As novel therapies like blinatumomab and ponatinib achieve excellent systemic control of B-ALL, central nervous system (CNS) relapse emerges as a primary hurdle. This was noted in this trial and others, highlighting a critical unmet need to develop effective, non-chemotherapeutic strategies for CNS prophylaxis and treatment.

With new CNS-active drugs dramatically improving survival after a brain metastasis diagnosis, some experts are now advocating for routine screening brain MRIs in high-risk patients. The goal is to detect asymptomatic lesions early, potentially preventing catastrophic neurologic events like seizures.

For patients with otherwise well-controlled disease who develop isolated oligoprogression in the brain, evidence suggests a better survival outcome from adding local therapy (like SRS) and continuing the current effective systemic therapy, rather than switching the systemic regimen entirely.

There is no consensus on managing a patient with stable HR+ disease on endocrine therapy who develops an isolated, treatable brain metastasis. While some oncologists would switch to a CNS-active systemic therapy like TDXD, others advocate for continuing the effective endocrine therapy while managing the brain met locally.

In metastatic TNBC, using sacituzumab govitecan (SG) first-line provides a progression-free survival (PFS) advantage that cannot be regained by using it second-line after initial chemotherapy. The PFS2 data from ASCENT trials shows starting with SG is definitively better than a chemo-first sequence.

The COMPEL trial provides strong evidence for a "treat through progression" strategy. For patients progressing on osimertinib monotherapy, continuing the TKI while adding chemotherapy significantly reduces the probability of CNS progression, highlighting its role as a CNS protectant even when systemic efficacy is waning.

The concept of an impermeable blood-brain barrier is less relevant once brain metastases are established. The barrier becomes highly permeable, or 'leaky,' allowing even large molecules like antibody-drug conjugates (ADCs) to penetrate the CNS. This suggests that any therapy systemically active in the periphery has potential CNS activity.

Zongertinib shows a meaningful intracranial response rate of ~44% in HER2-mutant NSCLC. This efficacy supports initiating systemic TKI therapy for patients with small, asymptomatic brain metastases and monitoring closely with short-interval scans, potentially avoiding or delaying brain radiation and its associated toxicities.

For EGFR-mutated NSCLC patients with brain metastases, even numerous ones (>30), potent systemic therapy like osimertinib plus chemotherapy is often initiated first. This can achieve high rates of complete intracranial response, allowing clinicians to delay or entirely avoid whole-brain radiation and its long-term toxicities.