Advances in Targeted Therapies for Non-Small Cell Lung Cancer - Episode 9

Considerations for First-Line Treatment Selection for Patients with mNSCLC and Brain Metastases

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A key opinion leader muses on the treatments she would consider for a patient with mNSCLC, an EGFR exon 20 mutation, and brain metastases.

Joel Neal, MD, PhD: Then, Zosia, what if this patient, two questions. What if this patient had brain metastases on diagnosis? Let's say a handful of small three to five-millimeter spots, maybe five total. What would your treatment approach be, and would you think about adding other drugs? You talked about the role of immunotherapy. Do you think about adding immunotherapy here for continuing chemotherapy or adding other drugs like antiangiogenics?

Zosia Piotrowska, MD: Both great questions. I think the first question about brain metastasis is certainly one that we encounter very frequently in the clinic, particularly in patients with EGFR mutations in their lung cancer. Again, as with the last question, I think the answer to this question would be somewhat different if the patient had a different type of EGFR mutation so I think this is an example of where not only do you have to understand that your patient has an EGFR mutant lung cancer, but why it's so critical to understand the specific subtype of EGFR mutations that patients have. The reason for that is for the common EGFR mutations like Exon-19 deletions and L858R mutations, we feel incredibly comfortable with the CNS efficacy of Osimertinib and patients like this with small CNS metastases, we would have really, I think no qualms about starting on an EGFR-TKI like Osimertinib and watching closely. Many of these patients will have good CNS response. It's a little bit more complicated in patients with Exon-20 insertions, first of all, because we don't have a targeted therapy option in that frontline setting and even in the later line setting, we may come back to this, but there's little data about the CNS activity of these agents and likely they don't have as much CNS penetration certainly as Osimertinib. For patients starting on first-line therapy, I actually think that for small asymptomatic brain metastases, we know that carboplatin and pemetrexed can have some CNS activity so I still, if they're very small, might feel comfortable starting the chemotherapy but I would watch that brain MRI very, very closely and I would see the patient together with my radiation oncology colleagues and really be ready to add in radiation stereotactic radiosurgery to those lesions if they're not responding to chemotherapy. I think in particular in the patients with Exon-20 insertions, it really is important to keep a close eye on the central nervous system. That does get to your second question, Joel, about what we might potentially add to chemotherapy. I think for patients with EGFR mutations, regardless of the mutation subtype, I don't typically use immunotherapy. I think there's still evolving but likely data about this, but so far, I think we assume that there's a little added benefit to adding immunotherapy to carboplatin-pemetrexed, certainly in the frontline setting here. Generally, I would use chemotherapy alone. However, in some situations, I will add an anti-VEGF agent, specifically bevacizumab, and that may be something to consider in a patient with small brain metastases to increase CNS activity. I often will use carboplatin-pemetrexed alone, but I think carbo-pem-bev, would also be a very, very, reasonable option here.

Joel Neal, MD, PhD: Yes, recently I've been favoring the carbo-pem-bev option, I know there's some data that say bevacizumab may be particularly active in EGFR mutant cancers, and they have a very specific angiogenic signal. So, I don't think there's too much downside to it, but I do try to avoid immunotherapy. So, this patient enjoys a response for six months, feels much better, great quality of life, brain mets if they were there, also controlled, we do see good CNS penetration. But unfortunately, the tumor starts to grow, do you recommend, repeat biopsy at the point of growth after chemotherapy? We always talk about repeat biopsies in all sorts of targeted therapies for lung cancer, what about before the targeted therapy, do you think it would have changed?

Zosia Piotrowska, MD: I think in this case, no. As you alluded to early on, we are talking here about what we consider truncal mutations, really driver mutations that occur in all of these cancer cells. I think once we've identified that EGFR Exon20 insertions in this cancer, we really don't have any reason to believe it would have changed at this point, and I think that as long as you have the testing from the start of treatment, it's certainly reasonable to act upon that. This may be a time, if you didn't have that testing, that you might go back and review do you have all of the testing, have all of the targets been covered? But since we already have it in hand, I don't see a role for additional molecular testing at this point.