Multimodality Approach Best for CNS Disease in NSCLC

Partner | Cancer Centers | <b>Yale Cancer Center</b>

Sarah B. Goldberg, MD, MPH, sheds light on the complex treatment paradigm for patients with lung cancer who have central nervous system metastases and highlights emerging treatment strategies for those with mesothelioma.

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.

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

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.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.

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

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.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.

How do approaches differ for patients with rarer driver mutations?

For ALK-positive NSCLC, there are several different ALK inhibitors available for use. Even if 1 agent has failed, sometimes another might be effective—even in the brain. As such, that could still be an option for patients even with progression on an ALK inhibitor.It gets more complicated [with these patients] because we have less data available. For these mutations, we know a lot less, but we are starting to understand that there probably will be activity in the brain for several of the drugs we use.

For example, with BRAF mutations, we use dabrafenib (Tafinlar) and trametinib (Mekinist). As far as I know, we have not seen CNS activity in lung cancer, but we know the drugs have good activity in melanoma. Therefore, this could be considered an option for these patients.

Is there a role for immunotherapy in these patients?

In other alterations, such as ROS1 and MET, there have been some studies that have shown benefit to the newer targeted drugs. However, until there are more data, it is hard to say that is the strategy that should be used. What is important to consider is if the drug not only has benefit but also, CNS penetration. It is not true that every drug has CNS penetration, although most of the newer drugs do.Immunotherapy is not typically active in patients with oncogene-driven tumors, regardless of CNS involvement. This is well-established in the EGFR- and ALK-positive space, where response rates to single-agent immunotherapy are well under 10%. Specifically, for patients with brain metastases, I would not trust that immunotherapy would be effective because I am not even sure that I would trust it in general. [This approach] is not one that I would use in earlier settings; if used at all, I would reserve it for the later lines of treatment. Other subsets of lung cancer with driver mutations may derive more benefit from immunotherapy, but again, we do not know much about the CNS response.

You also presented on mesothelioma at the 16th Annual Winter Lung Cancer Conference. What should be highlighted in that space?

Traditionally, what have been the treatment approaches for patients with mesothelioma and what strategies are on the horizon?

We are seeing some brain responses with immunotherapy in general, so we are taking driver mutations out of the equation. However, for us to use this approach in this space, we would need to see patients with driver mutations respond irrespective of CNS involvement.Mesothelioma is an extremely rare disease and we typically see it in patients who have had asbestos exposure. Occasionally, however, we will see it in patients who do not recall any history of asbestos exposure. This disease can be difficult to diagnosis because sometimes patients will have shortness of breath or experience pulmonary symptoms and be found to have pleural effusions. Sometimes, draining the pleural effusions does not show any evidence of cancer. I have seen patients go on for many months before a diagnosis has been made. Oftentimes, diagnosing mesothelioma requires a biopsy of the pleura itself. The disease often presents in an advanced stage; as such, it can rarely be considered a surgical disease.For more advanced disease or unresectable mesothelioma—the patients we most commonly see—chemotherapy does have activity. The standard chemotherapy we use for upfront treatment is cisplatin plus pemetrexed, but sometimes we will swap out cisplatin for carboplatin because of the toxicity. There was a study conducted a few years ago in which investigators added bevacizumab (Avastin) to cisplatin and pemetrexed. This approach improved survival by a few months, so that is also an option for patients. However, the majority of the patients in this population are not candidates for bevacizumab. Typically, [bevacizumab] is omitted from the regimen.

An important emerging strategy is to consider immunotherapy for these patients. Immunotherapy has been tested in mesothelioma after progression on frontline chemotherapy, and there does seem to be good activity in patients. Response rates vary, but we are seeing data on the order of 30%. There are many other studies looking at combinations of immunotherapy and chemotherapy plus immunotherapy in the frontline setting, but we are waiting on [more data from those trials]. Thus far, we know that single-agent immunotherapy can have benefit.


  1. Kim D-W, Tiseo M, Ahn M-J, et al. Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): First report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA). J Clin Oncol. 2016;34 (suppl; abstr 9007).
  2. Goss G, Tsai CM, Shepherd FA, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018;29(3):687-693. doi: 10.1093/annonc/mdx820.