Rechallenge with BRAF/MEK combo in melanoma

For BRAF positive melanoma patients, targeted therapy with a BRAF inhibitor combined with a MEK inhibitor can have amazing results in the destruction of melanoma!  Response rates are around 70-80%!!  While there are a few exceptions, the problem with this targeted therapy is that the benefit often evaporates around 6-9 months, with sinister melanoma developing the ability to work-around the treatment.  These peeps then go on to other treatments.  Sometimes those work, sometimes they don't.  If they don't, will taking BRAF/MEK again work?????

Now, there's this:   

Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study. Valpione, Carlino, Mangana, et al. Eur J Cancer. 2018 Jan 19.

Most metastatic melanoma patients treated with BRAF inhibitors (BRAFi) ± MEK inhibitors (MEKi) eventually progress on treatment. Along with acquired resistance due to genetic changes, epigenetic mechanisms that could be reversed after BRAFi discontinuation have been described. The purpose of this study was to analyse retrospectively outcomes for patients retreated with BRAF-directed therapy.

One hundred sixteen metastatic melanoma patients who received BRAFi-based therapy and, after a break, were rechallenged with BRAFi ± MEKi at 14 centres in Europe, US and Australia were studied, respectively. Response rate (RR), overall survival (OS) and progression-free survival (PFS) from the start of retreatment were calculated.

The median duration of treatment was 9.4 months for first BRAFi ± MEKi treatment and 7.7 months for the subsequent treatment (immunotherapy 72%, other 17%, drug holiday 11%) after BRAFi discontinuation. Brain metastases were present in 51 (44%) patients at BRAFi retreatment. The RR to rechallenge with BRAFi ± MEKi was 43%: complete response (CR) 3%, partial response (PR) 39%, stable disease (SD) 24% and progressive disease 30%, 4% missing. Of 83 patients who previously discontinued BRAFi due to disease progression, 31 (37.3%) responded (30 PR and 1 CR) to retreatment. The median OS from retreatment was 9.8 months, and PFS was 5 months. Independent prognostic factors for survival at rechallenge included number of metastatic sites , lactic dehydrogenase, while rechallenge with combination BRAFi + MEKi conferred a better OS versus BRAFi alone.

Rechallenge with BRAFi ± MEKi results in a clinically meaningful benefit and should be considered for selected patients.

In this study, 116 peeps who had taken BRAFi (a BRAF/MEK combo) for an average of 9.4 months stopped taking it for a variety of reasons ~ and had roughly 8 months of:  immunotherapy (72%), other treatment (17%) and drug holiday (11%).  They were then rechallenged with a BRAF/MEK combo.  Response rate for the rechallenge was 43% with 3% attaining a complete response, 39% a partial response and 24% gaining stable disease, although 30% had progressive disease and 4% were apparently lost to follow-up.  Of the 83 peeps who stopped BRAFi initially due to disease progression, 31 responded to the rechallenge - 30 with a partial response and 1 with a complete response.  Median OS from BRAFi retreatment was 9.8 months and PFS was 5 months.

Given the results of this study, the answer to the initial question I posed, is:  YES, a rechallenge with BRAF/MEK can work with a response rate of about 43% generally and 37% in those who progressed on BRAFi the first go round.  Response rates are not as high nor as complete as those attained with the initial treatment....but....they are there!!! Repeating treatment with BRAF/MEK is certainly an option in kicking melanoma in the teeth a bit, while seeking more effective, durable treatment.

It's something.  Thanks, ratties.  - c