S2000 is a cooperative group study through SWOG, part of the National Cancer Institute, and it’s a randomised phase II trial for patients with symptomatic melanoma brain metastases randomising them to a triplet regimen of encorafenib/binimetinib/nivolumab versus combination immunotherapy with ipilimumab and nivolumab.

What was the methodology and what were the findings?

For this study we focussed on patients with symptomatic melanoma brain metastases, the reason being that these patients do very poorly with immunotherapy treatments, even with ipilimumab/nivolumab. Typically less than 20% with immunotherapy have treatment response. Usually their progression is just over one month. So unfortunately very poor outcomes, probably because oftentimes they require steroids and have a lot of symptoms from their brain metastases.

So in this study these patients with symptomatic melanoma brain metastases, whose melanoma had a BRAF V600 mutation to be eligible for enrolment, were randomised to either a combination of immunotherapy and targeted therapy, so that’s the encorafenib, binimetinib plus nivolumab, or to standard immunotherapy with ipilimumab and nivolumab. Then our primary endpoint was assessing them for overall progression free survival. So that’s either intracranial, within the brain, or extracranial, so overall PFS.

What we found was that the group of patients who were randomised to the triplet regimen, that’s the targeted plus immunotherapy, actually had improved progression free survival. So the study met it’s primary endpoint and the six-month PFS rate was above 50% versus about 20% with the ipilimumab/nivolumab. Further, in the patients when we looked specifically at intracranial PFS there was even more of a difference. Median PFS was 8.7 months with the triplet versus 1.5 months with the ipilimumab/nivolumab arm.

Similarly, our response rates were also much higher. It was about 75% with the triplet arm intracranial response versus about 15% in the ipilimumab/nivolumab arm. So it looked like there was a benefit in response and improving progression in patients getting the triplet encorafenib/binimetinib/nivolumab regimen versus ipilimumab/nivolumab for symptomatic melanoma brain mets.

What is next for this study?

This group of patients, again very hard to treat with symptomatic melanoma brain mets, very poor outcome. We think that possibly a triplet regimen, if their melanoma has this BRAF mutation, a triplet regimen of targeted therapy plus immunotherapy may be a therapeutic option for them as opposed to starting them on just immunotherapy alone. But this approach would need to be explored in probably larger studies and also be compared to sequential targeted therapy, newer therapy designs. But we think that this may present another treatment option for currently a very challenging to treat patient population.