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EGFR Expansion: Optimizing EGFR Identification Across the Spectrum of Non-Small Cell Lung Cancer

  • Authors: Anjali Saqi, MD, MBA; Fred Hirsch, MD, PhD; Pasi Jänne, MD, PhD
  • CME / ABIM MOC Released: 1/31/2023
  • Valid for credit through: 1/31/2024
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  • Credits Available

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Target Audience and Goal Statement

This activity is intended for pathologists, oncologists, pulmonologists, and other members of the multidisciplinary team (MDT) involved in the care of patients with non-small cell lung cancer (NSCLC).

The goal of this activity is for learners to be better able to accurately identify EGFR mutations in patients with NSCLC to help provide the foundation for multidisciplinary treatment strategies.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Molecular heterogeneity of EGFR mutations occurring in NSCLC
    • Methodologies used to detect EGFR mutations in NSCLC
  • Have greater competence related to
    • Accurately identifying EGFR mutations across the spectrum of NSCLC
  • Demonstrate greater confidence in their ability to
    • Implement multidisciplinary strategies for EGFR testing in patients with NSCLC


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  • Anjali Saqi, MD, MBA

    Pathology and Cell Biology
    Columbia University Irving Medical Center
    New York, New York


    Anjali Saqi, MD, MBA, has the following relevant financial relationships:
    Consultant or advisor for: Bristol Myers Squibb Company; Genentech/Roche; Veracyte
    Research funding from: Boehringer Ingelheim Pharmaceuticals, Inc.; Genentech
    Other: I received honoraria/fees from the following: Dedham; Noreen Ellis Consulting; Qessential

  • Fred Hirsch, MD, PhD

    Center of Excellence for Thoracic Oncology
    Tisch Cancer Institute
    Professor of Medicine
    Icahn School of Medicine
    Mount Sinai Hospital
    New York, New York


    Fred Hirsch, MD, PhD, has no relevant financial relationships.

  • Pasi Jänne, MD, PhD

    Professor of Medicine
    Department of Medical Oncology
    Harvard Medical School
    Lowe Center for Thoracic Oncology
    Dana-Farber Cancer Institute
    Boston, Massachusetts


    Pasi Jänne, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie, Inc.; Accutar Biotech; Allorion Therapeutics; AstraZeneca Pharmaceuticals LP; Bayer; Biocartis; Boehringer Ingelheim Pharmaceuticals, Inc.; Chugai Pharma USA, LLC; Daiichi Sankyo, Inc.; Eisai, Inc.; Frontier Medicines; Hongyun Biotechnology; Merus; Mirati Therapeutics; Monte Rosa; Novartis Pharmaceuticals Corporation; Nuvalent; Pfizer, Inc.; Roche/Genentech; Lilly USA, LLC; Sanofi; Scorpion Therapeutics; SFJ Pharmaceuticals; Silicon Therapeutics; Syndax Pharmaceuticals, Inc.; Takeda Oncology; Transcenta; Voronoi
    Research funding from: Astellas Pharma, Inc.; AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Daiichi Sankyo, Inc.; Lilly USA, LLC; PUMA; Revolution Medicines; Takeda Oncology
    Royalties from: LabCorp; This is for postmarketing royalties from Dana Farber Cancer Institute-owned intellectual property (I am an inventor on the patent) on EGFR mutations licensed to Lab Corp.
    Owns stock (privately owned) in: Gatekeeper Pharmaceuticals


  • Lisa Cockrell, PhD

    Medical Education Director, Medscape, LLC


    Lisa Cockrell, PhD, has no relevant financial relationships.

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  • Lisa Simani, APRN, MS, ACNP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Lisa Simani, APRN, MS, ACNP, has no relevant financial relationships.

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EGFR Expansion: Optimizing EGFR Identification Across the Spectrum of Non-Small Cell Lung Cancer

Authors: Anjali Saqi, MD, MBA; Fred Hirsch, MD, PhD; Pasi Jänne, MD, PhDFaculty and Disclosures

CME / ABIM MOC Released: 1/31/2023

Valid for credit through: 1/31/2024


Activity Transcript

Anjali Saqi, MD, MBA: Hello everyone. I am Anjali Saqi. I work at Columbia University where I practice thoracic pathology. Welcome to this program entitled "EGFR Expansion: Optimizing EGFR Identification Across the Spectrum of Non-Small Cell Lung Cancer." Today I am joined by Dr Fred Hirsch and Dr Pasi Jänne. Today, the first thing we will be doing is setting the stage, and I'm going to pass the baton to Dr Hirsch to provide an overview of our evolving understanding of non-small cell lung cancer.

Fred Hirsch, MD, PhD: Thank you very much Dr Saqi. Lung cancer has undergone a tremendous development from a biological knowledge to leading to therapeutic progress. Mainly it is through the identification of oncogenic drivers, which are targetable for molecular targeted therapies. There are numerous oncogenic drivers identified in particularly lung adenocarcinomas. KRAS and EGFR represent the most common driver mutations in pulmonary adenocarcinomas. 

The picture, as I said, has changed tremendously over the last decade, and we continue to identify new mutations, new variations, and also we continue to get new drugs targeting these abnormalities. We know that there might be differences in the predominance of these mutations whether we are in the Western population or Asian population. That is particularly true for EGFR. For EGFR mutations in the Western population, the prevalence is around 12% to 15%, while in the Asian population, it is more than 40%, so there is a difference. For the other mutations, we do not see much of a difference, but we need to learn more about these differences. There might be subpopulations where there are different prevalences. 

We have seen a tremendous development in therapies targeting those abnormalities. We can see here particularly over the last few years, we have seen quite a lot of new Food and Drug Administration (FDA) approvals in lung cancer. We know that the identification of driver mutations is important, and we know that applying targeted therapies to the right populations is important. 

For patients with targeted therapies, there is clearly an outcome benefit compared to those without the driver. We know that the patients who potentially could have a driver mutation and not get molecular testing do not fare as well as those with optimal molecular testing and optimal targeted therapies. That phenomena has certainly led to a decrease in lung cancer mortality and increased survival, particularly in patients with advanced disease. We have also seen in recent years tremendous development when we are talking about early-stage disease and particularly for patients with EGFR mutations. 

KRAS and EGFR mutations are most dominant in pulmonary adenocarcinomas. KRAS is related to smoking habits and EGFR mutations and also ALK, ROS1, and RET are related to a never smoker status and particularly also related to female gender.

This session is about EGFR mutations particularly and when we are talking EGFR mutations, we are focusing on mutations in the tyrosine kinase domain and particularly in exons 18 to 21. Most of the mutations are in exon 19 and exon 21. 

We are learning more and more about rare mutations in the EGFR domain, particularly in exon 18 and exon 21. The most frequent exon 19 and exon 21 mutations, they are highly sensitive to targeting by the conventional EGFR drugs, the EGFR tyrosine kinase inhibitors, which we now have several generations of. More recently, we have very encouraging data for the more rare mutations, particularly in exon 20, which will be addressed by Dr Jänne. 

Here, we have an overview of EGFR mutations. The distribution between L858R or exon 21 mutations and exon 19 deletions is probably more or less equal. Then we have in between there the more rare mutations which we will discuss more in detail later. So with that brief introduction to the field, I will leave it to Dr Saqi to talk about the pathology of EGFR mutations in lung cancer and particularly adenocarcinomas. 

Dr Saqi: Thank you, Dr Hirsch. So as you mentioned, I will be discussing the pathology of EGFR mutations, and I will start by discussing a case and the pathology related to that. The case that I will be discussing today is from a 47-year-old woman who was a light smoker but had no other significant past medical history. She presented based on her symptoms of dyspnea for about 4 weeks, and imaging at the time showed the right lower lobe had lymphangitic carcinomatosis, and also she had an enlarged right hilar lymph node, bilateral mediastinal adenopathy, and enlarged supraclavicular lymph nodes. Following this, she underwent a PET scan, and the PET scan showed positivity in the thorax, the supraclavicular lymph nodes and also the retroperitoneal lymph nodes. The positivity in the retroperitoneal lymph nodes suggests that she probably has advanced disease. 

Based on these findings, she underwent a biopsy of the supraclavicular lymph node, and the biopsy showed an adenocarcinoma which had a solid pattern. The carcinoma was positive for TTF-1, which was compatible with an adenocarcinoma. In addition to that, immunohistochemistry was performed for anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), and both of these were negative. The next question is, she has an adenocarcinoma and immunohistochemistry (IHC) for 2 of predictive biomarkers, ALK and ROS1, are negative. What other testing could she potentially benefit from? 

Before I go into more details of this, I want to discuss a little bit about the molecular testing guidelines. The molecular guidelines have evolved very quickly. In 2018, the guidelines issued by the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) suggested EGFR, ALK, and ROS1. In the American Society of Clinical Oncology (ASCO) guidelines, BRAF was also suggested. These have quickly changed, and the most current guidelines from the National Comprehensive Cancer Network (NCCN) have added several other markers that should be tested, including MET, RET, NTRK, HER2, and KRAS.

The question is, who do we test? What do we test? How do we go about [it]? What do we do in pathology? I want to address these a little bit more. So the first question is, who do we test? The current guidelines suggest that the patients who should definitely receive testing are those that have advanced stage cancer, such as our patient, given that she has retroperitoneal adenopathy, and also those that have an adenocarcinoma. But in addition to that, whenever the possibility of an adenocarcinoma cannot be excluded, molecular testing should also be performed. For example, in some instances, we may not be able to have a diagnosis based on immunohistochemistry. For example, the tumor may not be positive for TTF-1 and other site-specific markers are negative. But given the CT findings, this is most likely a non-small cell carcinoma. Such a patient would also benefit from molecular testing.

Another example when we may want to do molecular testing is in a patient who is young, a never smoker, and has squamous cell carcinoma. If you have excluded squamous cell carcinoma metastasis from another site, a presence of squamous cell carcinoma in a never-smoker young patient is very unlikely. Possibly, this may be a component of adrenal squamous cell carcinoma. So these are the main instances when we should be performing testing. 

The next question is, when do we perform the test? There are 2 scenarios. First is when the person is first diagnosed, and it is important to perform testing in these advanced-stage patients. The next question is, should we be performing testing reflexively on all patients that have adenocarcinoma or non-small cell carcinoma in which a component of adenocarcinoma cannot be excluded? Should we be testing earlier-stage cancers? And this is something we can all discuss as a group, including what are some of the benefits of this? Certainly if you have reflex testing, it expedites the process rather than having to wait to hear whether the patient does have advanced-stage cancer, particularly because that information may not always be available to the pathologist. More and more, there are ongoing clinical trials now where we are trying to perform neoadjuvant targeted treatment on patients. So in such instances, at least in the future, perhaps testing even an earlier-stage cancer may be coming down the pipeline. Besides performing testing at [the] time of diagnosis, we also want to perform molecular testing at the time of disease progression or recurrence. So the question is, why should we do this? First, we want to confirm the original diagnosis of lung cancer, a lung cancer maybe in a distant site such as the liver still represents that same cancer and not a primary or second metastasis from elsewhere. Also, we want to identify if there has been any morphological transformation. Some patients who undergo TKI treatments have morphological transformation. For example, an adrenal carcinoma may transform and have a small cell morphology. 

The next question is, what do we test? So in pathology, we have the benefit of having many different specimen subtypes, and all of these can potentially give us the information we need. So we have cytology samples, we also have surgical pathology samples. Among these, and also within each of these groups, we have different types of specimens. We have fine-needle aspirations that are obtained by various different methods. We also have effusions, for example, a pleural effusion, and sampling of a pleural effusion may avoid having a patient undergo a more-invasive procedure. Also, we have surgical-related specimens, such as biopsies. And all of these specimens can provide ample material. They are proven to provide ample material in most instances. However, as the literature states, it is feasible in many instances, but unfortunately in some instances we do not have sufficient tissue to perform the necessary testing. 

Another point that I want to raise is that although really the tissue biopsy represents the gold standard, liquid biopsy does provide potential additional opportunities to perform testing. Relative to tissue biopsies, liquid biopsies are noninvasive. They give us the opportunity to have a more rapid turnaround, especially because no tissue is identified and they are very specific. However, there are some negatives to liquid biopsy, and probably the most negative impact is that it is not very sensitive. Patients that have more advanced disease or that have, for example, metastasized, are more likely to have a mutation detected by a liquid biopsy as opposed to someone who may have a localized early-stage tumor. The NCCN guidelines, for example, state that liquid biopsies can be considered in specific clinical circumstances. For example, if a patient is medically unfit for invasive tissue sampling, this may provide an alternative. If such testing is done and no mutation is identified, the recommendation is to actually go forward and obtain the tissue biopsy to determine if the exact mutation is present. 

What kind of testing do we want to submit? What kind of tests are available to us? Earlier in the case I mentioned that some immunohistochemical stains, for example, ALK, can help us identify translocation. But if that is negative, we want to go forward and examine other possible mutations, as Dr Hirsch outlined earlier. We can do this in 1 of 2 ways. We can identify these through a single-gene analysis or we can do multiplexed next-generation sequencing. While they both have some advantages and disadvantages, the recommended guidelines are to use multiplexed NGS. The single-gene sequencing, if you just look at it individually, has a smaller input and shorter turnaround time. Overall, as you combine all of the testing that is necessary, when we perform NGS, we are able to look at all the recommended markers in parallel. When you do all of these in parallel, the overall tissue requirement for NGS is less. It may be more cost effective, and it allows for multiplexing and detection of novel mutations.

The negative to this is despite having all of these guidelines, studies have shown that fewer than half the patients with NSCLC are currently being tested for all of the 5 major biomarkers, which include ALK, BRAF, EGFR, and ROS1. Also these days, we are testing for programmed death-ligand 1 (PD-L1), although that's by immunohistochemistry. Since 2018, the testing has only slightly improved in this population of NSCLC or lung adenocarcinomas. Even fewer patients undergo HER2 testing. The question is, why might this be the case? There was a global survey conducted by the IASLC on molecular testing in lung cancer. One of the most common reasons for not having this test performed is because of cost. Some of the other reasons that someone may not undergo molecular testing include quality or access, but cost is really the major barrier for not having molecular testing performed. 

So this was a brief overview of what we practice in pathology. But now I would like to open up the discussion to our group and basically ask, we all work in different major medical institutions and also we see patients from [the] community setting. I would like to first discuss the pathology, what is it, or what are the methods, and what are your experiences with molecular testing at your respective institutions?

Dr Hirsch: In my institution, we have more or less reflex testing for all of our lung cancer patients. But we are, as your institution, we are a highly academic institution, and the culture here might not be exactly the same as out in the communities because we have a lot of academic aspects to it as well. But 1 thing I probably should have mentioned is we do not only do molecular testing for finding the best treatment to the patient. Yes, we do, but it is important also to avoid a wrong treatment for the patient.

Dr Jänne might come to this later when we talk about EGFR therapy, specifically EGFR mutation is important because we have effective therapy against it. But if the patient is not tested and we give immunotherapy to this patient, we actually did not do this patient a favor. We know that in this particular subpopulation, immunotherapy is not the best way to treat patients. It is a bad treatment for EGFR mutation-positive patients. So it is important to emphasize also that we do molecular testing to avoid giving the patient the wrong treatment.

Dr Saqi: That's a very good point. It is not only identifying the correct treatment but also avoiding the incorrect treatment.

Dr Hirsch: Correct.

Dr Saqi: Dr Jänne, what is the practice in your institution?

Pasi Jänne, MD, PhD: For us, it is not a reflex test but it is an oncologist-driven test that is ordered. We do now reflex test early-stage lung cancers for EGFR mutations because of the approval of osimertinib in the adjuvant setting. That is 1 place we reflex test, but that is a single-gene analysis. For patients with advanced disease, we do panel-based NGS that is driven by an oncologist that ordered the test.

Dr Saqi: I wanted to get Dr Jänne's perspective, given that it is oncology driven, do you find this delays procedures, or how do you communicate with your pathologists, other clinicians so that you are getting things in a timely manner and the patients are being treated adequately and as fast as possible?

Dr Jänne: Thank you for that question. We do have a continuous discussion between the oncologist and the pathologist, especially when there is a more urgent need to get testing done depending on the patient's condition. Although most of the time for our patients, we cannot wait the 7 to 10 days it takes to get the NGS testing done. The difficulty is when the pathology specimen does not exist at our hospital, but is at an outside institution. In those cases, we have set up processes to get that specimen to our institution to then do the testing. There are multiple steps involved, and it does involve team effort and does involve communication with all interested parties.

Dr Saqi: The second question I have is regarding the major barriers to having molecular testing done is reimbursement or cost. Certainly, I think for advanced-stage cancer that is probably not as much of an issue. But about, you mentioned in your institution you have been testing in the early stage, is that been a factor, the cost or is how does your institution handle that?

Dr Jänne: Right. Since it is testing for a single gene where there is an approved therapy, it is less of an issue. We do not do NGS in early-stage disease because we only have the approval of an EGFR inhibitor. But there are of course clinical trials looking at neoadjuvant and adjuvant therapies, other adjuvant targeted therapies in both of those situations. And there we have methods to cover those costs for the testing.

Dr Saqi: Going back to the case, I wanted to say that molecular testing was performed on this patient, and an EGFR exon 20 insertion mutation was identified and there were no fusions identified, no other mutations. With that I am going to turn over to Dr Jänne to discuss how would this patient be managed.

Dr Jänne: Thank you so much. Let's look into a little bit more details about exon 20 insertions and what we know about the therapeutic landscape in this situation. As Dr Hirsch mentioned, this is a subset of EGFR mutations. In fact, it is the third most common EGFR mutation after the common exon 19 deletion and L858R mutations, and they make up about 12% of EGFR mutations. There are others that are even less common than the exon 20 insertions and they represent about 1% to 2% of all driver mutations in NSCLC. 

Exon 20 insertions represent a spectrum of mutations. They are not 1 mutation, not like a point mutation. In this schematic you can see exon 20 and the specific locations of the mutations. Some of them are in the C-helix portion of the receptor and others are in the loop following the C-helix. Why is this important? Mutations in the C-helix, such as the mutation called the insFQEA mutation, do retain some sensitivity to earlier-generation EGFR TKIs, whereas the ones in the loop following the C helix tend not to be sensitive to early-generation EGFR TKIs. So it is something to keep in mind when you get the pathology reports and many pathology reports have that indicated in them. There is a long tail of exon 20 insertions you can see in this bar graph. There are ones that are only identified 1 time. As was mentioned about testing, there are single-gene assays that test for exon 20 insertions. However, these assays miss about half of the exon 20 insertions because they are only looking for some of the known exon 20 insertions, not all of them. Whereas with NGS, as Dr Saqi mentioned, you can capture all of these different mutations, and hence NGS is a preferred method to look for exon 20 insertions and for genotyping our lung cancer patients in general. 

To summarize some of the therapy for this group of patients: these individuals unfortunately tend to have a poor prognosis vs those in patients who have common EGFR mutations or even those who have the uncommon exon 18 mutations because EGFR inhibitors work in those populations as well. The standard of care today for a patient in the frontline setting with an exon 20 insertion with advanced NSCLC is platinum-based chemotherapy. There are novel therapies now approved for patients with exon 20 insertions after they have been treated with frontline platinum chemotherapy.

If you look at the clinical features of our exon 20 insertion patients compared to common EGFR mutations, they are basically the same. The phenotypic population is the same. They tend to be in individuals who do not have a smoking history, and more commonly who are female gender. So the same phenotypic population, just a different type of EGFR mutation. If we look at outcomes of these individuals, as I mentioned, progression-free survival and overall survival is poor in patients with exon 20 insertions compared to those with the common EGFR mutations, and it is really similar to patients who do not have an EGFR mutation. As I mentioned, there is 1 subtype that is sensitive to prior-generation EGFR inhibitors, called the insFQEA mutation.

Patients who have been treated with these agents who have these exon 20 insertions with the insFQEA mutations tend to have a response. Now, Dr Hirsch also mentioned the aspect about immune checkpoint inhibition. This is a type of therapy that although it is used widely in lung cancer, it does not work very well in patients with EGFR-mutated NSCLC. The same is true whether or not you have an exon 20 mutation or one of the more common EGFR mutations. These cancers tend often to be PD-L1 negative, and even when they are PD-L1 positive, immune checkpoint inhibition has little or no efficacy.

Let's get back to our case. The patient received the standard of care, which would be first-line chemotherapy with carboplatin/pemetrexed. She had a partial response after 4 cycles and then went on to receive maintenance treatment with single-agent pemetrexed. Unfortunately, she develops disease progression after 6 maintenance cycles with further enlargement of mediastinal and cervical lymph nodes. She has an excellent performance status, and no central nervous system (CNS) metastases are identified. Now the question becomes, what is the therapeutic opportunity at this point? 

Currently approved agents, such as osimertinib given at double the standard dose (160 mg), have some activity but not great in this patient population, with a response rate of about 25%. Standard frontline treatment of platinum-based chemotherapy, which is a standard of care, has a medium progression-free survival (PFS) [of] about 7 months. And as I mentioned, immunotherapy is highly ineffective. There are 2 approved agents, amivantamab and mobocertinib, in the second-line post platinum-based chemotherapy setting, which we will go through in detail. 

This represents the NCCN guidelines for patients who have exon 20 insertions who develop progression. They can be treated in the subsequent-line therapy with either amivantamab or mobocertinib. 

For amivantamab, this is the FDA indication. Amivantamab is a bispecific antibody, meaning it has one-half of the antibody that binds EGFR and one-half that binds MET. During the development of this antibody, it was recognized that it had activity in patients with EGFR exon 20-mutated NSCLC. Following binding of this antibody, it promotes receptor endocytosis and degradation, and antibody-dependent cell-mediated cytotoxicity (ADCC)- and trogocytosis-mediated cell death, and thus tumor regression. The EGFR exon 20 patients were a part of the CHRYSALIS study and which is depicted here with a dose escalation. In cohort D, exon 20 insertion patients were specifically evaluated. In this population, there was 81 patients that were evaluated. The demographics are pretty similar to what I mentioned earlier. About 20% of patients had a history of brain metastases, and patients had up to 7 lines of prior therapy. All patients had platinum-based chemotherapy, and patients had a variety of prior-generation TKIs. 

The clinical activity is shown here; the response rate was 40%, the duration of response [was] 11.1 months, and the median PFS was 8.3 months. In the waterfall plot, you can see color coding based on the location of the exon 20 insertion. It does not appear that there is a clear efficacy mutation relationship that 1 particular set or location of mutations is more sensitive to amivantamab than the other, although the denominator is still quite small, and this is an area of additional work that is needed. 

What about side effects of amivantamab? There were side effects, including adverse events that led to discontinuation in about 10% of patients, dose reductions in about 13%, and dose interruptions in about 35% of individuals. Amivantamab has some unique toxicities. There are infusion-related reactions which can be seen in the majority of patients. Most of them are grade 1 and 2, but occasionally a grade 3 reaction is seen. There are also on-target EGFR toxicities, including rash, paronychia, dry skin, as well as some gastrointestinal (GI) type of toxicities, which we've seen with earlier-generation EGFR inhibitors like erlotinib and afatinib.

Following the accelerated approval of amivantamab, there is now a phase 3 trial ongoing in the frontline setting. Here, amivantamab is being given in combination with standard-of-care chemotherapy, carboplatin and pemetrexed, compared to giving chemotherapy alone. The primary endpoint of this study is progression-free survival, and we eagerly await the results of this trial, as it would open up the opportunity to treat our EGFR exon 20 patients with a targeted therapy in the frontline setting. 

Mobocertinib, which is the other approved agent, has a very similar FDA indication. Mobocertinib, however, is a tyrosine kinase inhibitor just like other EGFR TKIs such as osimertinib. It underwent some preclinical optimization to be more effective against exon 20 insertion mutations. It binds cysteine 797, and is a covalent inhibitor just like osimertinib. It binds wild-type EGFR weaker than mutant EGFR, which is a potential therapeutic advantage. 

The phase 1/2 and the EXCLAIM cohorts were what led to the regulatory approval in patients that had received prior platinum-based chemotherapy, especially in the EXCLAIM cohort. There are also patients in the first cohort that fit these criteria. These are the characteristics of the patients treated with mobocertinib; you can see again demographics are similar to other EGFR-mutated patients that I mentioned before. Patients were fairly heavily pretreated, again up to 7 lines of therapy, with the median being 2 in the post-platinum-treated cohort. All patients essentially had prior platinum-based chemotherapy, and about a third had prior EGFR TKI therapy.

The response rate was 28%. All of them were partial responses. The median duration of response was 17.5 months in this patient population. And here, too, the mutations are color coded based on the type of mutation, and you do not really see a clear mutation efficacy relationship here either. Although again, denominators are small and additional studies are certainly needed in the to see if there is such a relationship. The median duration of response I mentioned [was] 17.5 months, and a median overall survival of 24.0 months in this patient population. 

What about side effects? Mobocertinib has a different side effect profile than amivantamab and has much more of a GI-predominant side effect profile, with diarrhea being the number 1 toxicity. Among the side effects, most were low grade, although there were grade 3 diarrhea seen in this patient population as well. You can get some other EGFR toxicities, such as rash, paronychia, dry skin, and stomatitis, with mobocertinib as well. About 25% of patients had dose reductions, and depending on which cohort you looked at, either 10% or 17% of patients had a treatment discontinuation due to toxicity. 

Even with prior EGFR inhibitor therapy, mobocertinib can still have efficacy. You can see that some of these patients were treated with early-generation EGFR inhibitors or prior osimertinib or prior poziotinib. So there can still be efficacy in patients who have had prior EGFR TKIs. 

Mobocertinib is also in a phase 3 clinical trial compared to platinum-based chemotherapy here given as a single agent, not in combination unlike amivantamab also in the first-line setting. We also await results of this study; the primary endpoint here is progression-free survival.

I think what is not clear, as I mentioned, is that both amivantamab and mobocertinib are approved in this clinical situation. Is there a right order? Do you start with 1 and then go to the other, and which one should it be? And I think that will be subject of ongoing development as we move forward. As I mentioned, these 2 agents have a different spectrum of side effects, [with] infusion reactions and skin-related toxicities of amivantamab, and you can see the incidents there and how we typically deal with the side effects; whereas diarrhea and rash are more common side effects with mobocertinib. So it is a discussion point with patients. One is an oral agent, 1 is an intravenous (IV) agent, and there is a different spectrum of side effects. When choosing one of these agents, it is not just the efficacy, which at the end of the day is pretty similar for both drugs, but it is also the type of treatment and the side effect profile that is important here. 

What are we missing from our exon 20 inhibitors? Well, many of them, including mobocertinib and amivantamab, are not particularly effective against CNS metastases, and patients over time can get CNS metastases very easily. We need other effective exon 20 inhibitors that penetrate the CNS; this is certainly a need because if you are not treating CNS disease, you probably have a likelihood of overall lower efficacy of this class of agents. There are a few agents where we have data and are in clinical development. 

One is called sunvozertinib, or DZD9008, which is also EGFR tyrosine kinase inhibitor. And similarly CLN-081, which is also a covalent EGFR inhibitor as a sunvozertinib. We have started to see data on these agents. With sunvozertinib, the most recent data showed an overall response rate in the phase 2 trial of about 60%, and there were responses in the brain with a brain metastasis response rate of 48%, and [the] median duration response had not been reached. So that leads suggests that there is some activity in the brain of these next-generation inhibitors. You can see the side effect profile on the right hand on the slide and most of his on-target EGFR toxicity, rash, diarrhea, stomatitis that we are used to seeing with other EGFR inhibitors. 

Similarly, with the CLN-081 compound, there is a response rate of about 40%, and event-free survival of about 10 months, and a duration of response of about 10 months as well. You can see responses here in the waterfall plot, and "E" represents patients who received prior EGFR TKI therapy. Again, you can see responses after receiving other prior EGFR TKIs. The side effect profile, also mostly EGFR-driven rash, paronychia, diarrhea, fatigue, and stomatitis, shown on the right hand side, mostly low-grade and occasional grade 3 toxicities. 

So this patient received a cycle of amivantamab, and she had an infusion-related reaction which was managed effectively and she was able to continue therapy. She achieved a partial response after 2 months of treatment. She continues on treatment and has a grade 1 rash which is being managed. I think the question will be, what happens when amivantamab stops working? She could go on mobocertinib at that point or one of the next-generation investigational EGFR exon 20 inhibitors. There are several others in development. We are still looking for the osimertinib of exon 20 insertions. I do not think we are quite there yet, but hopefully we'll find one with these next-generation inhibitors. 

I'll now turn it back to Dr Saqi for some concluding thoughts.

Dr Saqi: Thank you very much for that very nice discussion and a summary of what has occurred, what is in the pipeline. So that's very important for us to know. And a few concluding remarks based on what was discussed. First of all, I want to say it is important. Pathology plays a very important role in this. We want to try to really identify all potential actionable targets because without that, patients will not get the appropriate treatment. And I think one of the other things I learned from our discussion here is there are different ways of approaching molecular testing. One is reflex testing and the other is not every institution has that, but whenever there isn't reflex testing, I think Dr Jänne, you brought up a very good point about having open lines of communication with the pathologist or the clinical team and the pathology team having open lines of communication to ensure that the appropriate testing is performed and in a timely manner.

And I think the other important thing is we have different types of testing available to us. There is NGS, single-gene analysis, and certainly there are instances where the single-gene analysis may be helpful, as was mentioned. But for the most part what is recommended and what is useful to identify broader range of targets is having parallel or NGS testing. And in some instances, liquid biopsy also plays a very important role. And I think having an educational or tumor boards discussing this would be very helpful as a group. And a couple of more points that I want to highlight is about the EGFR mutations themselves. EGFR exon 20 mutations, though they are not the most common type of mutations, they still represent 5% to 12% of all EGFR mutations. And there is a broad spectrum of EGFR exon 20 mutations.

And again, to be able to identify this, we really need to perform NGS testing because not all PCR based methods will identify the various types of mutations because this is very diverse field. And as far as treatment is concerned, the first line treatment is still chemotherapy, with the exception of rare EGFR exon 20 mutations, which are still amenable to the first generation of TKIs. And finally, for those that are not amenable to first line TKIs, there are two FDA approved drugs for patients that have been pretreated with chemotherapy. They have different safety profiles. So it's important to discuss that with the patient. And to summarize the final conclusion, EGFR exon 20 insertions should be included in the non-squamous genotyping. And with that, I want to just ask if there are any additional pearls you would like to share, Dr Hirsch, Dr Jänne?

Dr Hirsch: I think you summarized very nicely and I think we had a good conversation around the EGFR mutations. I think communication, multidisciplinary communication is extremely important these days.

Dr Jänne: I would agree. And just to add that to the last bullet point is that, you have to do broad panel-based testing in order to find the exon 20 insertions because it's important because they are approved drugs and drugs and development, and we want to always offer the best therapies for our patients. And if we do not know what is the genetic makeup of the particular cancer, we cannot do that as clinicians.

Dr Saqi: Right. And again, that our discussion has really focused on EGFR exon 20, but this goes for all mutations and not just for this group of patients. And with that, I want to thank you both very much for this great discussion and thank you to the audience for participating in this activity. And after this, please continue to answer the questions that follow and complete the evaluation.

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