Navigating Treatment Decisions in EGFR-Mutated Non–Small Cell Lung Cancer With Brain Metastases

Edward Garon, MD, University of California, Los Angeles, discusses the management of a patient with EGFR L858R-mutated non-small cell lung cancer (NSCLC), brain metastases, and suspected leptomeningeal disease to illustrate how central nervous system involvement influences diagnostic and treatment decisions.

He reviews his rationale for deferring upfront radiation and additional testing for leptomeningeal disease while discussing first-line options, including osimertinib alone, osimertinib plus chemotherapy, and amivantamab plus lazertinib. He also explains how symptom burden, patient preferences, and the anticipated impact of further testing informed his decision to initiate osimertinib followed by carboplatin and pemetrexed, with plans to continue maintenance osimertinib plus pemetrexed.

Transcript: 

Hello, this is Edward Garon from the David Geffen School of Medicine at UCLA. I want to present this case, I thought it was a little bit interesting in the setting of our current treatment paradigm, both from a diagnostic question as well as a therapeutic question.

The patient in question is a woman in her mid-60s. She presented really with a cough, the cough she described as being sort of bothersome increasingly over a few months. In addition, when being questioned by her primary care physician, the patient noted an approximate 10-pound weight loss over the past few months that was associated with a decrease in appetite. The patient also noted ringing in the ears, that was a significant symptom for the patient. She considered it to be worse on the left and described what she felt was some forgetfulness as well as a sense of disequilibrium.

The primary care physician, to work up the cough, obtained a chest X-ray. It wasn’t expected by the physician that much would be found, but it was concerning for multifocal pneumonia, although in the radiologist’s differential, there was concern for potential malignancy. Follow-up CT scan showed multiple nodules in the lungs. This was a CT of the chest, the largest one was nearly 4 centimeters. It was biopsied and was consistent with an adenocarcinoma of the lung. The molecular studies came back and showed an L858R mutation in the EGFR gene. 

As part of the workup, an MRI of the brain was obtained, and that showed multiple subcentimeter enhancing foci that were consistent with brain metastases. In addition, there were several foci that the radiologist noted of sulcal enhancement in the posterior fossa. These are felt to be concerning for leptomeningeal disease. The patient actually had been referred initially to surgery, surgery seemed very doubtful even before the MRI, but the MRI came back sort of right as the patient was seeing the surgeon. The patient was then referred to see me, and from my perspective, I think this raised a few questions. One, this is a patient with known brain metastases, do you refer the patient to radiation oncology for consideration of radiation? Two, this is a patient where there is at least a suggestion of leptomeningeal disease on the scans, do you perform additional testing, such as either an MRI of the spine or sampling with a lumbar puncture to look for leptomeningeal disease? Or do you just proceed with treatment? And then the third question really is, at the time of proceeding with treatment in a patient with known brain metastases and potentially leptomeningeal disease, choosing between either single-agent osimertinib, osimertinib along with chemotherapy, or the combination of amivantamab and lazertinib.

So I’ll go through the way that I addressed each of these three questions. There, as you can imagine, in a case like this, are no right, no wrong answers.

First, in terms of radiation oncology, I did not refer the patient to radiation oncology in this case. I think that we have moved away from radiation frequently in the upfront setting in patients with known driver oncogene–positive disease, particularly EGFR-mutant disease. Certainly in patients with innumerable brain metastases where whole-brain radiation really would be the only appropriate treatment, that is a situation where I definitely have shied away from radiation. I think that there are some cases in between where there are a small number of larger lesions. But in this case, noting that there were several fairly small lesions, along with this question of leptomeningeal disease, I opted not to refer the patient to radiation oncology.

The second question is whether to work up the potential leptomeningeal disease further. In this case, I chose not to work this up further. I have a major focus in biomarkers and one of the rules I always tell people when they’re trying to develop a biomarker, particularly someone from industry, is you’re not going to generate a lot of enthusiasm with a biomarker that the result is something people don’t want to have. The more definitive diagnosis of leptomeningeal disease is not something I’m necessarily looking to have in this case, and don’t know how helpful it will be. 

We know that leptomeningeal disease is often difficult to find on a lumbar puncture. It frequently comes back negative, and that goes into my consideration somewhat, and the question then becomes, what will I do if disease is positive? Hopefully someday I will present a case like this, and we will have good therapies for a disease that involves the leptomeninges, and as a result, I would want to know that this does in fact involve those areas so that I could treat the patient more effectively. But right now, I didn’t suspect that it was likely to change my overall treatment plan, which was going to be a treatment plan that included EGFR-directed therapy.

In choosing between the three options, it’s interesting because historically we’ve tended to diagnose leptomeningeal disease in patients who were at advanced stages of disease with multiple prior therapies. We are now seeing in some cases where even in an upfront diagnosis we will have evidence of leptomeningeal disease. In previously treated patients, I often had a bias of not treating systemically or not being enthusiastic about treating systemically, noting that really the patient’s life expectancy was largely going to be driven by the disease in the central nervous system. However, with improvements in targeted therapies, we know that some patients can do quite well for a significant period of time with effective treatment, systemic treatment, that targets the EGFR gene. In this case, the patient was very eager to start therapy. They were feeling quite lousy, so among the three very reasonable options, I started with osimertinib with the plan to add in chemotherapy as soon as we were able to get insurance authorization.

In this case, once the authorization came through, the patient came back in for a visit, was very appreciative that she was feeling much better after starting treatment with the osimertinib, and was eager to initiate the chemotherapy. Although I will note that in practice, that is not always the case. Sometimes the person will come in and they will say, “I’m feeling so good now. Why bother adding chemotherapy?” But in this case, the patient is now on both osimertinib and carboplatin and pemetrexed. She just received her last cycle of the carboplatin and will be continuing with maintenance therapy with the osimertinib and pemetrexed.