Myth Busting: Do Systemic Therapies Affect Brain Metastases?

Mark G. Kris, MD


December 08, 2022

This transcript has been edited for clarity.

It's Mark Kris from Memorial Sloan Kettering, speaking today about information I learned at ASCO this year, and also beginning a new series of talks about myth busting. The myth I'd like to break today is that systemic therapies for lung cancers do not affect established brain metastases.

What are the clinical facts? The first is that people who have a brain metastasis have metastatic lung cancer. When you look at the natural history of disease in these people, the greatest risk to their life and health is systemic disease. Even in the presence of brain metastases, most patients still succumb from their systemic disease, so the approach to these patients has to be initiating the most effective systemic therapy as quickly as possible.

Giving them a systemic therapy from the start makes the most sense, not delaying that for any reason. Doing that gives you the best shot at improving long-term outcomes because you're treating the problem that's the greatest risk to them.

What's the biology here? This is where the myth comes. There's a difference between the blood-brain barrier and the blood-tumor barrier. The issue for patients who have established brain metastases is that these therapies have to traverse not the blood-brain barrier, but the blood-tumor barrier. In those cases, the blood-brain barrier is altered and drugs can penetrate.

There's this idea that drugs can't get through no matter what. The penetration is different with the blood-brain barrier and the blood-tumor barrier. The practical consequence of this is that as effective as a drug is systemically, it's going to be that effective in the brain.

That's exactly what was shown in two trials presented at ASCO this year. One was by Josh Sabari, using the drug adagrasib. In that report, there was a response rate in the brain of 32% and a response rate systemically of 37%. These were identical when you looked at the confidence intervals; they overlapped.

The other abstract was by Ernest Nadal. There, the regimen was carboplatin, pemetrexed, and atezolizumab. The response rate systemically was 45% and the response rate in the brain was 42%.

These findings prove the point that as effective as a drug is in the systemic circulation, it's going to be that effective in the brain.

I recommend that when you have a patient with brain metastases at diagnosis, put together your multidisciplinary team. You really need a neurologist and perhaps a neurosurgeon. You have to decide whether there is a serious or critical metastasis that demands immediate attention. Now, that's not usually the case, but when it is, you have to address that and I encourage you to get the help of a neurologist or a neurosurgeon.

The second thing is that you try to initiate systemic therapy with the best regimen possible as quickly as possible. Again, you're going to have the same chance in the brain as you're going to have systemically. It's important that you monitor the brain while you're treating it. I would urge that you monitor the CNS whenever you're monitoring the systemic disease. As we said already, the benefit in one area is going to be mirrored in the other.

I'm not saying that there isn't a role for local therapy; I absolutely believe that. However, I'd ask you to rethink when that is going to happen, and whenever possible, think about approaching the brain as another side of oligo disease. If it is oligo-persistent disease after induction or after a time on therapy, that would be the time to add radiation.

I'm not saying that the blood-brain barrier isn't important. It's very important, and it's critical for preventing brain metastases that have not yet occurred. There, CNS penetration of the drug and the effectiveness of the drug together are critical determinants. That's a different situation and not what I'm talking about today. I'm talking about people with established brain metastases.

I'm busting the myth. If a drug works systemically, it'll work in the brain. You have to give your best drug. With these abstracts, we're talking about penetration to the brain and saying these drugs are good because of that. Yes, they are good, but please remember that those response rates I talked about are still very low.

What we really need are more effective drugs. More effective drugs are going to be the best way to control systemic disease, which is the real risk to life and the health of our patients, as well as CNS disease. They'll happen at the same time.

Mark G. Kris, MD, is chief of the thoracic oncology service and the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center in New York City. His research interests include targeted therapies for lung cancer, multimodality therapy, the development of new anticancer drugs, and symptom management with a focus on preventing emesis.

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