Round 3: Treatment for Patient Case 3

The panel discusses optimal initial management of brain metastases in the third round, comparing evidence for combination immunotherapy with the role of CNS-directed therapy.

To hear arguments related to treatment for patient case 1, see Round 1.

To hear arguments related to treatment for patient case 2, see Round 2.

Dr Jose Lutzky: We are now moving to our third and final case. And this is that of a 65-year-old man that presented to his primary doctor with fatigue, asthenia, and enlarging nodular lesions on his trunk, and these were palpable on physical exam, and also left axillary adenopathy. ECOG-performance status was 1, biopsy of one of the skin nodules showed melanoma, and molecular testing showed that this was a BRAF wild-type melanoma. The LDH was over 2 times the upper limit of normal of 225, it was 520. The PET CT showed widespread metastatic disease to the lung, liver, and bone metastasis. And the MRI of the brain showed 3 sub-centimeter metastatic lesions.  

And to solve this dilemma, I will ask Dr Tarhini to tell us why we should use systemic therapy first, and then Dr Smithy will tell us whether we should use radiation therapy first. 

Dr Ahmad Tarhini: All right. Thank you, Dr Lutzky. It's another very interesting case and a lot of data to support the use of systemic immunotherapy in this setting. 

So this is a patient with brain metastases, asymptomatic, large tumor burden overall, systemically, with the 3 brain metastases, sub-centimeter, asymptomatic there. The data here for IPI + NIVO, and primarily IPI-3 + NIVO-1, is supported by 2 major studies, the CheckMate-204 study and the ABC study, both tested IPI + NIVO in this patient population and had a short interval MRI at about 6 weeks just to keep an eye on those patients and ensure that if we have to do an intervention at some point, this can be done early on, let’s say at 6 weeks after initiating systemic therapy. If you look at the data in both studies, they're comparable. CheckMate-204 was a larger study, 101 patients enrolled. The ABC study had about 35 patients, but overall, the data is comparable, meaning the likelihood of response, both intracranially and systemically, is about the same, so roughly 50%, 55% chance of having an objective response intracranially and systemically. These were durable responses in the majority of patients, and we've seen let’s say significant benefits both in terms of overall survival and progression-free survival as well.  

Now, considering the asymptomatic patient population, the key factor here in terms of the asymptomatic patient population is the lack of the need for corticosteroids. The patient did not need prednisone, Decadron, etc, that may impact the chance of response to immunotherapy. Now, in the symptomatic patient population data, is also comparable between CheckMate-204 and the ABC study in terms of the chance of response is less now, the chance of response drops down to about 20% or so, and the survival also drops about 30% or so, let's say at 3 years out in the symptomatic patient population appears to be the key factor here is the requirement of corticosteroids that interfere with a chance of response to immunotherapy. So anything we can do for those who require steroids, to transition them away from steroids, I think is a key factor. I think this is the key thing. 

Now, in terms of patients who have a BRAF mutation, now we have data with BRAF/MEK inhibition, with COMBI-MB with dabrafenib + trametinib, with ENCO + BINI, and the response rate, intracranial is actually high. So with the dabrafenib + trametinib, response rate was 56%, but the problem is the duration of the response. The median duration of response was only about 6 months. So, very little benefit, really. So while patients may respond to BRAF/MEK inhibition, intracranially, the median duration of response is very limited. 

So, I think it supports systemic therapy up front with immunotherapy in patients who are asymptomatic, not requiring steroids. And those who require steroids, doing certain interventions to take them off steroids, whether it is BRAF/MEK inhibition or other means to eventually transition to immunotherapy.

Dr James Smithy: Great. So I think Dr Tarhini laid out some really strong data for the efficacy of checkpoint blockade intracranially, and I think it will benefit a large percentage of patients, and there are patients who will have durable responses and will do very well. I think just I want to emphasize that in this little bit vague or initial presentation, you need to really use an interdisciplinary team to determine what is best for these patients. I think even with asymptomatic brain metastases, there are radiographic and anatomic features that could play into your decision-making in  

this process, and I think there can be metastases near very highly valuable neurological real estate, like near the midbrain or like other structures, and depending on the patient's, I’d say, tolerance and propensity to be like, “Okay, what does this look like if I progress?  

If I am in the unlucky part of patients that do not have a response to IPI + NIVO, would I feel more reassured if we just radiate this upfront and then use these as an adjunct as well?” 

So I will say from ASTRO, which is the national radiation oncology society guidelines, any patient with 4 or fewer asymptomatic brain mets, SRS is a recommended local approach for these as well. And I think our radiation oncology colleagues are often very happy to discuss these patients together and consider, maybe it's a risk-benefit discussion with the patient and saying maybe meet with the radiation oncologist, doing systemic therapy first may be an option, but maybe everyone will sleep better at night if we radiate, and then maybe also do therapy as well in the first-line setting.  

I think SRS is really a low-toxicity and highly effective approach to a lot of these melanoma brain mets. We know from some large retrospective series, like from Huntsman Cancer Institute, that you can get 76% durable control for brain metastases and the median local control rate for these can be up to 2 years as well, which is pretty, I think, promising. So I think definitely if your patient is willing to tolerate the potential for progression and the effect of quality of life if you're unlucky with one of these systemic approaches, I think that's okay.  But I will say I think almost every patient would benefit from a discussion with a radiation oncologist at the outset to consider radiation in this setting as well. So, that’s all I'll say about radiation.