Intracranial Response Rates from RET Inhibitors

Jared Weiss, MD: Let’s focus on brain metastases, because these are a major source of harm to our patients.

Benjamin P. Levy, MD: You and I again have had a lot of experience in the trial with selpercatinib. We've seen it firsthand, and we've obviously read it here, and CNS [central nervous system] metastases are sometimes the bane of our existence, specifically for patients without drivers. We're challenged always, and we try so hard not to give whole brain radiation to patients anymore, and radiation oncologists are finally on board with this in some ways, the advent of novel radiation techniques. Can you give your experience with CNS metastases for RET fusion–positive patients and what we think the prevalence is, and how important is it that we can give these drugs that elicit meaningful responses in the brain?

Jared Weiss, MD: Our patients care the most about quality of life, right? They tell us that again and again. In terms of quality of life, of course we need to think about the harm from the disease and the harm from the treatments. In terms of the harm from the disease, the brain is tightly packed upon itself. It's densely packed in there, and any extra mass, such as from cancer, can cost terrible suffering, headaches, nausea, vomiting, confusion, falls. Brain metastases are a big deal in terms of the suffering they cause. And you mentioned the toxicity of whole brain [radiation], that manifests itself over time. In the era when all we had was chemotherapy, unfortunately our patients didn't live long enough to really manifest those neurocognitive effects and be harmed all that much by them, and so we didn’t worry about it that much. Happily, we now have this new problem that we have patients living for years, and over those years they suffer much more from the effects of whole brain [radiation].

In terms of frequency of the problem, our friend and colleague from New York, Alex Drilon, MD, has looked at this rigorously. You mentioned the problem with ALK. He looked at ALK, RET, and ROS1, I believe. And numerically, as we all see in practice, ALK was the highest for cumulative incidence of brain metastases. RET was somewhere in between, and ROS1 was the least. Zooming in on RET, that study found that a quarter of RET patients will have metastases at diagnosis, and 46% will have metastases at some point in their lives. That sounds about right to me.

My experience is consistent with the trial, which is that when you treat patients with one of these agents who have brain metastases, just like the other brain-penetrating agents, like osimertinib against EGFR, or alectinib against ALK, you see dramatic intracranial efficacy. It's quick, it works, and so for all but my most dramatic CNS presentations, I'm using upfront TKIs [tyrosine kinase inhibitors] when I find brain metastases.

Benjamin P. Levy, MD: I would agree, well stated. A response rate for selpercatinib in the brain of 90%. It’s a small number of patients, but this mirrors, like you said, some of the data we've seen in other genotypes, and brain metastases are prevalent. These mutations have a tropism to go to the brain. These cells that harbor this mutation have a tropism for the brain. It has altered the way that we handle these patients, and the way that we also communicate with our radiation oncologists, and the way that we communicate with patients. I would agree.

My experience in many of the patients who we had, at least on the selpercatinib study, is that these responses happened quickly. They're durable, they're meaningful, they circumvent the need for even SRS [stereotactic radiosurgery], or whole brain radiation, or steroids, all of these things that impact quality of life. You and I can agree we're playing the long game with these patients, and it's important, we're not playing the short, 3-inning game. It's trying to figure out how we can sequence therapies and give the best therapies in an ultra-thon, not even a marathon. I think that all targeted therapies have, especially for patients with brain metastases, altered the treatment paradigm and altered the way that we navigate patients through treatment. It's been certainly a welcome change.

Jared Weiss, MD: I agree with all that. The only thing I would add as an educational point is that if you're using a TKI to control brain metastases, you need to survey the brain frequently. In my practice, for RET, that means every 3 months. I don't know, do you survey any more or less frequently than that?

Benjamin P. Levy, MD: No, that's right based on the data, I try to get an MRI for patients with known brain metastases every 12 weeks or 3 months. If they don't have brain metastases, and I'm surveilling, I'd probably do it every 6 months, but I don't think we have any great data on that, and we need to be careful with these patients.

Transcript Edited for Clarity