EGFR Tyrosine Kinase Inhibitors for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Podcast

Additional Information: A video abstract, and the podcast and transcript can be viewed in the online version of the manuscript. Alternatively, the podcast and the video abstract can be downloaded here: https://doi.org/10.6084/m9.figshare.23975517.

1 **uning Le: [00:00]

Hello. Thank you for joining us for this podcast entitled EGFR Tyrosine Kinase Inhibitors for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations. My name is **uning Le. I am an Assistant Professor from UT MD Anderson Cancer Center. Today, we have three other experts in the field for this discussion. Dr Daniel Costa, can you please introduce yourself?

2 Daniel Costa: [00:27]

Hello. I am Daniel Costa. I am a Thoracic Medical Oncologist at Beth Israel Deaconess Medical Center. I am the group leader for our Thoracic Oncology Program and an Associate Professor of Medicine at Harvard Medical School.

3 **uning Le: [00:41]

Dr Eric Nadler, can you please introduce yourself?

4 Eric Nadler: [00:44]

My name is Eric Nadler. I am a Head and Neck and Thoracic Oncologist at Baylor University Medical Center in Dallas, and I run health informatics for thoracic and head and neck cancers in the US oncology networks. I have a huge database of information from which to cull.

5 **uning Le: [01:04]

All right, Dr John Heymach, can you please introduce yourself?

6 John Heymach: [01:07]

Hi, I am John Heymach. I am a Thoracic Medical Oncologist and I am Chair of the Department of Thoracic and Head and Neck Medical Oncology at MD Anderson Cancer Center.

7 **uning Le: [01:15]

All right. For today, first of all, I want to ask Dan to provide some background information on what we really mean by saying uncommon EGFR mutations, and what are uncommon EGFR mutations’ role in lung cancer?

Infographic

8 Daniel Costa: [01:34]

Thank you, ** with the emergence of COVID-19, those numbers changed markedly, but they are still not probably where we want them [22].

First and foremost, single genetic testing panels in the metastatic setting really do not exist anymore. So, most patients are being tested for more than one thing at a time, and that has been true for at least 3 years now [22]. And if you look at next-generation sequencing adoption throughout the nation, it went from about 30% in mid-2020 to now—more than 90% of all testing is next-generation sequencing. Now, [there are] lots of challenges with next-generation sequencing because that could be both plasma and tissue, and sometimes both. And of course, in our national community of practicing oncologists, there is a lot of heterogeneity in how people test, and what people test, and which tests they use. Whether or not it is both RNA- and DNA-containing, or whether it's just tissue or plasma [23, 24]. That being said, it is certainly moving in the right direction [25, 26].

But a couple of big points here that deserve mention. The first is, are we testing all the non-squamous, or are squamous actually being tested? And we know we can see EGFR and KRAS and other mutations in squamous histologies and certainly that is happening more and more. The second thing is, turnaround time has pushed a lot of people toward testing plasma-based approaches initially, sometimes in lieu of tissue-based testing, just because of the ease of it, and the turnaround time of some of the plasma-based approaches, and whether that be Guardant® or cobas®; they tend to be quicker than our tissue-based counterparts [27,28,29]. Lastly, there is a lot of geographic heterogeneity in our testing. I work in Texas in a large community practice and almost all of our patients are being tested in non-small cell lung cancer in the advanced setting. But you go to the state to the left or the right of me, and those rates could fall to 70% even today. So, it is a challenging, complicated time, and things like this podcast I hope will help inform and educate [to perform] at least tissue-based testing, and when that is difficult for turnaround time and tissue, you could add plasma to that easily; [it] should be done in all patients with non-small cell lung cancer [30]. And like I said, over the past 3 years, our numbers have more than doubled but they are still not where any of us would consider optimal.

11, 31, 32]. And both of those would be classified as PACC mutations. So, that is consistent with the data I mentioned before; that PACC mutants seem to be more sensitive to afatinib. In case reports, osimertinib, a third-generation drug, has demonstrated variable activity against L747P, with some studies saying that [this] mutation is resistant to osimertinib, others saying that there is some sensitivity [33,34,35]. So, I think we need more data really to see how that settles out.

Now, one other challenge that is worth mentioning is tumors sometimes have more than one mutation occurring in the same gene. We call these compound mutations. As an example, and this was actually early work from Dan Costa that I think really highlighted some of this: tumors will often have a mutation in, for example, the G719 and a 709 mutation or a 758 mutation at the same time. So, there are pairs of mutations that commonly occur together, and there is not an easy way to predict what the sensitivity is going to be other than to test those directly. So, there I think we are going to need to just have a large retrospective database to get clues, use the preclinical modeling, and then test them prospectively in the same type of clinical trials that we mentioned before. You know, in some recent meta-analyses, outcomes in patients who had EGFR inhibitors were generally better among patients with compound mutations if they had a classical mutation like a deletion 19, or an L858R with the second mutation, as compared with when there were two rare independent compound mutations [22]. So, if you have got a classical mutation as part of the compound mutation, it is more likely to be sensitive, is what the data are suggesting. And there are data supporting that those compound mutations, if they have a classical mutation as part of it, that are often sensitive to erlotinib, gefitinib, so first-generation drugs, or afatinib [36]. But if they have got two uncommon mutations, afatinib seems to perform better [36]. There are also some data saying that osimertinib is effective against certain compound mutations [22]. In one study, and it was just with four patients, there was a response rate of 75%, among those four patients, to osimertinib if they had a compound mutation that did not include deletion 19 or L858R [13] (Table 1).

In the recent Unicorn study, there was an encouraging response rate and progression-free survival in patients with some uncommon mutations [15]; so, in patients who had an uncommon mutation plus an L858R, or exon 19 deletion, or T790M, the response rate was 61% and the median progression-free survival was 30 months [15]. And in a much larger retrospective database with over 8000 patients with next-generation sequencing data, among patients who received osimertinib, there were eight patients who had a T854A mutation plus an L858R classical mutation [37]. And there the response rate was 80% and median progression-free survival was 10 months [37]. So, in summary, the real-world data can help support treatment decisions for some mutations, but we just do not have enough data from enough different mutations to make firm decisions for every mutation that comes along. A major unmet need is to develop more data with more different drugs so that we can best start matching drugs with mutations.

23 **uning Le: [33:03]

From today's conversation, we have heard [about] many different EGFR mutations, some at the mutational level, sometimes we use different words to refer to as uncommon, atypical. So, Dan, let me ask you, is it a problem that we have so many different names and different nomenclatures around the mutation? Is it a barrier for physicians to know how to offer the best treatment for a specific EGFR mutation to a patient?

24 Daniel Costa: [33:32]

Yes, I think that this is a major, major issue that needs to be addressed. I think that the lack of standardization on how to both classify the diversity of EGFR mutations and how to ask our partners in the diagnostic setting to use any classification that we use creates a lot of potential places where there could be both gaps in knowledge and also gaps in implementation of the evolving knowledge that we have been discussing here from preclinical models to prospective, real-world, retrospective datasets. The information is not always easily accessible to a practicing provider. I think, as Eric pointed out, although there had been an uptick in the use of more comprehensive genetic profiling, including next-generation sequencing that can capture the breadth and diversity of both single or compound EGFR mutations, the explanation of an identifiable mutation is not always easy for a provider to understand and to link to both FDA approval of particular EGFR inhibitors and also NCCN or other large guidelines that exist. And, obviously, I think for physicians that are specialized in EGFR-mutated lung cancer, similar to myself, John, and a few academic oncologists that do this on a day-to-day basis, like yourself **uning, obviously we can keep up with the evolving use of different terminologies and we can adapt much easier with the ideas of using a mutation-rich, structure-based classification where we are almost just focusing on a particular mutation, and then understanding all the work that has gone on from preclinical models to all clinical studies. But I think that this does not translate well for a community practicing oncologist. Obviously, it will be important to get Eric's perspective, what he hears from colleagues and others. But I do believe that one clear unmet need is to have better reporting where all this knowledge that we've gathered since the discovery of the EGFR mutations in 2000 and through 2004 to now is put together so that the clinician can read [and] understand in simple terms what that particular mutation means from sensitivity to inhibitors; give them a list of the FDA-approved inhibitors, and why they were approved, and also other options such as NCCN guidelines where they can use off-label. And then match with the clinical scenario, like if they see a patient with brain metastasis and then they have the ability to select between drug X or Y, based on both efficacy, clinical parameters, toxicity, expectations, and others. So, I think that this is a major unmet need to address, **uning.

25 **uning Le: [36:42]

Eric, can you also comment? I think you probably work with more diagnostic platforms as well. Can you also comment on what is your perspective of this challenge with so many mutations and so many different nomenclatures?

26 Eric Nadler: [36:57]

Well, I completely agree with Dan, and he stated it beautifully. But the challenge is when you're working outside of a large academic institution where they have a strong preferential internal testing platform. In the community or in smaller academic centers, you are talking about potentially two or three different platforms that are being used by every practitioner, sometimes more [38]. In my institution, the hospital uses one, and I routinely use another one. And then when I see patients in second and third opinions, I am seeing different tests. And the challenge is, each one of these testing companies reports this information in their own unique and distinct way with no homogenization of how they classify the mutation itself; whether it be typical or atypical, how they describe the mutation, whether it be the full mutation out to seven or eight digits, or kind of lump and group it into a more simplified form. There are few, if any, recommendations in terms of treatment in any of these reports that really direct you in terms of recommended treatments. And equally importantly, and I'll just mention, it does not direct you toward a clinical trial if one is available in your community or neck of the woods, which I think would be very helpful as well. So, one would hope that over the next 12–24 months that the testing communities themselves both simplify the reports, make it more streamlined and homogenized, so that we have a repeatable and understandable form in which this information is communicated to us. And lastly, that this is coupled with both NCCN or IASLC or other types of guidelines that are given to the practitioner, as well as clinical studies that they could look for that are within 100 or 200 miles of them. And I think all of these things would be important; and they are all underway. So, I am not saying anything that is not currently being discussed and happening, but I think that is very important, that this really gets codified in a rigid way that you can look at a report, know what you are looking at, and know how to take that report and make actionable decisions based on it.

27 **uning Le: [39:24]

To summarize today's discussion: an update to NCCN Guidelines® [4] regarding G719X, L861Q, and S768I is supported by a growing body of clinical evidence. A new characterization system allowing prediction of sensitivity to TKI for infrequent, often we call them uncommon, EGFR mutations exists now [and] we can classify them into four different classes based on the structural functions, evidence supported preclinically [1]. Real-world data and the mutation database are improving with clinical evidence for EGFR TKI selection against different uncommon EGFR mutations. However, clinical trial or prospective data are still lacking [39]. Therefore, that is an unmet need for us to conduct clinical trials to improve what we currently have. Last, broader uptake of next-generation sequencing for tumor molecular profiling, and the availability of better guidance for physicians, are key obstacles to address going forward so that we can offer precision oncology to our lung cancer patients. I thank you for your attention and I also want to thank Dr Daniel Costa, Dr Eric Nadler, and Dr John Heymach for joining us today.

Change history

27 October 2023
A Correction to this paper has been published: https://doi.org/10.1007/s11523-023-01010-3
09 December 2023
A Correction to this paper has been published: https://doi.org/10.1007/s11523-023-01020-1

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Authors and Affiliations

The University of Texas MD Anderson Cancer Center, Houston, TX, USA
**uning Le & John Victor Heymach
Baylor University Medical Center, Dallas, TX, USA
Eric Nadler
Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Daniel B. Costa

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**uning Le
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Medical writing support for the development of this podcast manuscript, under the direction of the authors, was provided by Jim Sinclair, PhD, of Ashfield MedComms, an Inizio Company, and was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the podcast manuscript for medical and scientific accuracy as well as intellectual property considerations.

Conflicts of Interest/Competing Interests

**uning Le has received consultant and advisory fees from AstraZeneca, BluePrint Medicine, Boehringer Ingelheim, Daiishi Sanko, Eli Lilly, EMD Serono, Hengrui Therapeutics, Janssen, Spectrum Therapeutics, and Novartis; and research funding from Arrivent, Eli Lilly, Boehringer Ingelheim, Teliegen, and Spectrum Pharmaceuticals. Eric Nadler has received payment for speaker bureau and speaker arrangement from Merck, AstraZeneca, Genentech, G1 Therapeutics, Jazz Pharmaceuticals, and Blueprint Pharma. Daniel B. Costa has received personal fees (consulting fees and honoraria) from AstraZeneca, BluePrint Medicine, Janssen, Pfizer, and Takeda/Millennium Pharmaceuticals; consulting fees from Teladoc and Grand Rounds by Included Health; and nonfinancial support (institutional research support) from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Daiichi Sankyo, Merck Sharp and Dohme Corporation, Merrimack Pharmaceuticals, Pfizer, Spectrum Pharmaceuticals, Takeda/Millennium Pharmaceuticals, and Tesaro. John Victor Heymach has received research support from AstraZeneca, Boehringer Ingelheim, Spectrum, and Takeda; holds an advisory role with AstraZeneca, BMS, BrightPath Biotherapeutics, Chugai Pharmaceuticals, EMD Serono, Boehringer Ingelheim, Catalyst, Eli Lilly, Genentech, GlaxoSmithKline, Hengrui Therapeutics, Janssen Global Services, Mirati Therapeutics, Nexus Health Systems, Pneuma Respiratory, Refle**on, Spectrum, Sanofi, and Takeda; and has received royalties and licensing fees from Spectrum.

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Le, X., Nadler, E., Costa, D.B. et al. EGFR Tyrosine Kinase Inhibitors for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Podcast. Targ Oncol 18, 807–817 (2023). https://doi.org/10.1007/s11523-023-00994-2

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Accepted: 17 August 2023
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DOI: https://doi.org/10.1007/s11523-023-00994-2

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EGFR Tyrosine Kinase Inhibitors for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Podcast

1 **uning Le: [00:00]

2 Daniel Costa: [00:27]

3 **uning Le: [00:41]

4 Eric Nadler: [00:44]

5 **uning Le: [01:04]

6 John Heymach: [01:07]

7 **uning Le: [01:15]

Infographic

8 Daniel Costa: [01:34]

23 **uning Le: [33:03]

24 Daniel Costa: [33:32]

25 **uning Le: [36:42]

26 Eric Nadler: [36:57]

27 **uning Le: [39:24]

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27 October 2023

09 December 2023

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