The Use of TKIs in Patients With Brain Metastases

Edgardo S. Santos Castillero, MD, FACP: One of the problems that is critical for these EGFR patients is, as you know, 20% to 30% of patients with this disease present with brain metastases. Brain metastases is something that could be the Achilles tendon for these patients. Can you tell us more about that? For example, if a patient has a brain metastases, asymptomatic or with symptoms, would you give a chance to the patient to respond to osimertinib? As you know, that is responding quickly, or do you go with stereotactic radiosurgery, like CyberKnife? Tell us about your management of early brain metastases asymptomatic patients.

John V. Heymach, MD, PhD: This is a great question. We have a lot of debates about this. I’m sure you do too, Eddie. In fact, we had 1 this week. What’s commonly happening is that somebody presents with 1 or 2 small brain metastases. My approach, because osimertinib has such good CNS [central nervous system] penetration, is if they’re small and asymptomatic, I offer the patient the option of not getting radiation up front and just using osimertinib. It’s interesting that some patients very much like this because they want to avoid radiation. Some are concerned and want the security of getting the radiation first.

The situation we’ve had recently—and I’m sure you’ve run into this situation as well—is if we’re staging a patient, and we don’t know if they have EGFR mutation, and you find that there’s brain metastases. In this case, we referred the patient to our neuro-oncology group, and they’re a wonderful group. They’re great at giving gamma knife. They can get it ready to go, and the result comes back and says “EGFR mutation.” In 1 case, we literally had the patient going into the room. Then the question is this: Do you pull the patient out of the room and say, “Listen, let’s wait a couple of months and see if you need it?” Or do you go ahead with the radiation up front?

Nowadays, I try to get the EGFR result back before I do radiation because you can avoid radiation in a lot of patients or avoid it for a long time by just starting with osimertinib. The responses are good.

There are a couple of other issues that come up. One example we had with the patient was this: They were all set up for radiation, we got the result back, and they said, “I’ll just go ahead with the radiation.” Sure enough, that ended up being a patient who developed radiation necrosis later, and we spent months dealing with radiation necrosis. Even though the gamma knife worked beautifully, it’s not a free lunch. It’s much better tolerated than whole-brain radiation, but you do get radiation necrosis and other toxicities from it. This patient has been dealing with radiation necrosis for months now as a result, so I wish we had stopped and given the osimertinib there as well.

The other situation is this: What if they’re symptomatic? I’ve had some cases where somebody may be symptomatic, but they may not be. If you ask them, “Have you had headaches lately?” They may respond, “Yeah, I have had headaches. Maybe I’ve had a bit of double vision now that you mention it, but it hadn’t been bothering me. I thought I just needed new glasses.” This is often the situation if somebody is mildly symptomatic. Do you give the TKI a chance? I would often consider it. On the other hand, at least my approach is this: If I see that somebody has gotten serious brain metastases with a lot of edema, if it’s causing dilation of their ventricles, or if it’s near their brain stem or something else and I feel like we’ve got very little margin to wait, I tend be safer and go ahead with the radiation right away while I’m doing the tyrosine kinase inhibitor. That’s the approach I’ve taken, but osimertinib clearly does have good CNS activity.

Another issue to mention is what dose to use. There was a study called BLOOM that tested a higher dose instead of the standard 80-mg dose. They went to 160 mg of osimertinib. For me, that’s something I consider with my patients with brain metastases: going to the higher dose, just because you’ll get better levels in the CNS of the drug as well. Even though 80 mg is the approved dose, I at least consider the higher dose if I’m concerned that somebody has got serious brain metastases. This is an area we still struggle with all the time. What’s your approach if somebody is asymptomatic up front with new brain metastases?

Edgardo S. Santos Castillero, MD, FACP: As you said, there are symptoms that tell you that we better move with CyberKnife depending on the lesions and the locations. That is critical. Another area that is a concern for me is the cerebellum because that is a critical area. It has vital functions for a human being located in the cerebellum, and it is easy for the patient to get into trouble. If there are cerebellum lesions, I may go quickly with a CyberKnife or gamma knife depending on how many lesions they have.

I agree with you. It depends on what kind of symptoms the patient describes. With so many patients we see in clinic with lung cancer, I still haven’t seen any case in which I need to use, for example, osimertinib double dose because of leptomeningeal disease, for example. I have not had that case, thank God, because you know those are difficult cases to treat. I didn’t have the chance to use the 160-mg dose, but that would be my approach. If the patient has symptoms, go deep on the history prior to jumping immediately to the radiation therapy. I totally agree in that sense with you also.

Transcript edited for clarity.