Choosing Early-Line Therapy for NSCLC With an EGFR Exon 20 Insertion


During a Targeted Oncology case-based roundtable event, Gregory Riely, MD, discussed the case of a patient with advanced non–small cell lung cancer who had an EGFR exon 20 insertion. This is the first of 2 articles based on this event.


Gregory Riely, MD, PhD (Moderator)

Vice Chair of Clinical Research, Department of Medicine

Memorial Sloan Kettering Cancer Center

New York, NY


A 56-year-old woman presented with persistent cough and mild progressive dyspnea over the previous month, with some chest discomfort, especially during routine exercise​. She is a mother of 2 teenage children and a former light smoker, with no other notable medical history​. Her ECOG performance status was 1​.

A CT/PET-CT scan showed a mass in right lower lobe, right pleural metastasis, and right malignant pleural effusion​. A brain MRI is negative for brain metastases​. Transbronchial lung biopsy showed adenocarcinoma​. Tissue next-generation sequencing (NGS) showedan EGFR exon 20 insertion mutation (V769_D770insASV). Her PD-L1 expression was negative​.

What are you most likely to offer this patient as first-line therapy, assuming clinical trial is not available?

Chemotherapy plus bevacizumab
Chemotherapy plus immune checkpoint inhibitor
Other tyrosine kinase inhibitor


  • Please discuss your treatment selection. Why did you select your answer? What factors determine your first-line treatment approach?

SHAYMA KAZMI, MD: There have been the CHRYSALIS [NCT02609776] data with amivantamab [Rybrevant], and you can’t cross compare trials, but the overall response rate [ORR] was a little higher in the [clinical trial (NCT02716116) of] mobocertinib [Exkivity].1,2 The thing that I like more about [mobocertinib], it’s a TKI [tyrosine kinase inhibitor] and has CNS [central nervous system] penetration as opposed to amivantamab which is a large antibody and does not, and most of these patients are going to relapse in the brain. So, if I had to pick between the 2, mobocertinib would be what I’d go.

Any time there is a [molecular] target, I try to choose that first. I always have chemotherapy as backup, either with an immune checkpoint inhibitor or bevacizumab [Avastin] as a backup, but I prefer to do the targeted therapy first.

RASIM GUCALP, MD: I think it’s difficult to make the decision evidence based. Until there are [results from frontline trials], we are using our gut feelings [when using the targeted therapies as] single agent upfront, but we can always use the chemotherapy in the second line. There is a problem with the insurance. I don’t know if they will give the permission. That was the reason I [chose] amivantamab, but it’s just a gut feeling.

GREGORY J. RIELY, MD, PHD: For first-line therapy, I will typically use chemotherapy plus bevacizumab or chemotherapy alone, depending on the patient sitting in front of me. That is [due to] this idea that the drugs have all been studied in the second-line setting. But I certainly hear what you’re saying—that you have these targeted therapies. You can always fall back to platinum-based chemotherapy as a next line for those patients who don’t respond. This is regardless of insurance issues.


The patient received carboplatin/pemetrexed chemotherapy and achieved a partial response.​ Now 4 months later, the patient is reporting worsening back pain and shortness of breath​. CT scan shows progression in primary tumor and a new adrenal metastasis​. Repeat brain MRI shows no metastases​.

What are you most likely to offer this patient as next-line therapy (assuming clinical trial is not available)?

Chemotherapy plus immune checkpoint inhibitor
Other tyrosine kinase inhibitor

RIELY: What would you pick in the second-line setting?

GUCALP: In our population, compliance is a very important issue. We prefer anything IV [intravenous], despite knowing the first dose [of amivantamab] has a lot of allergic reactions. But, in our population, we go with IV more than the oral drugs.

RIELY: IV versus oral is a big difference between the 2. It is interesting that when we talk about new drugs, we like pills, and for some patients pills are great, but not everybody. There is value for the IV [agent].

MAURA HAGAN, MD: Amivantamab had a response rate of 40% and the mobocertinib was around 28%.1,2 And so even though it’s hard to do cross trial comparisons, it’s easier to tell a patient they have a 40% chance of this working compared with 28%. Having said that, the duration of response was longer with mobocertinib, so that’s an advantage. But, from my perspective, I’m probably going to start with 1 drug and when they progress, try the other drug. So they’re going to get both, it’s just a matter of what you can afford and what adverse events you’re going to want to put up with first.

RIELY: That’s a key thing. We have these data…but they’re all single-arm studies in patients who have had prior treatment. None of them include patients who had the other drug, so we don’t know anything about which drug should we give first. Frankly [we have] no biology to tell us which way to go on that as well.

PAUL UNGER, MD: As someone who’s a generalist in practice and doesn’t see as much lung cancer as others in this group, these are drugs I [am not familiar with]. I’ve never seen this mutation before. But to be fair…these are compelling drugs with interesting mechanisms of action. But, if we’re all agreeing that these rare mutations are in the 1% to 2% range, if you’re looking hard for them and have the right assay to find them, that means out of the next 100 patients I see with metastatic lung cancer, probably no one will have [an EGFR exon 20 insertion]. Even ones that we think of as “common” rare mutations like ALK—I’ve been looking for ALK for a very long time, I’ve yet to find it in routine clinical practice.

UNGER: We found 1 before crizotinib [Xalkori] was approved, unfortunately, for a young non-smoking woman. It was classic [presentation] but no drug was available.

RIELY: It’s an interesting phenomenon around how we understand these rare events and as oncologists how we know what to do in this situation. We’re not going to know all these drugs for every disease.

UNGER: That’s the importance of the NGS report because they’re very good about telling you what’s there and then a good cataloging of standard FDA-approved therapies that might be relevant to that treatment. We could find it anyway, even if it was not listed, but that is a very good collaboration between pathology and oncology in terms of that information.

RIELY: The reports are sometimes a mess and hard to find what you need. But it is so nice when you look at that report and it makes clear where you’re supposed to go.

GUCALP: If these patients have brain metastases, do you use osimertinib [Tagrisso] over the other drugs?

RIELY: I would still stick with mobocertinib over osimertinib. There are data for osimertinib at 160 mg, a double dose, in patients with EGFR exon 20 insertions. The ORR was around 25%.3 It’s [from the POSITION20 study; NCT03191149]. There is a suggestion of efficacy, and we all think of osimertinib as a good drug for [treating] the brain [metastases]. To me, it’s less about penetration of the drugs and it’s more about the therapeutic window. Osimertinib and mobocertinib are very similar drugs. I think mobocertinib is a = bit more tweaked to hit EGFR exon 20. Osimertinib has been tweaked a bit in the other direction to hit EGFR 19 deletions and L858R. But I think it’s a provocative point that Dr Gucalp raises.


1. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662

2. Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol. 2021;7(12):e214761. doi:10.1001/jamaoncol.2021.4761

3. Zwierenga F, van Veggel B, Hendriks LEL, et al. High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial. Lung Cancer. 2022;170:133-140. doi:10.1016/j.lungcan.2022.06.012

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