Systemic Therapy Choice Linked to Radiosurgery Outcomes in Brain Mets

Advancements in treating brain metastases often center on stereotactic radiosurgery (SRS), the established standard of care. However, research from Rupesh Kotecha, MD, and the Miami Cancer Institute has shown that systemic therapy selection plays a pivotal role in improving outcomes for these patients.¹

By categorizing therapies based on their ability to penetrate the central nervous system (CNS), a study which analyzed 101 patients with lung cancer treated for 524 brain metastases highlights a compelling progression. Notably, higher CNS activity was shown to correlate with significantly longer intracranial progression-free survival (PFS).

This discovery challenges traditional perspectives, emphasizing the importance of tailoring systemic therapies not just for systemic disease control but also for optimizing brain metastasis outcomes.

In an interview with Targeted Oncology^TM, Kotecha, chief of radiosurgery and director of central nervous system metastasis with Baptist Health Miami Cancer Institute, provided an overview of the study, its findings, and clinical implications.

Lung with cancer cells: © catalin - stock.adobe.com

Targeted Oncology: Can you summarize the key objectives and research on systemic therapy selection and its impact on brain metastases outcomes?

Kotecha: In general, when we consider treatment for brain metastases, although stereotactic radiosurgery is essentially the standard of care, the systemic therapy decisions and their impact on overall patient outcomes must also be taken into account. All of these patients have metastatic disease, so they should receive, and do receive, a variety of systemic therapy agents.

At Miami Cancer Institute, we have a large population of [patients with] lung cancer brain metastases. When we review our data, about two-thirds of our [patients with] brain metastases have lung cancer as the primary tumor. This is slightly higher than the national average, where approximately 50% of brain metastases cases are from lung cancer.

Given our diverse patient population and the fact that lung cancer represents the largest proportion of patients treated with radiosurgery, we recognized the importance of examining the impact of systemic therapy selection on brain metastases outcomes. Additionally, the diversity within our lung cancer population translates into a variety of molecularly profiled subtypes, further underscoring the need to assess this relationship.

Who was included and what types of systemic therapies were evaluated?

We included 101 [patients with] lung cancer, 75% of whom were Hispanic, and they were treated for 524 brain metastases. To evaluate systemic therapies, we did not analyze individual agents due to the immense variation across 100 patients. Instead, we grouped them into categories, a method we had previously published when studying systemic therapies and their intracranial responses in the literature. The therapies were categorized based on CNS penetration: low penetration (<25%), intermediate penetration (25%-50%), and high penetration (>50%). Patients were placed into one of these categories, allowing us to evaluate their systemic therapy group.

For this study, we examined 3 key outcomes: intracranial PFS, overall survival (OS), and the response rate following radiosurgery.

Could you go over the findings from this study?

We found that the systemic therapy choice had a specific correlation with intracranial progression-free survival. For instance, patients treated with chemotherapy alone, chemotherapy plus immunotherapy, or chemotherapy with targeted therapies showed distinct differences in intracranial PFS. Similarly, patients without prior, concurrent, or future systemic therapy exhibited different outcomes. Patients receiving therapies with the highest CNS penetration had an intracranial PFS of 16 months, compared with just 3 months for those without systemic therapy. Low CNS activity agents provided 4 months of PFS, while intermediate agents offered 8 months. This progression—from none (3 months), to low (4 months), to intermediate (8 months), to high (16 months)—demonstrates a clear improvement in intracranial PFS as CNS activity increased.

There are 2 important takeaways from that. One, it validates our initial categorization that we had come up with years earlier in categorizing systemic therapy agents. Number 2 is that it means we should think about following patients more closely, or that patients are at higher risk of failure if they are not receiving CNS-active agents. Obviously, whenever possible, we should give patients agents that have the best intracranial activity once they are diagnosed with brain metastases.

What areas of future research do you believe are important to further understand this relationship between systemic therapy and brain metastases outcomes?

The key point is that integrating PFS was an end point in this study. Interestingly, the proportion of patients who had a complete or partial response to their brain metastases did not differ significantly based on the activity of the agent. If you look at the low-, intermediate-, and high-CNS activity agents, the intracranial response rates were 55%, 59%, and 50%, respectively, so there was no correlation with their response. This indicates that the response is primarily driven by the radiosurgery, while systemic therapy is improving the overall intracranial PFS of the patient.

Now, this does translate to some differences in OS. However, further research is needed to tease this out. What is the pattern of failure being affected by the use of different CNS-active agents? It is not the initial response in the brain metastasis, so it must be the response elsewhere.

As we make systemic therapy selections, I think this data will become increasingly important—particularly as patients transition to receiving systemic therapy alone. This raises the need to revisit what is actually impacting intracranial PFS, the response patterns, and OS in our patient population. If all patients receive stereotactic radiosurgery and we remove that from the equation, what would the differences in the data or results be? I think this is a subject for future research and of specific interest to us.

REFERENCE:

La Rosa A, Yarlagadda S, Kutuk T, et al. Impact of systemic therapy selection on brain metastasis outcomes in lung cancer patients treated with stereotactic radiosurgery. Abstract presented at: 2024 American Society for Radiation Oncology Annual Meeting; September 29-October 2, 2024; Washington, DC. Abstract 2551.