Clinical insights regarding the treatment of patients with BRAF-mutated metastatic melanoma presenting with symptomatic/asymptomatic brain metastases.
Hussein Tawbi, MD, PhD: If we are discussing our lady who's a 47-year-old with a singular lung metastasis and an elevated LDH, if we are to do her brain MRI and actually found asymptomatic brain metastases, then our treatment options become very clear at this point. We have very clear data for ipilimumab and nivolumab being highly effective in asymptomatic melanoma brain metastasis inducing response rates of up to 55%. The vast majority of those response rates are durable. We reported back in 2021, the three-year data indicating that in patients that have a response at 12 weeks in the brain, there was an overall survival benefit of 92% at three years so highly effective. BRAF and MEK inhibitors have activity in the brain. If she has a brain metastasis, you can be sure that you can shrink it down with a BRAF and MEK inhibitor with a response rate of close to 60% in the brain. However, PFS is much more limited. The PFS in the brain is about half of what it is outside the brain so you're talking about six months. This is why even in the absence of DREAMseq, we would recommend ipilimumab and nivolumab as a combination for this patient. Now, as a variation to the theme, again, I said, this patient, we just did MRI of the brain as a screening and we find asymptomatic brain metastasis, then IPI-NIVO is the option. Until we have data from nivolumab and relatlimab in the brain, this is the current recommendation. Let's say that this patient actually presented with headaches, numbness or left upper extremity weakness, or some evidence of symptomatic brain metastases. We do the brain MRI and she has a lot of cerebral edema and we have to start her on steroids to control her symptoms. In that specific case, ipilimumab and nivolumab has actually shown to have a very small response rate of about 18%, and that response rate is durable, but again, is very limited. In that case, you could consider BRAF and MEK inhibitors or a triplet combination. That's what we just published also in Lancet Oncology this year from TRICOTEL which is a phase two trial that looked at vemurafenib, cobimetinib, and atezolizumab. The patients that seemed to derive the most benefit were symptomatic patients with a BRAF mutation. Specifically, because the regimen involves a four-week run-in with them and COBI so some of those patients actually that were on steroids, were able to get off the steroids or decrease the dose significantly before they got their first dose of immunotherapy at week four with atezolizumab. Those patients seem to have done well. Again, if you consider brain metastases, the options are pretty clear if the patients are asymptomatic and not requiring steroids but if they're symptomatic and requiring steroids, then it's a more difficult discussion. I should add either way, you have to discuss this with a multidisciplinary team with a radiation oncologist than a neurosurgeon involved just to make sure that the patient is appropriate for systemic therapy as opposed to doing local interventions like MRI for surgery.