H. Jack West, MD: Let’s turn to the patient with an EGFR mutation who has brain metastases, specifically subcentimeter, and is asymptomatic. We get a routine MRI [magnetic resonance imaging] and find that. Historically, we would reflexively reach out to our radiation oncologist either for whole brain, previously, and increasingly now stereotactic radiosurgery. But we now have osimertinib with very good CNS [central nervous system] activity. Are you comfortable deferring on radiation for these patients and seeing what systemic therapy can do first?

Charu Aggarwal, MD, MH: That’s the beauty of having osimertinib. I think if they’re asymptomatic, I’m comfortable following the patient. If the patient is compliant, and if the radiation oncologist feels comfortable and there’s no surrounding edema, I’m very comfortable using osimertinib with close MRI follow-up.

Hossein Borghaei, DO: Yeah, I’d do the same. In fact, I’m so comfortable because my radiation oncologists are comfortable with that, and they’re the ones who usually get nervous. But I think as a team, we’ve decided that for the small, asymptomatic patient population, going with a systemic therapy is just as reasonable, so that’s what we’ve done.

H. Jack West, MD: We also have similar data with ALK inhibitors, and I think we have a similar degree of comfort. What about for patients without a driver mutation? Are you comfortable with giving immunotherapy or chemoimmunotherapy, or is it really just something where we have to have targeted therapies with known intracranial activity?

Hossein Borghaei, DO: I’ve been a little bit more comfortable with really small asymptomatic brain metastases in the I-O [immuno-oncology] world. There are some data generated, phase II studies, suggesting that in a patient population with non—small cell lung cancer, single-agent I-O can have activity. So, again, as long as we have close follow-up of these patients with small asymptomatic brain metastases, I’ve been comfortable starting with chemotherapy/I-O and observing. Obviously, the size and all of that sort of becomes a discussion between the radiation oncologist, us, and the patient. If there’s a lot of edema and all of that, then I feel a little bit less comfortable not treating. But, as I said, for the really small, subcentimeter asymptomatic ones, I’m willing to start with the systemic therapy.

Charu Aggarwal, MD, MH: I’m more comfortable starting systemic therapy, but I’m not as comfortable just leaving it be. I think we are more comfortable sandwiching a stereotactic radiosurgery approach if I’m doing just I-O alone or chemotherapy/I-O in these nondriver mutation patients. But I agree: I think more and more, our radiation oncologists are also feeling comfortable with the idea of beginning systemic therapy first.

H. Jack West, MD: And close monitoring.

Hossein Borghaei, DO: Yeah, very close monitoring. Absolutely.

H. Jack West, MD: Many patients with an EGFR mutation will end up getting chemotherapy but not with a concurrent immunotherapy. What would you say is the role, if any, for immunotherapy in these patients? Would you give it as a single agent? If so, when? Or are you so pessimistic about the activity of immunotherapy in these patients that you would not pursue it?

Hossein Borghaei, DO: I probably wouldn’t pursue single-agent I-O off a trial or anything like that for this particular patient population because the bulk of the data still suggest, and most of the data are retrospective, that the single-agent I-O is probably not as effective for the EGFR or molecularly-driven tumors, or a lot of them at this point. If I have a trial that uses a combination of different immunotherapy approaches, then I think I’m a little bit more inclined to do it; or a trial with I-O plus a VEGF inhibitor. But, to me, as a standard of care, if they’re progressing on the TKI [tyrosine kinase inhibitor] and I don’t have any other options, then I think, again, platinum doublet chemotherapy or IMpower150 is the way I would rather go with this patient population.

H. Jack West, MD: Charu?

Charu Aggarwal, MD, MH: I don’t think it’s a matter of being pessimistic. I think it’s just a matter of being realistic with what the data are telling us. I think it’s very clear that immunotherapy over a TKI approach in the EGFR-mutant population is a bad idea, as demonstrated by the phase II trial that was published earlier this year, where patients with high PD-L1 expression went on to receive pembrolizumab first with an EGFR mutation, and they had zero response rate and actually fatal pneumonitis. So I would be very cautious to offer immunotherapy as a single agent, even if PD-L1 is high in these patients. And I often talk to patients, and patients struggle with why we are not offering pembrolizumab when they see it on TV, when they’ve already seen that their PD-L1 result is 60%, but it’s a matter of educating them that chemotherapy may, indeed, be the better way to go.

H. Jack West, MD: I think that’s a great point. I’m specifically thinking in terms of the relapsed and progressing setting. My personal approach is that I’m less optimistic about how well it’s going to work, but I want to give every patient the benefit of the doubt and the opportunity to benefit, even if it’s going to be a later-line option. It wouldn’t necessarily be my routine second-line choice. That may be a group where I would be really more inclined to do docetaxel/ramucirumab or something before that, so I wouldn’t exclude these patients.

But to your point about underscoring that these patients with driver mutations should not get immunotherapy up front, even if they have high PD-L1—don’t take the bait. It doesn’t mean the same thing in a patient with an activating EGFR mutation or an ALK rearrangement, and could poison the well in terms of toxicities with TKIs later. So that’s a great point. We’ll need to learn more, and we will. Fortunately, EGFR mutation—positive patients are being studied much more for the potential efficacy and combinations for immunotherapy.

Transcript Edited for Clarity