Vamsi, for patients, we know that eventually they do unfortunately progress on our best drugs, including osimertinib [Tagrisso] What are you doing after that?

 I think that’s a space where our practice is really, because it’s a lot of clinical scenarios that actually fall on what systemic therapy should be used there. Some of it is dictated by the disease burden and location of mets [metastasis], like especially CNS [central nervous system] mets. I know there’s a lot of controversy around continuation of osimertinib beyond progression with chemotherapy. We had 

 [vascular endothelial growth factor] inhibitor, as you probably saw from all of our colleagues discussing this in the past, we have a very high range of practice patterns there post progression. What do I do in my practice? I generally try to avoid using PD-1 [programmed cell death protein 1] combination. I tend to use platinum pemetrexed with or without 

 inhibitor and I do continue osimertinib, especially in patients who have CNS mets. But I know there are several colleagues who use this approach.

You mentioned continuing osimertinib. Shinen Lin in our group did an analysis, and I think it really surprised us, that after patients had their first progression on osimertinib, if we consolidated with radiation, the second progression was actually over a year, it was 12.8 months. Now that’s not a randomized prospective study. That’s a retrospective analysis and I have to say we know that there are caveats in terms of patient selection, but still for patients we selected, which was a lot, that did seem like an option. What’s your practice there at first progression on osimertinib? Do you think about consolidating with radiation or ablative therapy and continuing?

 That’s a very good point, John. Often, if it’s a very limited progression, if it’s an oligoprogressive disease, there are different patterns of progression on osimertinib. It really depends on the extent of the disease burden and measure of progression. Going back to Heather’s point about benefit of chemotherapy, and I’m actually really looking forward to seeing the FLAURA2 study data. I’m not sure when that’s going to read out. But I think we’ve come a long way in terms of disease monitoring as well. I think we have...differently in terms of how we kind of design these trials. I kind of wonder if we perhaps shouldn’t be treating with chemotherapy/osimertinib up front, but however, there may be some speed point, maybe at maximal response like for persisters. I know, John, you’ve done a lot of work in that space. Perhaps identifying a point where we can introduce chemotherapy sooner might be a way to go here.

Yes. Very interesting. Stephen, what’s your practice for osimertinib progressors here? Let’s say that they can’t be consolidated with radiation.

 Certainly, I agree that there’s all kinds of progression, and what we’ve learned over time is not to throw the baby out with the bath water, that osimertinib is still doing a large role in many of these patients. In some cases, we’ll tolerate a little bit of progression in some areas. Maybe we don’t need to so quickly move on to the next thing. But we’re strong believers in biopsy, not just to characterize resistance and identify actionable mechanisms of resistance but also to be sure there’s not histologic transformation, something that’s probably under reported, both small cell and squamous cell. Thus, we’ll send out for liquid biopsy, do a tissue biopsy. And I would agree with my colleagues that the standard is chemotherapy, and we don’t know if we have to continue the OSI [osimertinib] or not. The COMPEL [Chemotherapy Plus Osimertinib Against Chemotherapy Plus Placebo in Patients With Non-small Cell Lung Cancer (NSCLC)] trial will give us some insight, but I will say that it has been my practice, despite the negative IMPRESS [Gefitinib Plus Chemotherapy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer Resistant to First-Line Gefitinib] trial, to continue OSI [osimertinib] if patients have a history of brain metastases.

Videos

Vamsidhar Velcheti, MD, and Stephen Liu, MD, discuss their treatment approaches for patients with EGFR-mutant NSCLC who progress on osimertinib.

Sequencing Treatments in EGFR-Mutant NSCLC

Heather, you’ve heard about the different options. What goes into your treatment decisions about what to use first for these patients? I know you treat a lot of 

- [epidermal growth factor receptor]-mutant non-small cell lung cancer there in California.

 Yes, we certainly do have a lot of patients who have 

-mutant non-small cell lung cancer. We do tend to use first-line osimertinib [Tagrisso]. I will mention that we do have the US Cooperative Group led by ECOG-ACRIN [Cancer Research Group] with osimertinib plus bevacizumab [Avastin]. Now, we’ve seen some data in the last few months that we all have to still wonder what is that role of combining 

[vascular endothelial growth factor] with osimertinib, though there’s lots of data with some of the other 

 [epidermal growth factor receptor] TKIs [tyrosine kinase inhibitors] and lots of research over many years, as you and I know well, John.

 But, at this point, we’re still tending to use osimertinib. I think about whether adding chemotherapy is a good question. We’ve seen some data again with first- and second-generation drugs, ongoing trials with osimertinib with chemotherapy. But until we see data that clearly shows that that additional toxicity is truly going to lead to longer survival. And not just, I think, progression-free survival [PFS] when you’re combining things isn’t enough. If you’re going to combine up front, we need to see that OS [overall survival] benefit. At this point, I’m still just using osimertinib, but these are all the things I’m thinking about and talking about with patients and certainly excited to see more trials because we’ve really struggled with that.

Heather, let me dig into that point you were making in a little more detail about progression-free survival versus overall survival. Let’s say you take osimertinib and chemotherapy. Let’s say progression-free survival is a bit longer, but that amount longer is just about the amount of time as if you had used them separately instead of using them together. If that were the case, do you think it should be approved and is it something you would use in that setting?

 In the data that we have so far, there have been 2 trials with gefitinib [Iressa], I believe, it was a first-generation drug. In Japan, they did a beautifully conducted trial of patients who either got first-line

 TKI alone or with chemotherapy and mandated that for those getting 

 TKI, next step had to be the same chemotherapy that they would have had in combination. You had these end points, PFS1, PFS2, and then OS. The PFS1 was better with the combination than with the single drug, but when you looked at PFS2, which was the time point where every patient had to have both the 

 and TKI and chemotherapy, they were identical…except there was a survival benefit to giving the combination. Also, that’s why we’re all still so intrigued and that’s I think why the next-generation osimertinib plus chemotherapy study is ongoing.

The other data we have came out of India. It was a well conducted randomized trial of gefitinib plus or minus chemotherapy. The challenge there is that many of the patients who got just the gefitinib never got chemo-platinum doublets, and so you can’t really look at OS differences because there it becomes a matter of availability of drugs. That also showed this PFS and OS benefit. However, it wasn’t the same sort of comparison, we’ll conduct a trial given limited resources they had to do it.

Thus, there’s these questions, and I think from a patient perspective you have an option of a year or two or maybe longer just taking a TKI and have life pretty normal versus jumping in to this IV [intravenous] infusion and being kind of stuck with having to go in regularly. There’s a big decision point from that perspective, from a patient quality of life. Now, if it involves longer survival, I think a lot of people would make that decision, but until then I think that’s why we haven’t seen a lot of pickup of using the combination or of any combinations, chemotherapy or 

 [vascular endothelial growth factor receptor] IV. Anything that involves infusion people wanted to wait.

I think there is at least a possibility that giving them 2 up front, even if PFS2 isn’t longer but you might kill more of these more drug-tolerant persisters that you’re not killing with the 

 inhibitor. That’s why you might get longer overall survival. From your perspective, does it take longer overall survival before you’d stick them together up front?

 Yes. I think so. It does take a while to get to that end point and of course if some new miracle gets developed along the way, then that changes things. But at least from where we stand right now with the options, though they’re growing, but still limited post-OSI [osimertinib], I think that that OS benefit is important if you’re going to bring chemotherapy in early. Chemotherapy needs to be there at some point. I’m a big believer in chemotherapy for patients with 

-mutated tumors but not necessarily up front.

OK. Well, thanks. That’s really insightful comments there. It’s been really helpful.

Heather Wakelee, MD, shares insight on factors to consider when approaching the optimal first-line therapy for patients with EGFR-mutant advanced NSCLC.

Selecting First-line Treatment for EGFR-Mutant NSCLC

 entitled, “Key Updates in Lung Cancer in 2021.” I am John Heymach, chair of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center in Houston, Texas. I’m joined today by a panel of experts in the field of lung cancer. I would like to welcome my esteemed fellow panelists to introduce themselves. Heather.

 Hi, I’m Heather Wakelee. I’m the chief of Medical Oncology at Stanford University. It’s great to be here with all of you.

 Hi, I’m Ani Balmanoukian. I’m director of Thoracic Oncology at the Angeles Clinic and Research Institute, which is a part of Cedars-Sinai affiliate.

 Hi. Stephen Liu, director of Thoracic Oncology at Georgetown University in Washington, D.C. Nice to see everyone.

 Hi, Sandip Patel, Medical Oncology, director of the Early Therapeutics Program at UC [University of California] San Diego.

 Hi, this is Vamsi Velcheti. I’m the director for the Thoracic Oncology Program at NYU [New York University] Langone.

Again, welcome everybody and thanks for joining me today. We’re going to discuss a number of updates in non-small cell lung cancer and small cell lung cancer that were presented at the recent ESMO [European Society for Medical Oncology] Meeting in 2021, the IASLC [International Association for the Study of Lung Cancer] Meeting in 2021, and the ASCO [American Society of Clinical Oncology] Meeting this year as well. We’ll discuss the data in the context of other recent updates to the treatment landscape. There’s obviously a lot that’s happening right now, so there’s no shortage of important material to cover.

Let’s get started on our first topic, and the first topic is one that’s very near and dear to my heart is treatment of 

 [epidermal growth factor receptor]-mutant non-small cell lung cancer. I’ll start by introducing this. I think we’re all familiar with the fact that there are few areas where more progress has been made than in 

-mutant non-small cell lung cancer. We know about two-thirds of patients with 

mutations present with classical mutations or typical mutations, of course the L858R or the exon 19 deletion. About one-third present with atypical mutations. Those atypical mutations include exon 20 insertions, which is one of the largest groups of atypicals, and then a host of other atypicals as well, and there’s progress on all of these fronts.

We’re going to start off and I’m going to ask you, Ani, do you want to just take us through some available treatments when we talk about tyrosine kinase inhibitors [TKIs] and other treatments for 

-mutated lung cancer has definitely come a long way, as you just mentioned. There are now 5 treatment options available for patients in the frontline setting. The first generations that we are aware of, which are gefitinib [Iressa] and erlotinib [Tarceva]. These reversibly bind to 

. There are also the second-generation options which include afatinib [Gilotrif] and dacomitinib [Vizimpro]. These are irreversible inhibitors, and then, of course, there’s the third generation which is osimertinib [Tagrisso] which is also an irreversible inhibitor.

OK. Well, thanks. Sandip, what do you consider to be the standard of care now if somebody walks in here with an 

 mutations, so exon 19 or L858R in the metastatic setting, in places which osimertinib is available, that likely represents a best standard of care based on its CNS [central nervous system] penetration, the FLAURA [AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer trial] data in comparison to first generation, and then also from a toxicity standpoint. In areas in which osimertinib may not be available, there’s very provocative data for chemotherapy plus gefitinib, for example, and a variety of other combinations that I’m sure we’ll be talking about, including 

 [vascular endothelial growth factor] inhibitors plus TKIs. I think in those jurisdictions in which osimertinib is available, it represents a strong standard of care. And in those in which not, chemotherapy plus gefitinib is a very reasonable option.

 Sandip, let me ask you. I’ve heard the concern from some people that osimertinib is also approved for T790M [threonine at amino acid position 790] positive or resistance, and I’ve heard some physicians say, well, they’re not sure what to use afterwards so they hold it in their back pocket and start with one of the first- or second-generation drugs because they may be able to use osimertinib later. What are your thoughts about that?

 I think when we look at the FLAURA data which tries to recapitulate some of that experience, there are up to a third of patients that really never get a chance to get on osimertinib. And the issue with the first-generation 

inhibitors, which for a while were best in class for a really long time, is really their lack of CNS activity. Brain metastasis is a major issue for patients with driver mutation lung cancer such as 

-mutated lung cancer. And so often, it’s really hard to test for T790M in the resistance setting in a timely manner when patients are declining. I think that’s part of the benefit that we saw in FLAURA is the drugs only work if you get a chance to take them, right? And everyone had an opportunity to take osimertinib in the frontline setting. In my practice, osimertinib represents the best therapy I can give in the frontline setting, and that CNS protective effect, whether we’re talking 

 or other driver mutations, really can’t be understated in my opinion.

Ani Balmanoukian, MD, Sandip P. Patel, MD, and Heather Wakelee, MD, review currently available treatment options for EGFR-mutant advanced NSCLC and discuss their approach to frontline therapy.

Stephen Liu, MD, Georgetown University

Articles

Sequencing Treatments in EGFR-Mutant NSCLC

Selecting First-line Treatment for EGFR-Mutant NSCLC

Treatment Landscape for EGFR-Mutant Advanced NSCLC