Managing Brain Metastases in Melanoma



Jeffrey S. Weber, MD, PhD: As I remember in the abstract, there was verbiage suggesting that with these new data from both the CheckMate 204 study and the Australian study that Georgina presented, which was called the ABC study, maybe we could do without stereotactic radiosurgery. Do you do without stereotactic radiosurgery in patients who get ipilimumab/nivolumab with brain metastases?

Axel Hauschild, MD, PhD: We don’t have very much experience in combining the 2 immunotherapeutic agents plus stereotactic surgery. We have more experience in using anti—PD-1 alone plus stereotactic surgery. That’s what I need to declare here, but it could make sense. We have at least some animal models, one publication also in humans, which indicate there might be synergism and additive effects if you combine radiotherapy. But it depends. I was really impressed by ipilimumab plus nivolumab at ASCO. Those are the best data I have seen: not because the response rate is very high, surprisingly high—and the response rate in the brain and outside of the brain is exactly the same—but because the duration of responses was so pretty. There were data on tyrosine kinase inhibitors where we expected to see very high rates, and they also showed good extracranial responses, but it appeared that the duration of response is shorter. So, the quality of the response is eventually higher and the number of CRs was surprisingly high, at a range of 20% for ipilimumab plus nivolumab. And, therefore, I think in these sorts of patients, if the patient can tolerate the toxicity and the patient got good, informed consent, I would say that this is a treatment of choice.

Caroline Robert, MD, PhD: I would like to say something, because when you ask this question, this is really a point that makes me a little bit uncomfortable. We know, as you say, that with radiosurgery, we get rid of the metastases. Rapidly, it works well, and I think we absolutely have to evaluate this combination. I agree. The results are impressive, but with radiosurgery up front or with radiosurgery if it doesn’t work right away. And it’s difficult not to propose to a patient who has 3 brain metastases accessible to radiosurgery that you’re sure there are no other metastases. For example, you can treat these 3 metastases with radiosurgery. Of course, the problem is not solved definitely, but you can at least have an immediate, good effect, and I think this procedure has to be incorporated in our clinical trials.

Jeffrey S. Weber, MD, PhD: Reinhard, do you forego stereotactic radiosurgery in a metastatic, newly diagnosed patient with multiple small metastases, treat them with ipilimumab/nivolumab, and then wait? Or would you treat them with radiosurgery?

Reinhard G. Dummer, MD: We are in a constant discussion with our radio-oncologists, and there are 2 developments based on the ASCO abstract. First, we now use ipilimumab/nivolumab combinations in patients who have multiple brain metastases and then we take a close look at the distribution and the size. If a lesion has a size over 5 mm, it gets stereotactic radiosurgery, and our radio-oncologists now agree to do so even if other brain metastases are around. We had a problem with this, because they really insisted to do whole brain radiation. Actually, we got rid of that now, because they also have some confidence that the systemic therapy works. If it’s working incompletely, though, if we can control most of the metastases but a few are regrowing, then we use additional stereotactic irradiation. And I think with this, we have really improved the care of these advanced patients and we avoid significant toxicity, because some of them will make it in long-term disease stabilization and maybe even cure—we don’t know. So, we have to be very careful with this long-term toxicity and interventions that damage cognitive functions.

Jeffrey S. Weber, MD, PhD: Let’s switch gears a little bit. One of the interesting things about radiosurgery is that it does cause an inflammatory tumor microenvironment, which might, in my view, add to the efficacy. Although it could add to the toxicity of ipilimumab and nivolumab. But what about another way to induce inflammation in the tumor and turn a cold tumor into a hot one? That’s T-VEC, one of these direct herpes virus injections. Axel, do you have much experience with this?

Axel Hauschild, MD, PhD: We used it in a number of patients inside and outside of clinical trials. In Germany, it’s available. It’s approved and reimbursed from the very first day. That’s the beauty in Germany. Once a drug is approved, it’s available on the same day, which means we have early experience. I have seen nice responses in the early clinical trials. The Germans were not involved in the very first trial, which was called the OPTiM trial, to bring the drug to the market. But we were involved in ipilimumab plus/minus T-VEC, and I have 2 patients still in complete response with numerous lesions, even without the drug. So, the drug was given for just 3 months—in another case, it was given for 9 months—and we caused a complete response, which is long-lasting.

Caroline Robert, MD, PhD: Yes, but you had ipilimumab.

Axel Hauschild, MD, PhD: We had ipilimumab in these patients. For those who didn’t have ipilimumab, we are seeing responses, and we are also seeing responses in lesions that have not been injected.

Jeffrey S. Weber, MD, PhD: You were part of the trial that Jason Chesney presented at this year’s ASCO.

Axel Hauschild, MD, PhD: Yes, that’s accepted now in the Journal of Clinical Oncology, and it will be published very soon. It’s doubling the response rate. It’s doubling PFS. They are impressive data, I would say, and therefore, there is some sort of action. The most important clinical trial is certainly now the pembrolizumab plus/minus T-VEC trial, which is still recruiting. It’s halfway done right now. I think this is a good trial. But as is routine, we cannot use it, simply because the combination is not approved and we are very restrictive with combinations we use when these combinations are not approved.

Jeffrey S. Weber, MD, PhD: But I think everybody does look forward to the results of pembrolizumab plus T-VEC versus pembrolizumab alone.

Transcript Edited for Clarity

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