Benjamin Levy, MD: We talked a lot about these drugs being leveraged in early stage disease, but I think we need to remember that immunotherapy and targeted therapy, specifically targeted therapy, got its start in the advanced stage setting. As I mentioned in the introduction, EGFR has been chapter 1 of this precision medicine story. Alex, do you want to walk us through the standard of care treatment for advanced EGFR patients, specifically exon 19 and 21, and the FLAURA data?

Alexander Spira, MD: The FLAURA data are some of the most phenomenal data we’ve ever seen; osimertinib frontline treatment should be given, hands down. It is better tolerated, there is better efficacy, and of course, the CNS [central nervous system] penetration. I think some of the benefit there compared to some of the older EGFR drugs is it’s better at covering T790M, but also that systemic coverage is phenomenal. I think in all of our experiences, it’s better tolerated too. As I said, it’s one of those things that has made an amazing difference in our patients’ lives and is now a no-brainer.

Benjamin Levy, MD: The median PFS [progression-free survival] is close to 19 months, and CNS control…all seem to be better than first-generation TKIs [tyrosine kinase inhibitors], not only in the study, but also in my experience as well. Uncommon mutations and EGFR, we need to remember that the FLAURA data were exon 19 and 21. What do you do for those patients with uncommon mutations? We’ve got 2 sets of data. We’ve got afatinib with a large data set, but we also have a paper with osimertinib.

Alexander Spira, MD: The first thing I do is I look it up. I’ll be honest, and I’m not going to be embarrassed. There are a lot of mutations. I even got one the other day I’d never even heard of. What do you do with that? That exists.

Benjamin Levy, MD: We’re not talking about exon 20, by the way.

Alexander Spira, MD: It was a weird exon 19 that I’ve never seen before. I struggled with the data on afatinib. Afatinib is a tough drug. The starting dose is too high; I’ve never been able to give it. I always start with a reduced dose, usually around 30 mg. I think the reality is that I struggle with that. What I tell people is, “Let’s try Osi [osimertinib] first, and let’s see how it goes.” I just have a hard time with afatinib. It’s one of those things if the PFS is, it’s probably not going to be 19 months, even if it’s a year; a year on that drug is tough. A year of that drug is tough, and quality of life is important. If it works, great. Again, I find it super helpful. There are a lot of data on these random mutations, even if not in the paper, or even structural data. People smarter than me have done some of this modeling, so you can ask them.

Benjamin Levy, MD: I think of all the things you said, this has become the standard of care. I’m more inclined in the uncommon mutations to use osimertinib. Afatinib is a tough drug, but I look it up as well. I think there are so many rare mutations outside of exon 20, there may be preclinical data that may be informative and some case reports of what may work best. When I’m teaching fellowship, I say if there’s an EGFR exon 19/21 [mutation], it’s a very easy decision up front. It’s a very easy decision, there’s not a lot of nuance. But what to do at the time of progression can be challenging. Jonathan, we have had some updates in potentially how to leverage some of these newer therapies in the resistant setting, either as third line or even some of your data in combination with necitumumab, which I think is more treatment-naive, but you’ll have to inform me on that. The Ami [amivantamab] plus lazertinib data, you want to walk us through the data that were just presented as an oral session yesterday, and then maybe some of the other data?

Jonathan Wesley Riess, MD: I want to go through the data, and I also want to talk about just in general, what to do at the time of osimertinib resistance because as you mentioned, we have great data from FLAURA, a median PFS close to 19 months, and overall survival benefit compared to earlier-generation EGFR TKIs. But invariably, the majority of patients do develop resistance. I generally look for the mechanism of resistance and see, first by plasma, but often by tissue, there’s small cell transformation and so forth, where you really need to know the tissue and other squamous transformation. That’s generally my first step. We have, for example, clinical trials looking to match up the mechanisms of resistance, whether it be MET amplification, other bypass tracks, or on-target EGFR mutations. There were some really nice data presented at ASCO [American Society of Clinical Oncology annual meeting] this year. For example, one by [Catherine] Shu, [MD,] looked at amivantamab and lazertinib in patients with EGFR-mutated non-small cell lung cancer after progression on osimertinib and platinum-based chemotherapy. They did show some activity with the combination. The overall response rate by blind independent central review was 36%, and so they did show some activity. That showed the proof of principle that you can do targeted therapy after and get a response.

I think some questions remain. You can rechallenge patients with osimertinib after going on platinum-based chemotherapy and other treatments and get some activity and re-responses. That’s been well established with osimertinib and other EGFR TKIs, but it does show that there are options. We are presenting at a poster discussion on Monday our NCI [National Cancer Institute]-sponsored trial of osimertinib and necitumumab, which is an EGFR monoclonal antibody. We had different cohorts in patients who were pretreated and progressed on a prior EGFR TKI. I would say the take-home message from that once again is you can get re-responses. We did show some activity in EGFR exon 20 insertion, meeting the primary end point, and patients did have responses after progressing on osimertinib previously. What’s interesting is it looks like in patients who have those bypass track mechanisms of resistance, MET and so forth, we don’t see much activity, which makes sense, but in patients who don’t have those, there were some who did respond.

Benjamin Levy, MD: Chaitali, how do you approach a patient on osimertinib who has disease progression? What chemotherapy are you using? Are you doing a rebiopsy on these patients? Is it tissue, is it liquid? What’s your general approach for these patients?

Chaitali Nangia, MD: I think it all starts from where the progression is and what’s going on. It starts from there. If this is a local recurrence, like you said, a local recurrence, you guys will easily handle and it can be handled locally, then that’s the best approach and keep going. But if there is no local approach and it is a systemic symptomatic progression, then I would switch them to a platinum-based doublet if I can’t find a clinical trial. I have re-challenged patients after a break, and in my experience, there’s a fair chance the osimertinib will work again. And if it's an isolated brain metastasis and you can radiate it out and keep going, then that’s what I’m going to do.

Benjamin Levy, MD: Any other comments on this? Heather, are you routinely doing tissue biopsies and liquid biopsies on these patients? I know you have a lot of clinical trials in this setting. We have a clinical trial that we share, a chemotherapy, Bev [bevacizumab], Atezo [atezolizumab] trial, but what are you doing in these patients?

Heather Wakelee, MD: Usually it’s a liquid biopsy, and then depending on the ease of doing the tissue biopsy, if we don’t get an answer from that, we’ll make a decision based on timing because oftentimes these patients do become symptomatic. If they’re not symptomatic, it’s oligoprogression, we’re not going to biopsy because we’re going to treat definitively, and then whatever comes next may or may not be the same thing, so I don’t find it’s helpful. But at the time of systemic progression when we know we need something new, then usually it’s liquid biopsy, and I’ll think about the tissue biopsy if I need it. But because that’s going to take a few weeks, we usually need to start treatment earlier than that, [so I] don’t always get the tissue.

Benjamin Levy, MD: It is everyday carboplatin/pemetrexed or carboplatin/pemetrexed/bevacizumab, the IMpower150 regimen?

Heather Wakelee, MD: Usually my chemotherapy choice is going to be carboplatin and pemetrexed, and I’ll add in bevacizumab if there’s more of a disease burden, if there’s liver involvement and other things like that. We have our clinical trial, so with that, that’s plus or minus immune therapy, and I think there’s definitely a question about when we bring in the checkpoint inhibitors for the patients with EGFR. You mentioned the IMpower150 trial, which was carboplatin, paclitaxel, and bevacizumab plus or minus atezolizumab, where in the subset of patients with EGFR, there was a benefit. But there was no benefit in the IMpower130 regimen, which was without the bevacizumab, otherwise the same. That EGFR subset had no benefit at all, and we’ve seen other subsets of data where in the EGFR setting, there are probably no data. The one I always go back to is, there an analysis from the ATLANTIC studies. It was the best data that I’ve seen where they looked by EGFR mutation and PD-L1 [expression], and in that setting single-agent immune therapy worked in maybe 15% of patients if they had high PD-L1 and an EGFR mutation, but really didn’t if there was low PD-L1.

So in a patient who has an EGFR mutation—especially the L858R, because there are differences between deletion 19 and L858R—and high PD-L1, I will bring in immune therapy with chemotherapy, usually in the trial, but sometimes without. Or if they’re not eligible for the trial, that’ll be third or fourth line, I think about it. But I always talk to patients about how it’s less likely to work, so I don’t have expectations too high. I also make sure people always know if we’ve done immune therapy, we can’t do osimertinib at the same time, and we can’t give osimertinib for a few months after because that risk of pneumonitis is really high. That’s always my caution. So if I have a patient with brain metastases that are being controlled with osimertinib, and they have systemic progression and I want to keep osimertinib going for the brain, I don’t do immune therapy. I’ll think about chemotherapy. That was kind of a long answer.

Benjamin Levy, MD: No, it’s great. Alex, do you have any other thoughts?

Alexander Spira, MD: You said it great Heather, same thing, I’m not a big believer in bevacizumab. I have a hard time mechanistically. I know there are certain people who are adamant about it and certain people who are adamant about IMpower150. It’s hard enough to get people to switch from a TKI to chemotherapy, but switching to paclitaxel, which is real chemotherapy, am I right? It’s hair loss, neuropathy, etc. But I’m pretty much the same. On a tumor board, I biopsy a lot more than I do in real life because the reality is I’d love to have a biopsy, but there’s COVID-19. It’s 2.5 weeks to get a biopsy because everything is down, and it’s another 4 weeks to get your NGS [next-generation sequencing] back, so it’s 2 months. I’m a liquid kind of a guy.

Benjamin Levy, MD: I would say the one time I always get a biopsy is if they have TP53 and RB1 mutations. Those have a much higher rate of small cell transformation, so I always get a biopsy on those folks.

Alexander Spira, MD: I just had 2 people who have small cell transformation, it’s real.

Transcript edited for clarity.