Grants from Novartis. J.B.A.G. Haanen: Grants from MSD, grants from Bristol-Myers-Squibb, and grants from GlaxoSmithKline Consulting or advisory role for MSD Oncology, Pfizer, Bristol-Myers-Squibb, Novartis, Neon Therapeutics and Roche/Genentech. J.V. van Thienen: Advisory board/consultancy voor MSD en BMS. All other authors have declared no conflicts of interest.