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Multimodality Approach Best for CNS Disease in NSCLC

Brandon Scalea
Published: Monday, Feb 18, 2019

Sarah B. Goldberg, MD
Sarah B. Goldberg, MD
Radiation is still a staple in the treatment of patients with lung cancer who develop central nervous system (CNS) metastases, but novel targeted therapies are also showing promising CNS activity, said Sarah B. Goldberg, MD, MPH.

For example, in patients with ALK-positive non–small cell lung cancer (NSCLC), results from the ALTA trial showed that the use of brigatinib (Alunbrig) not only extended progression-free survival (PFS), but also demonstrated intracranial responses. As a result of these encouraging data, brigatinib received an accelerated approval from the FDA in April 2017 for use in patients with metastatic ALK-positive disease who are resistant to prior crizotinib (Xalkori).

Results showed that the confirmed objective response rate (ORR) for brigatinib at 180 mg daily was 53% (95% CI, 43-62) and the median PFS was 13.8 months.1 Specifically, in those with measurable, active brain metastases who were treated with the 180-mg dose (n = 18), the intracranial ORR was 67%. In patients with brain metastases treated with a 90-mg dose of brigatinib (n = 26), the intracranial ORR was 42% (95% CI, 23-63).

In the EGFR-positive space, osimertinib (Tagrisso) has emerged as an effective CNS-active drug. In an analysis of 2 phase II trials of patients with T790M-positive advanced NSCLC and CNS metastases, the disease control rates in the CNS was 92% with osimertinib.2

Goldberg, an assistant professor of medicine at Yale Cancer Center, also discussed approaches in development for the treatment of patients with the very rare, aggressive cancer mesothelioma. In patients with advanced disease or unresectable mesothelioma, chemotherapy has been found to have activity. However, in those who have progressed on frontline chemotherapy, immunotherapy is another important emerging approach to consider.

In an interview with OncLive, Goldberg shed light on the complex treatment paradigm for patients with lung cancer who have CNS metastases and highlighted emerging treatment strategies for those with mesothelioma.

OncLive: What are the current approaches for managing CNS disease in patients with oncogene-driven lung cancer?

Goldberg: Brain metastases are, unfortunately, very common for patients with lung cancer in general; this is probably even more true for patients with oncogene-driven tumors—specifically those with EGFR and ALK abnormalities. There are several options available for patients with brain metastases.

The historic option has always been radiation; this is usually our approach for patients without oncogenic drivers. Radiation [approaches] could either be stereotactic radiosurgery or whole brain radiation. However, an important additional option to consider for patients with oncogene-driven NSCLC is targeted therapy, especially in patients where a targeted therapy is available with known CNS activity. So, these are the main options: radiation—specifically stereotactic radiosurgery—or targeted therapy.

Osimertinib is a drug with known CNS activity, but what is next for those who progress on that TKI?

This is a very complicated question. Before talking about time of progression, we need to decide which patients should receive which strategies: radiation or targeted therapy. For a drug like osimertinib, that has excellent CNS activity, patients can have very high response rates as well as improvement in disease burden in the brain and body. The durability of the brain metastasis response and the systemic disease response can be quite high. In those cases, I often will consider waiting on brain radiation, especially if the lesions are small and in a location that is not particularly concerning, or if the patient is asymptomatic. I might consider treating [the patient] with an EGFR TKI, such as osimertinib alone, in that case.

The question of progression and resistance is one that does come up, unfortunately, because even in the cases where we have an excellent drug that has great activity in the brain, resistance does still develop. Sometimes it develops in the body and the brain is still controlled. Sometimes the brain metastases progress and new lesions develop.

If the brain is progressing alone and the body is still controlled, radiation could be considered with continuation of the EGFR inhibitor. That approach has been evaluated more in retrospective studies with earlier-generation TKIs, but it is still an option to consider. Otherwise, if there is overall progression that includes CNS progression, there may need to be a change in systemic therapy anyway. In those cases, if the patient has not had radiation—or even if they had—radiation is probably still a good strategy before switching their systemic therapy.




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