Rethinking Clinical Trial Design to Include Patients With Brain Metastases

Patients with brain metastases have historically been excluded from a large share of oncology clinical trials. That exclusion has left much of the field’s evidence for central nervous system (CNS) drug activity resting on indirect signals, such as first site of disease failure, in trials that mandated local therapy before starting systemic treatment, rather than data generated directly in populations with active brain metastases.

In an interview with CancerNetwork® at the 2026 SNO ASCO CNS Metastases Conference in Boston, MA, Lizza Hendriks, MD, PhD, said that continuing to exclude these patients is no longer ethical once an early-phase signal of CNS activity exists. Hendriks described how relying on extrapolated phase 3 data creates ambiguity, as trial designs that require local therapy before systemic treatment make it impossible to know whether a local or systemic intervention produced a given response.

Hendriks laid out a phase-by-phase framework for correcting this, beginning with rational inclusion of patients with brain metastases as soon as a phase 1 signal of general efficacy is established, followed by a dedicated brain metastases cohort, with or without leptomeningeal involvement. She also connected this discussion to the FDA’s Project Optimus initiative, noting that as sponsors explore lower doses to improve tolerability, those doses must still be evaluated for adequate CNS efficacy, as a lower systemic dose can carry reduced activity in the brain.

Hendriks is a 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.

Transcript:

CancerNetwork: 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?

Hendriks: 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. 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. [Alternatively], 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.

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 the FDA now 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.