Treatment outcomes of patients with cutaneous melanoma harbouring rare BRAF mutations


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Tamsin Nash1, Pavlina Spiliopoulou1, Yun Yi Tan1, Jeff Evans2, Ashita Waterston1
1Beatson West of Scotland Cancer Centre, 2University of Glasgow

Abstract

Background

Patients with classical BRAF V600E/K–mutated cutaneous melanoma represent a distinct cohort of patients, for whom combined targeted treatment (TT) with BRAF/MEK inhibition is standard of care. However, clinical experience with TT is limited in patients with non-classical BRAF mutations (non-V600E/K). Retrospective analyses of cases suggest that the response to TT is inferior in these patients compared with that in patients with classical BRAF mutations

Method

Between 2013 and 2020, primary or metastatic samples from patients with melanoma were sequenced for BRAF aberrations, either by Sanger sequencing or next-generation sequencing. Clinical notes of patients with activating BRAF mutations treated at a regional tertiary cancer centre were reviewed. BRAF mutation, patient and disease characteristics, progression-free (PFS) and overall survival (OS) were recorded.

Results

Twenty-seven out of 331 (8%) BRAF mutated melanomas, carried a non-V600E/K mutation.

Ten out of 27 patients (37%) were female patients and 17/27 (63%) male. Median age was 71 (56-90) years at diagnosis. Median primary tumour thickness was 4mm and 10/17 (59%) of tumours were ulcerated. The distribution of non-V600E/K mutations was: K601E=22%, V600R=18.5%, D594N=15%, T599dup=11%, V600_K601delinsE=7%, L597S=7% and 4% for each of mutations G596R, V600_K601delinsGlulle, D594A, D594G and L597E.

Of the patients with non-E/K BRAF mutations with advanced disease requiring systemic treatment, 8/16 (50%) received immunotherapy (IO) and 8/16 (50%) received TT, as first line treatment. Four out of eight (50%) treated with TT received combined BRAF/MEK inhibition and 4/8 (50%) received BRAF inhibition alone.

We compared outcomes of patients with non-E/K BRAF mutations treated with TT (n=8) with patients with classical BRAF mutations treated with TT (n=29). Although PFS was comparable (3.1m vs 5.2m, p=0.52), there was a trend for longer OS (6.3m vs 10.3m, p=0.07) in patients with classical BRAF mutations treated with first-line TT.

Conclusion

Our results - on a small number of patients - suggest that patients with rare BRAF mutations may have inferior survival outcomes with first line targeted treatment, compared with patients with classical BRAF mutations.

Impact statement

Our findings add to the limited clinical knowledge on rare BRAF mutations in melanoma and may help guide treatment decisions on this small subset of patients.