From Moonshot to Ground Shot: Advancing CNS Metastases Care

At the 2026 SNO ASCO CNS Metastases Conference, Lizza Hendriks, MD, PhD, delivered a keynote speech to a room full of peers and colleagues about how the entire treatment landscape of central nervous system (CNS) metastases can evolve. Later, in an interview with CancerNetwork®, she discussed the conceptual shift she believes the CNS metastases field needs to make, and how much progress has been made in overcoming the blood-brain barrier as a treatment obstacle. She also addressed how clinical trial exclusion of patients with brain metastases affects the field’s evidence base, as well as which outdated standards of practice persist in current guidelines, the importance of integrated multidisciplinary care, and the biggest remaining gap between what is scientifically possible and what is being done in clinical practice.

Hendriks is a pulmonologist and professor of thoracic oncology at Maastricht University Medical Center+ in the Netherlands, where she leads the clinical lung cancer research department and chairs the Innovative Cancer Diagnostics Therapy group at the GROW School for Oncology and Developmental Biology at Maastricht University. Her research focuses on brain metastases in patients with lung cancer.

CancerNetwork: What was the topic of your keynote speech?

Hendriks: The whole conference centers around the concept “From moonshot to ground shot”. I centered my presentation on this topic, to see how we can evolve in treating and preventing brain metastases, with a focus on lung cancer.

What would you say is the biggest conceptual shift you think the CNS metastases treatment field needs to make right now?

We need to look more at the patient as a whole ecosystem. Not only looking at the brain metastases, but at the tumor microenvironment, body composition, and the immune system of the patient, and not treat brain metastases as a single entity, but consider the patient as a whole.

What would it take to achieve that? Would it be extra funding, or just more concentrated efforts?

Probably all of it, but I think multidisciplinary collaboration—”from bench to bedside”, like we heard already multiple examples of at this conference—is very relevant. Academic collaboration, but also collaborations with industry, and very importantly, patient input, [are significant as well]. In the end, if we all work together and combine data, then we can get somewhere.

The blood-brain barrier has been a defining obstacle in treating brain metastases for decades. How much of that barrier problem is solved today with newer CNS-penetrating systemic therapies, and how much remains unsolved?

It’s really improving. You need to invite even prevention of brain metastases and treating of brain metastases [into the conversation], because if you treat brain metastases, the blood-brain barrier and the blood-tumor barrier is compromised, and even less CNS-penetrating agents can reach the brain metastases and induce a response, although often it’s not durable. With better CNS-penetrating agents—mainly tyrosine kinase inhibitors [TKIs], but also immune checkpoint inhibitors, where the T cells cross the blood-brain barrier—it’s becoming less of an issue, and we have better and longer CNS control. What I also see in early-stage clinical trials is that starting adjuvant CNS-penetrating TKI, or starting adjuvant immune checkpoint inhibitors, really reduces the incidence of brain metastases for these patient populations.

A lot of pivotal trials will exclude, or include fewer, patients with brain metastases. How much of the field’s evidence base do you think is affected by that?

First, I would like to start by saying that it’s not ethical to exclude these patients. If you have, in early-phase clinical trials, a signal that the drug is effective in the CNS, you should allow these patients in. Of course, you can have some limitations, that, for example, patients with symptoms are excluded, or are only enrolled in a specific cohort, but I think we need to put all our efforts into proving early that a drug is effective in the CNS, and then allow these patients in.

Currently, we quite often have clinical data extrapolated from a phase 3 clinical trial, where, for example, it is suggested that a drug is effective in the CNS. But if you mandate local therapy upfront and then start a systemic therapy, you never know whether the local therapy or the systemic therapy induced the response. Or if you look at, for example, the first site of disease failure, of course, if the patient doesn’t have a relapse in the brain, then the drug is [likely] effective in the brain. But this is not a way to move forward. We really should start from phase 1 to rationally get data for patients with CNS metastases.

So starting in phase 1 would be the best way to begin including these patients?

Yes. This is also what the Torino Group advocates. If you have your phase 1, and you get a signal for efficacy in general, then you need to start a specific brain metastases cohort, with or without leptomeningeal metastases. If you have a signal in the brain, you can even further evaluate the best dose to treat the brain metastases, because now the FDA has Project Optimus, to see whether you can lower those specific drug doses. But it could compromise the results in the CNS, because sometimes a lower dose has less CNS efficacy. We also need to find the best phase 2 dose specifically for CNS metastases, and then have to randomize a clinical trial with CNS-specific end points incorporated to really show efficacy in the brain.

Is there a standard practice that still exists in brain metastases management that might be a bit outdated?

It is still in the guidelines, but I think upfront brain radiotherapy is quite often recommended without taking into account all the actionable genomic alterations and therapies we have. This has historically been in the guidelines because most previous systemic therapies were not CNS active, but we’re now seeing more data that targeted agents, but also immune checkpoint inhibitors, have efficacy in the CNS. Of course, we cannot change our clinical guidelines before we have randomized evidence that show omitting upfront radiotherapy is the best way to move forward, but for CNS-penetrating TKIs, for example, for osimertinib [Tagrisso], we now have data that, especially for patients with small brain metastases, it is safe to omit upfront radiotherapy and continue the TKI. Of course, with CNS monitoring. But with this strategy, you can spare the risk of radiation necrosis for at least subgroups of patients.

What is the importance of integrated multidisciplinary care when treating someone with brain metastases?

It’s very important. For me, all patients with CNS metastases deserve a dedicated [multidisciplinary team (MDT)] discussion, so with a neurosurgeon, a neuroradiologist, a radiation oncologist, someone who knows about systemic therapy efficacy also in the brain, preferably also nurses, et cetera, with input from the patient. There is indeed some data that when patients are discussed in an MDT, in a significant percentage of these patients, the treatment proposal changes. It’s biased data, but there are also hints that survival improves for these patients. These patients deserve an MDT discussion, and it’s also a quite easy and cheap way to improve care for our patients.

Ae there any places where you see gaps, universally, between radiation oncologists and medical oncologists in that multidisciplinary care?

I think we still need to educate each other. Radiation oncologists don’t always know about the intracranial efficacy of our drugs. On the other hand, I think as people prescribing systemic therapy, we don’t always know the effects of specific radiotherapy techniques and whether it’s safe or not to omit radiotherapy. Also, for neurosurgery, at least in the Netherlands, we quite often overlook neurosurgeons. There is a bigger place for neurosurgery [in care]. We really need to educate each other.

What we did in our institution, in our region, is have care pathways really written down, as well as what’s the effect of systemic therapy, contraindications for radiotherapy, and indications for surgery. That way, even when you cannot attend the MDT, or if you need to make an emergency decision, at least you have the care pathway to fall back on, to have some evidence-based guidance.

What’s the biggest gap remaining between what’s scientifically possible and what’s done in clinical practice right now?

Increasing the molecular subtyping of patients. We can do a lot, we can test a lot, but if you subdivide according to specific mutations, for example, EGFR mutations are a very heterogeneous group of mutations, where we know that even for classical activating mutations there are differences in sensitivity to TKIs. We have the co-mutations, et cetera. To get real evidence for all these specific patient populations, it’s very difficult, although I think we have the drugs to test them.

Broadly, what trials in CNS metastases are you most excited for? What upcoming advancements excite you most in the space?

Well, to advertise for my own clinical trial, we have an upcoming trial with the EORTC Lung Cancer Group, in collaboration with the brain tumor group and the quality of life and translational committee, to evaluate ivonescimab, the bispecific against VEGF and PD-1, and to evaluate the best treatment sequence—upfront radiotherapy or upfront systemic therapy—with intracranial progression-free survival as the primary endpoint. We also have very meaningful secondary end points like time to next CNS intervention, time to next line of systemic therapy. This is quite interesting.

Also, [there are great] trials from colleagues, for example, the Swiss colleagues. I showed a trial [NCT06620380] during the keynote where they used pharmacoscopy to evaluate new drugs for patients with brain metastases who have exhausted all other treatment options. They resect the brain metastasis, then they test multiple drugs at the same time on the resected specimen, and then the drug with the best predicted efficacy is given to the patient. I think this is a very exciting field, and I look forward to seeing more data.

Reference

Hendriks L. Breaking barriers, redefining brain metastases treatment concepts. Presented at the 2026 SNO/ASCO CNS Metastases Conferece; August 13-15, 2026; Boston, MA.