Naiyer Rizvi, MD: Jacob, tell me about oligometastatic progression. Do you biopsy these patients? Do you resect them? Do you radiate them? Or do you just switch to chemotherapy? What's your approach?

Jacob Sands, MD: That's a great topic, and to me this is relevant also to our prior discussion about using pembro [pembrolizumab] alone initially. But let's say you have someone who is on osimertinib with the L858R mutation, and they have progression at a single site. I would tend to radiate that site, in some cases resect, although generally radiation I think tends to be easier in many cases. But if they’ve got multiple sites of disease that are all under control and a single site of progression, then I would tend to treat that single site. Now, would I test for some kind of resistance mutation at that time? Yes, very potentially, and in many cases what I’ll do is send cell-free DNA testing to see if something shows up like MET, for example. But in many cases, I'd be just treating that single site and then continuing osimertinib onward. Or per the prior discussion of [pembrolizumab] alone in somebody who does not have a mutation, similarly, progression at a single site while otherwise disease control, radiate that site, and continue the therapy.

Naiyer Rizvi, MD: Leora, what about more clear, broad, widespread, changing therapy-type progression? How do you approach those patients?

Leora Horn, MD, MSc: For those patients we'll start off by sending cell-free DNA, and if we don't get anything there and we are just still seeing EGFR, I might biopsy those patients. We’re looking for things like C797S mutation because maybe you're going to add erlotinib, or gefitinib is what I've added for patients who have C797S, assuming that it's in trans, or we'd look for MET because we have a trial for patients who are MET amplified. We're not looking for the MET exon 14, we're looking for MET overexpression or MET amplification. And then we're learning some of the other mechanisms of resistance to osimertinib. For the majority of the patients, chemotherapy does become the next line of therapy, but if we can continue a targeted therapy or put them on a dual targeted therapy, that's what we would do.

Naiyer Rizvi, MD: Josh, tell me about your experience with small cell transformation in these patients? Do you see it?

Joshua Bauml, MD: Yes. We do see it, and it's scary. We don't really have a lot of data about what to do in that setting. I think that it's one of the reasons why I do tend to get both a plasma and a tissue biopsy if it's accessible because knowing that someone has histologic transformation is important. And it's not just small cell lung cancer. They can also have squamous transformation, as there was just a paper out of Memorial Sloan Kettering Cancer Center, showing that that is a common issue with the use of first-line osimertinib. I think that we know very little about mechanisms of resistance to osimertinib. All of our series are based upon very small numbers. I think that knowing more with larger numbers will be very useful. I would say to Jacob's point that I think that oligometastatic ablation in targeted therapy is a little different from immunotherapy because we have actually a good amount more data in the targeted space. We know resistance develops in a heterogeneous fashion. We know that a single site can progress, while we can have good disease control, and there are good series that have been done showing that doing this improves outcomes in the long term, more so than any other treatment that we use for lung cancer. I think that this is a real space where we can help patients.

Transcript Edited for Clarity