Vokes Explores Biomarker Testing and Treatment Landscape for EGFR-Mutated Lung Cancer

Natalie Vokes, MD

Assistant Professor

Department of Thoracic/Head and Neck Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

Peers & Perspectives in Oncology: What are the NCCN recommendations for frontline testing in patients with non–small cell lung cancer (NSCLC)?

VOKES: The guidelines for nonsquamous NSCLC in this era strongly recommend that you do biomarker testing for genomic biomarkers prior to administering immune checkpoint inhibitor therapy.¹ [There are at least 9] known targetable drivers that we have. For most of us, the way to get at these 9 targets is through broad-based panel next-generation sequencing and some commercial companies: Caris, Tempus, and others are doing whole-exome sequencing, so you end up with much more data than that. Historically, we were doing DNA-based testing that is not as sensitive and specific for fusions, so a lot of the commercial assays now include RNA, and that is going to be a better assay for fusion testing that tends to be done universally for tissue-based assays but is more variable for blood-based assays, including some of the rapid assays. Just know what your test will or won’t be detecting. We are now doing concurrent tissue and plasma.

We at [The University of Texas] MD Anderson Cancer Center [in Houston] have in-house panels, but our in-house blood panel is essentially the old Guardant panel and our tissue panels are a variant of the FoundationOne panel. But Tempus and Caris are very attractive these days because they do whole-exome [sequencing], they do whole transcriptome, and all those data are sitting there. Even if there’s a biomarker that becomes available in 2 years, they can look back. I think they’re pushing the forefront a little bit there.

[In] patients with metastatic lung cancer who have a targetable driver oncogene, for most of these targets, the standard of care should be the targeted therapy, not immunotherapy [IO]. There are some nuances to this. KRAS [inhibitors] are approved in the second line, and BRAF is provider specific whether you start with your immunotherapy and then go to your BRAF inhibitors vs the other way around. We’re looking at some retrospective data to see what the outcomes are, and in that first look retrospectively, it looks like if you start with the IO and then move to the targeted therapy, they may do better, but guidelines are flexible for those. But for ALK, EGFR, RET, NTRK, and ROS1, very clear standard of care should be to start with the targeted therapy for those because IO doesn’t work that well. There’s always the concern that you’ll have a higher rate of toxicity if you go from IO to the targeted therapy compared with the other way around.

Are liquid biopsies reliable for measuring tumor mutational burden (TMB) if there is insufficient tissue for biopsy?

They’re comparable. If you look at some of the correlation plots, there’s a nice linear correlation, but it just depends on your cutoff. You’re going to have some patients who fall [on] either side, particularly if you have a blood-based assay that includes germline sequencing that’s probably going to be better than one that does not. Some of the germline correction still leads to an overcall on your TMB. But if you have a very high TMB on blood [testing results], you can count that. If you have a very low TMB on blood [testing results] but your tumor shed is reasonable, you can count [on the fact] that the patients who are in the middle are probably not going to be great immunotherapy responders anyway, because they’re in that middle of the TMB [range]. That tells you what you need to know.

How should EGFR testing be done?

All patients with metastatic lung cancer should have EGFR testing.² The most important exons are 18 through 21. Those are going to be the regions of the protein that lead to activating change. All patients should get these. Our most common activating EGFR mutations are exon 19 deletion and [exon 21] L858R. There’s a lot of nuance, particularly with the exon 19 deletions. There’s a lot of work being done to characterize how some of these more complicated insertions and deletions affect the binding of the drugs to the target. There are some good papers to look at that. If I see a noncanonical exon 19 deletion, I have started to look up those papers and see how the osimertinib binding changes. I’m putting a marker on that; that’s coming in the future. But for now, these are the buckets that we think about for EGFR.

We’ve been talking about barriers to biomarker testing in the lung cancer field for the past 5 to 10 years. Despite all the progress, a lot of these issues still apply.

The International Association for the Study of Lung Cancer studied this a couple of years ago and put together a report highlighting some broad categories where there can be barriers, including timing, lack of awareness, access, quality, and cost.³

Could you summarize the outcomes of the key trials in EGFR-altered NSCLC?

The FLAURA trial [NCT02296125] is osimertinib [Tagrisso] vs first-generation [EGFR tyrosine kinase inhibitors (TKIs)]. Osimertinib [was also the comparator arm] for FLAURA2 [NCT04035486] and for MARIPOSA [NCT04487080].

Across all these contexts, the osimertinib arm is performing comparably [Table^4-6]. You have 14 months’ median PFS in the L858R groups [for osimertinib in both FLAURA and FLAURA2] and then the central nervous system disease [CNS] groups [ranging from 15 to 25 months], and then you have 18 to 21 months in the exon 19 group.^4-6 For osimertinib/chemotherapy, median PFS is in the mid-20–month [ranges] across all these different categories. For amivantamab [Rybrevant] plus lazertinib [Lazcluze], the overall median PFS is 23.7 months, so very comparable to osimertinib/ chemotherapy [from FLAURA2].⁶ But within the subgroups, those subgroups are not necessarily capturing that best PFS group. The other thing is that the osimertinib in the L858R group overperformed relative to any of the other arms, so it looks like in the L858R group, amivantamab/lazertinib didn’t do as well. I think it’s certainly within range here of the other numbers, but it doesn’t seem to be adding a lot of value for the L858R group, which we know does a little worse. Within these categories and certainly within the category of CNS disease, we’re seeing a longer PFS in the osimertinib/chemotherapy group.

The way that I’m assimilating these data personally is for the front line. The choice for me is osimertinib vs osimertinib/chemotherapy. At our institution, we do a lot of local consolidation as well, so we’ll treat with an induction period and then we’ll irradiate residual disease sites or even operate sometimes, and that’s...something that can be thrown into the mix. I think amivantamab/lazertinib is a good option. There are data for giving amivantamab after osimertinib progression. The way I think about it is osimertinib vs osimertinib/chemotherapy in the front line, and then we can do amivantamab/lazertinib in the second or third line.

If a patient has cardiac dysfunction with osimertinib, can they have the same issue with amivantamab? Do you rechallenge after stopping treatment?

Yes, there can be [that issue] in those patients. I would probably give them a chemotherapy washout and then recheck their echocardiogram and then potentially rechallenge. I do echocardiograms every 6 months and check, and then I do ECGs [electrocardiograms] every 3 months also for the QTc [corrected QT interval prolongation], but I haven’t had it happen.

I’ve had 2 cases of pneumonitis. I had 1 patient die of pneumonitis from osimertinib. I had 1 patient who had a mild case, and then we switched to gefitinib [Iressa] because there were better data for pneumonitis for that, and he did very well on that. But it depends on how bad the pneumonitis is, because you can still get pneumonitis with the first-generation TKIs.

How do you proceed after disease progression in the first line?

After progression, if somebody starts on osimertinib monotherapy, then you have chemotherapy, you have chemotherapy plus immunotherapy, and you have amivantamab/lazertinib. Those are my standards of care. I tend not to give IO at progression, but part of it is because I’m saving them for clinical trials, because we do have a lot of these IO clinical trials coming, none of which have [had] positive [findings] so far, but we have to keep trying. Amivantamab/lazertinib is a nice option. The response rates aren’t high [in later lines], but they’re comparable to docetaxel.⁷

What do you do if patients develop MET amplification?

We do have some trials. We have a trial [NCT06083857] that we’re just opening that’s amivantamab plus a MET inhibitor, tepotinib [Tepmetko], so we’re trying to do that. We previously had the ORCHARD trial [NCT03944772], which also used a MET inhibitor. If there’s no clinical trial, then I usually put them on EGFR TKI with a MET inhibitor. We usually continue [the EGFR therapy] because theoretically, you don’t want the EGFR to grow back. I wouldn’t say it works for that long, but it can still buy you half a year.

Do any data support the combination of osimertinib with IO?

Osimertinib plus IO was looked at in the late 2010s, and the toxicity was high, in particular pneumonitis, so all those trials were stopped early and there wasn’t any benefit from the IO.^8,9 The combination is going to be hard. There were a lot of early IO trials that looked at combination ALK inhibitors, and all had toxicity. Although the pneumonitis was very osimertinib specific, there was more transaminitis with some of the other TKIs. What we are doing now is different IO strategies in the second line. We had the phase 3 HARMONi trial [NCT06396065], which is an ivonescimab plus chemotherapy trial that enrolled very quickly and is now being read out. We have a trial [NCT05704634] of an IL-6 [receptor antibody] plus cemiplimab [Libtayo]. We’re doing some T-cell engager trials and others like that. So we have different IO strategies but not the TKI combination, just because of safety.

Are you able to continue using maintenance pemetrexed in patients with low glomerular filtration rate?

I tend to pull it, particularly if it’s the context [of the FLAURA2 trial], where they’re on another drug. If it’s single agent and I’m not confident that I have anything better for them, then I will push it to that threshold, but then after that, I stop it because it does make me nervous. I also feel like I’m cutting them out of trials.

_{DISCLOSURES: Vokes previously reported receiving research funding to her institution: Mirati and Circulogene; and receives consultant fees from Sanofi, Regeneron, Eli Lilly, and Oncocyte.}

_REFERENCES

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