Brain metastases are a common complication in patients with non–small cell lung cancer (NSCLC) and are challenging to treat. Recently, several immunotherapies and targeted agents have shown activity for NSCLC brain metastases.

Approximately 20% of patients with NSCLC present with brain metastases at the time of diagnosis, and, over the course of the disease, approximately 25% to 50% of patients with NSCLC develop brain metastases. The brain has classically been considered somewhat of a sanctuary site, meaning that tumor cells in the brain may be partially protected from drugs due to the blood-brain barrier. This is a major area in lung cancer research because brain metastases are a source of substantial morbidity. Once a patient has them, they are very difficult to eradicate. So, targeting brain disease is critical.

Gamma Knife surgery delivers highly focused radiation to tumors in the brain. For patients who have too many lesions to individually radiate, we can use whole-brain radiation, which can be quite toxic. In terms of systemic therapies, some of the tyrosine kinase inhibitors seem to work well, and there is definitely some benefit to immunotherapy in this setting as well. Many of our treatments do not penetrate the blood-brain barrier, and, even if they get through, they have to be in an unbound form to work. I do not think that chemotherapy works well on the brain. Thus, I think that patients with brain metastases need a targeted therapy or immunotherapy.

We know that immunotherapy works in the brain with antibodies and T cells—checkpoint inhibitors and modified T cells—that are able to get across the blood-brain barrier. With respect to targeted agents, osimertinib was associated with fewer brain metastases in the ADAURA trial, which is a very exciting and interesting result. Regarding TKIs for ALK – and, essentially, all of the newer-generation TKIs that are being developed for advanced NSCLC, they are being brought forward with that in mind (ie, the need to reach the brain).

If a patient only has a couple of brain metastases and they are less than 2 cm in diameter, I would probably be comfortable starting with immunotherapy and watching. We always try to do that if we can in an attempt to preserve a patient’s cognition as much as possible. But if you have therapy that you know is going to work, at some point, you just cannot do that. And, if the tumors are much larger than that or if there are a lot of them, I would probably radiate the brain and use Gamma Knife if I could before starting immunotherapy. If a patient has a molecular driver that can be targeted and they are asymptomatic, sometimes we will use osimertinib before giving them a significant amount of radiation.

Overall, we are seeing real progress in this disease, although there is still a lot of work to do. With targeted immunotherapy, we are able to target both systemic and brain disease, and the key is to move it earlier in the course of the disease to achieve even greater effects.