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Precision in Progress: Advancing Personalized Care in EGFR Mutation–Positive NSCLC Care

The first part of this webinar will be Setting the Scene: Individualized Testing and Treatment of EGFR-Mutated Non-Small Cell Lung Cancer.

Individualized Testing and Treatment of EGFRm NSCLC

I will discuss:

• The current state of biomarker testing;
• The guidelines, highlighting the heterogeneity of EGFR-mutated non-small cell lung cancer;
• Common mutations;
• Uncommon mutations;
• Exon 20 insertions; and
• What are the data and what are the standard of care for the management of those patients with common EGFR mutations.

Patient Stratification to Define Optimal Treatment Approaches

Obviously, when we treat a patient with lung cancer, and more specifically, EGFR-mutated non-small cell lung cancer, we take into account many aspects, not only of the patient's age, performance status, comorbidities, the extent of the disease, including the tumor burden, CNS disease. Is this an upfront metastatic or recurring patient after a treatment at a non-metastatic stage? And primarily the type of molecular alteration and the subtype of EGFR mutation, co-mutations and maybe ctDNA.

ESMO Living Guidelines 2025: 1L EGFR-Mutant NSCLC¹

For patients with common EGFR mutations or L858R exon 19 deletion, we have very clear guidelines. For example, here on the slide, the ESMO Guidelines 2025 recommending for patients with metastatic disease, amivantamab plus lazertinib, or chemotherapy plus osimertinib, or EGFR TKI single-agent being the preferred option for the treatment of those patients.

Options for EGFR-Mutated NSCLC Tumors

We know that EGFR-mutated non-small cell lung cancer is more than the common EGFR mutation, exon 19 deletion, L858R. We also have exon 20 insertions, for which the standard of care in the first-line setting is chemotherapy plus amivantamab, and we have uncommon mutations such as the S768I, L861Q, G719, for which the recommendation is probably less clear and possibly leading to a treatment with a second-generation EGFR TKIs.

How Novel Therapies Are Transforming EGFR-Mutated NSCLC Care: Common EGFR Mutations in Early-Stage and Locally Advanced Disease

It is also very important to consider not only metastatic disease, and I will spend some time on the data on EGFR-mutated metastatic non-small cell lung cancer. Briefly, we also have some data in the non-metastatic stage.

Trials Targeting Common EGFR Mutations (Ex19Del or L858R) in Early-Stage/Locally Advanced Disease

Patients with resectable EGFR-mutated non-small cell lung cancer. Some recent data for these patients based on the ADAURA trial, setting the standard of care with adjuvant osimertinib. In patients with unresectable locally-advanced EGFR-mutated non-small cell lung cancer, chemoradiotherapy followed by osimertinib consolidation. This is the LAURA trial.

ADAURA: Adjuvant Osimertinib After Complete Resection for Stage IB-IIIA EGFR-Mutated NSCLC

In patient with resected EGFR-mutated non-small cell lung cancer. This is for patients with common EGFR mutations L858R, exon 19 deletions. We have the data from the ADAURA trial that was conducted in patients with stage IB to stage IIIA disease, stage IB with a tumor higher than three centimeters. Patients underwent surgery, then possibly adjuvant chemotherapy if indicated, and then were randomized to receive osimertinib as adjuvant treatment or placebo. The duration of adjuvant treatment was three years.

ADURA: Results in Overall Population

In this trial, we see a significant and high benefit in favor of osimertinib, not only in terms of disease-free survival. This was the primary endpoint of the trial, a hazard ratio of 0.28, so reduction by more than 70% in the risk of disease recurrence, disease progression with osimertinib and leading to an overall survival benefit for these patients.

ADAURA: DFS by Subgroup (Overall Population)

Very interesting to see the subgroups of patients not only based on the type of EGFR mutation, exon 19 or L858R. Benefit was observed in both groups. Also based on stage, we see a benefit across stage IB, stage II, stage IIIA with adjuvant osimertinib, obviously, the benefit being higher in patients with more aggressive disease that is stage III disease.

AURA: Osimertinib After Definitive CRT in Unresectable Stage III EGFR-Mutated NSCLC

For patients with unresectable locally advanced EGFR-mutated non-small cell lung cancer, we have the data from the LAURA trial. LAURA assessed consolidation with osimertinib or placebo after chemo radiotherapy, which is the standard of care for those patients with unresectable disease. Again, this is common EGFR mutations. Here the duration of consolidation was not pre-specified and osimertinib or placebo was continued until disease progression or toxicity.

LAURA: Endpoint Results - PFS and OS

Again, we see that consolidation osimertinib is associated with significant benefit. You can see in the placebo arm how aggressive is EGFR-mutated non-small cell lung cancer even diagnosed with locally advanced stage. We have a reduction by more than 80% in the risk of disease progression, and we have an overall survival benefit as well.

So consolidation osimertinib after chemoradiotherapy and adjuvant osimertinib after surgery are now part of the standard of care for those patients.

Common EGFR Mutations in Advanced, 1L Treatment

Trials Targeting Common EGFR Mutations (Ex19Del or L858R) in Advanced Disease, 1L Setting

Moving to the patients with metastatic disease. We have again several trials that have been reported over the past two years. Three major trials to discuss for these patients with common EGFR mutations, exon 19 deletion, or L858R:

• The FLAURA trial, historical trial that set osimertinib as the standard of care;
• FLAURA2 with chemotherapy plus osimertinib; and
• MARIPOSA with amivantamab plus lazertinib.

Let me go through the data from this trial.

FLAURA: 1L Osimertinib vs Erlotinib or Gefitinib for EGFR-Mutated Advanced NSCLC

FLAURA is the historical trial that demonstrated the benefit in patients with metastatic EGFR-mutated non-small cell lung cancer.

FLAURA: Survival

The benefit of osimertinib versus the first-generation TKIs in erlotinib or gefitinib moving from a PFS around 10 months with the first-generation TKIs to a median PFS of nearly 19 months with osimertinib. This eight months benefit translating into an OS benefit with a similar range moving from up to 38 months with osimertinib.

FLAURA2: 1L Osimertinib ± Chemotherapy in EGFR-Mutated Advanced NSCLC

More recently, we have seen data with an escalation, intensification of the standard of care through the combination of osimertinib plus platinum-based chemotherapy. This was compared to osimertinib. This is a FLAURA2 trial, again metastatic patients with EGFR-mutated non-small cell lung cancer common mutations.

FLAURA2: Final OS (Key Secondary Endpoint)

In the FLAURA2 trial, not only we have a PFS benefit moving from 18 months to more than 24 months median. This benefit is observed also in terms of overall survival, as you can see on the slide. Now with chemotherapy plus osimertinib, we may reach a four-year median overall survival for the patient.

Clearly, these data show that if we increase the duration and the efficacy of first-line, we move to an overall survival benefit. The main component of the overall survival being the first-line. This is because many patients actually do not receive second-line, and because after first-line, the duration of second, third-line is actually more limited.

FLAURA2: Osimertinib ± Platinum-Based Chemotherapy in EGFR-Mutated Advanced NSCLC

We see a benefit with the combination of osimertinib plus chemotherapy, not only in patients with or without CNS metastases. In patients with more aggressive disease, we see a higher benefit. Clearly, patients with CNS disease, we see a major benefit with a combination of osimertinib with chemotherapy. This is probably a little bit less true in patients without CNS disease or in patients with a disease that is less aggressive.

MARIPOSA: Amivantamab + Lazertinib vs Osimertinib as 1L in EGFR-Mutated NSCLC

The third trial in the first-line setting for these patients with metastatic non-small cell lung cancer common EGFR mutation is the MARIPOSA trial. Here the strategy is different because this is a chemo-free regimen, amivantamab plus lazertinib. Lazertinib is a third-generation TKI, quite similar to osimertinib. Amivantamab is a bispecific EGFR MET antibody. We have a dual-targeting of the EGFR with this combination.

MARIPOSA compared amivantamab plus lazertinib to osimertinib, again in this first-line setting.

MARIPOSA: OS

This is a positive trial, kind of same range than the FLAURA2, not only in terms of PFS. Again, moving around two years of median PFS and increasing with a significant benefit in terms of overall survival, hazard ratio of 0.75, similar to FLAURA2. Again, we see that we can increase the duration of first-line leading to an overall survival benefit.

MARIPOSA: Mechanisms of Amivantamab + Lazertinib Resistance

Probably one of the key differences between FLAURA2 and MARIPOSA not only is the delivery of chemotherapy or not, but also with MARIPOSA, with this dual-targeting of the EGFR, we are modifying the biology of the tumor with resistance mechanisms that cover the MET amplification or MET activation, which is quite frequent after osimertinib single-agent or osimertinib with chemotherapy. Probably here we are modifying the biology of the tumor.

Next slide.

Common EGFR Mutations in Advanced, 2L+ Treatment

Then moving to the second-line setting. Most of the data have been generated post osimertinib. We see that the standard of care is now evolving from osimertinib as a single-agent to osimertinib plus chemo to amivantamab plus lazertinib. As of today, most of the data have been generated after osimertinib as a single agent.

Trials Targeting Common EGFR Mutations (Ex19Del or L858R) in Advanced Disease, 2L+ Setting

We have multiple trials here. I will discuss some of the key data.

MARIPOSA-2: Treatment After Osimertinib Failure in Advanced EGFR-Mutated NSCLC

Currently, the most recommended option in the second-line setting post osimertinib is the MARIPOSA-2 regimen. MARIPOSA is not selecting patients based on a given resistance mechanism, so there was no need for a rebiopsy to identify some of the resistance mechanisms.

Chemotherapy plus amivantamab is the experimental arm in blue versus chemotherapy, carboplatin-pemetrexed being the historical standard post osimertinib.

MARIPOSA-2: PFS (Primary Endpoint) and Second-Interim OS

MARIPOSA-2 demonstrates the benefit of chemotherapy plus amivantamab in those patients versus chemotherapy. Moving from 4.5 months to 6.5 months median, this is significant with a tendency towards a significant benefit in terms of overall survival. This combination is the preferred option in the second-line setting post osimertinib.

TROPION-Lung01/05: Dato-DXd in Previously Treated Patients With EGFR-Mutated NSCLC

There are other new drugs that are coming in this setting. The second-line setting post osimertinib antibody-drug conjugates such as datopotamab deruxtecan. This is an antibody drug conjugate that is targeting TROP2. It is approved in the US post osimertinib based on the TROPION-Lung01/TROPION-Lung05 trials that assessed datopotamab deruxtecan post osimertinib in those patients with EGFR-mutated non-small cell lung cancer.

TROPION-Lung01/-Lung05 Pooled Analysis: Efficacy

Demonstrating a quite high response rate higher than that of chemotherapy, more than 40% with a signal in terms of PFS around six months.

OptiTROP-Lung04: Sacituzumab Tirumotecan in EGFR TKI-Resistant, EGFR-Mutated Advanced NSCLC

We have also other data with TROP2-directed antibody drug conjugates, such as sacituzumab tirumotecan, recent data presented in 2025. Sacituzumab tirumotecan versus carboplatin pemetrexed in the second-line setting after disease progression after third-generation TKI.

SAVANNAH: Savolitinib + Osimertinib in EGFR-Mutated Advanced NSCLC With MET Overexpression/Amplification Following Progression on Osimertinib

Data generated in a Chinese population.

ORCHARD Module 10: Biomarker-Directed Study in Advanced NSCLC Following Progression on 1L Osimertinib

Also some very nice data with the combination of osimertinib plus datopotamab deruxtecan in this setting.

ORCHARD Module 10: ORR

Showing that maybe the continuation of EGFR inhibition is important when starting a treatment with TROP2-directed antibody drug conjugate. There are some phase III trials ongoing assessing these options.

SACHI: Savolitinib + Osimertinib for Advanced, EGFRm/MET-Amplified NSCLC

Another strategy in the second-line setting is to do a rebiopsy of the tumor to look at the resistance mechanisms, especially what is the most frequent one after exposure to osimertinib is the activation of the MET signaling pathway. So we can identify MET overexpression or MET amplification.

The SACHI trial, assessed in the second-line setting in those patients with MET amplification after exposure to EGFR TKI. The continuation of EGFR TKI, so osimertinib plus savolitinib, which is a MET inhibitor or MET kinase inhibitor versus chemotherapy.

SACHI: PFS in Prior 3rd-Gen EGFR TKI-Treated Subgroup

This trial was conducted in China and shows the benefit of the combination of savolitinib plus osimertinib versus chemotherapy moving from three months median PFS to almost seven months. This is quite clinically meaningful. These data are currently being replicated globally in the SAFFRON trial with this combination, savolitinib plus osimertinib.

COMPEL: Osimertinib + Platinum-Based Chemotherapy in EGFR-Mutated Advanced NSCLC Following Progression on 1L Osimertinib

Many data with new agents. Finally, maybe we can do some things that is more simple if we do not have access to this innovative agent. This is a COMPEL trial. COMPEL is an academic trial that looked after osimertinib at when you switch to second-line chemo with platinum pemetrexed to compare discontinuation of the TKI or continuation of osimertinib.

Historically, the sequencing, meaning the discontinuation of the TKI was recommended based on all trials conducted. At the time, gefitinib was the standard of care, the IMPRESS trial.

COMPEL: PFS and CNS PFS

Here in the COMPEL trial, in those patients with common EGFR mutation without a CNS disease progression, it is better to continue the TKI when starting second-line chemotherapy with a benefit in terms of PFS. This is probably something that is quite easy to implement, especially if access to amivantamab to TROP2-directed antibody drug conjugate is not possible in the second-line setting. It also highlights the need to continue the inhibition of the EGFR signaling pathway, along with the delivery of the lines of systemic treatment.

This was a lot to cover, but it shows that there is a lot coming. There is a lot of new strategies available, not only in the first-line setting but also in the subsequent line setting. Probably these patients with common EGFR mutations are quite a model for the other less common mutations. Zofia will discuss these aspects. Thank you.

Uncommon EGFR Mutations (S768I, L861Q, G719X) in First Line, Second Line, and Beyond

Dr. Zofia Piotrowska (Mass General Brigham Cancer Institute): Thank you, Nicolas. That was an incredible overview of a huge body of data. It is really exciting to see how this field has changed over time. I would say equally importantly, to keeping up with all of the data is also keeping in mind that these different EGFR mutations are increasingly different in how we approach them.

So it is really important to keep in mind that when we talk about EGFR-mutated lung cancer now, we really have to be more specific to say, is this a patient with a classical EGFR mutation, which are the exon 19 deletions and the L858R point mutations in exon 21? That is really where all of the data you just heard about is really most applicable.

These are the most common mutations. They are sensitizing to the TKIs. They are the most common scenario that we uncover, but we also find patients who will have these uncommon EGFR mutations, which we will talk about next and the EGFR exon 20 insertions. As you will see, each of these is treated differently. An important step as you take care of patients with EGFR-mutated lung cancer is really to keep in mind what type of mutation does this patient have.

Let us take a moment and talk about the uncommon EGFR mutations and what treatment options we have for those patients.

Trials Targeting Uncommon EGFR Mutations (S768I, L861Q, G719X) in First Line, Second Line, and Beyond

There are a number of trials specifically focusing on these patients with uncommon EGFR mutations, which we will talk about, including both the use of TKIs approved in other settings, including afatinib and osimertinib. Also, some encouraging data with amivantamab and lazertinib, which you heard about in the MARIPOSA trial, but using this combination for patients with uncommon EGFR mutations.

Then we have some new TKIs that are in development, specifically looking at patients with EGFR mutations. We will go over those.

Atypical (Uncommon) EGFR Mutations: A Heterogeneous Group Defined in Many Ways

Before we do that, it is worth spending a moment talking about the nomenclature here. There is a lot of different ways to refer to these atypical or uncommon EGFR mutations. In some ways, I think of it as a category of exclusion. If it is not a classical EGFR mutation, exon 19 or L858R, and it is not an exon 20 insertion, it really falls into this category of atypical mutations.

We used to call these the uncommon mutations, the G719 mutations, L861Q and S768I. These were the common/uncommon mutations. As you can see here, this is really quite a diverse group of mutations. There can be many of these rare ones. Sometimes they can occur as compound mutations, either two uncommon mutations occurring together or an uncommon with a common mutation.

Truthfully, I think for most patients where they have a common mutation together with an atypical, we tend to treat them like a classical mutation. However, you have to keep in mind that sometimes these passenger mutations can impact the likelihood of response.

I wanted to mention, you may hear the term PACC mutations, which refers to a nomenclature system that the MD Anderson Group recently published and we have started to use more and more. This is a nomenclature based on the structure of these mutations. This stands for the P-loop Alpha-C helix. You do not have to remember that.

What you do have to remember is that PACC mutations, of which you can see that many of these include G719 and S768I are structural, at least thought to be most sensitive to second-generation EGFR inhibitors. There are some trials now specifically developing drugs for the designation of PACC mutations.

I will refer you to the paper by the first author was Robichaux in Nature, which talked about the structure classification, which has a lot of good data. If you have a rare EGFR mutation and you are not sure what category it falls into, I have found this work by MD Anderson quite helpful.

Really right now we can think of these different mutations, whether we call them the PACC or atypical mutations as a unique entity. The question is, how do we treat these patients?

Afatinib is Currently the Only Approved TKI for Uncommon Mutations

Right now, actually, as of today, the only approved TKI for patients with the uncommon mutations, and here we are really referring to the original approval was for the common/uncommon mutations like G719 and others is afatinib. Actually, just a couple of years ago, we presented a randomized study of first-line use of afatinib, the second-generation EGFR inhibitor versus platinum doublet chemotherapy in patients with uncommon EGFR mutations.

This was a study done in Japan. It confirmed what we know that TKIs are superior to chemotherapy for these patients include in terms of progression-free survival. You can see that the objective response rate to afatinib was higher. It was about 60% in the overall population, and the median progression-free survival was better with afatinib than chemotherapy 10 versus 5.7 months.

Equally importantly is if you look at the different types of mutations here, you can see that the response rate in the patients with G719 mutations was higher, for example, than those with L861Q. Again, a challenge of talking about these uncommon mutations is that there can be quite a bit of heterogeneity between these different mutations, but I think afatinib is a very reasonable option, and currently in the United States, the only approved option for patients with the uncommon mutations. I hope that will change in the near future.

Osimertinib has Activity, but Varies by Mutation Subtype

Many of us do use osimertinib for these uncommon mutations, largely based on retrospective data and clinical experience. Here you can see some data from a real-world registry of patients with uncommon mutations and a meta-analysis shown on the right. Again, what I will highlight here is that there can be quite a bit of heterogeneity between response. For example, for patients with G719 mutations, the response rate was about 47% to osimertinib and the median PFS was about nine months. Whereas for the L861Q mutations, it was higher about 80% and median PFS of 16 months.

Again, they are highlighting this heterogeneity. Interestingly, under the MD Anderson structural classification model, the L861Q mutations are structurally similar to the classical mutations, which may explain the increased benefit of osimertinib for these patients.

Nevertheless, based on these data, we can say that osimertinib does have activity for these patients. In some cases, we will use this in an off-label fashion for patients with uncommon mutations, particularly given some of the toxicity concerns that we can see with second-generation EGFR inhibitors, which are associated with higher rates of diarrhea and others.

UNICORN: Phase 2, Single-Arm Trial of First-line Osimertinib for NSCLC With Uncommon Mutations

There was also another study also called UNICORN, but a different study. This was done in Japan looking at first-line osimertinib for patients with uncommon mutations. This was a prospective study. Once again, here we saw that you can see that these patients do respond. The responses are highest in the L861Q mutations and that the median progression-free survival widely varies and was actually relatively short in the patients with the G719 and S768I mutations.

While osimertinib can have some activity, clearly we need to do better for these patients with the uncommon mutations.

CHRYSALIS-2 Cohort C: Amivantamab + Lazertinib in Uncommon Mutations

An intriguing data set that we saw presented at ASCO last year was the data for amivantamab and lazertinib for patients with uncommon mutations. This was data from the CHRYSALIS-2 study. There was a cohort for patients with atypical mutations including the ones listed here, the common ones G719, L861, S768I and others.

They broke these down by treatment-naïve, so first-line use and second or third-line. So post TKI and post chemotherapy. Amivantamab and lazertinib actually had activity in both contexts. You can see here the objective response rate in the later line setting was 48%, with a median PFS of eight months. These numbers were even more impressive in the first-line cohort here. Objective response rate of 57%. Median PFS of 19.5 months. Median overall survival not reached in this data set.

That as we heard with MARIPOSA for classical mutations, amivantamab and lazertinib is a regimen that does have some toxicities that we have to balance. It is not currently approved for the atypical mutations, but it is something that I consider for patients where off-label use is an option or certainly in the context of a clinical trial, if you happen to have one available. I suspect that maybe this will be an approved option for our patients at some point in the future.

Agents in Development for Uncommon EGFR Mutations and PACC (G719X, S7681) Mutations

There are new drugs in development for the uncommon mutations including a few that I wanted to highlight. The first is firmonertinib. This is a drug that is being developed to target both the uncommon mutations and exon 20 insertions. You can see here that in a cohort of first-line use, so treatment-naive patients with PACC mutations, firmonertinib has been one of the drugs where the PACC designation has really been used to select patients eligible for the study.

We saw that two different dose levels were tested, 160 milligrams and 240 milligrams. The response rates were quite high actually, in both but 52% at 160 milligrams and 81% at 240 milligrams. The median PFS was 16 months at the higher dose and 11 months at the lower dose.

Based on these initial data, where here I will highlight that these cohorts were quite small, but there is a phase III study now ongoing, which is a study of first-line firmonertinib versus investigator's choice osimertinib or afatinib in patients with PACC mutations. This is called the ALPACCA trial. This will be a very interesting study to keep an eye on.

Then we also have a drug from Black Diamond Therapeutics now called silevertinib. Here again you can see this was a drug that was developed to have activity against uncommon EGFR mutations as well as some of the acquired resistance mutations. These are still early data shown here on the slide. But we are seeing some patients having tumor shrinkage and partial responses with the atypical mutations. This is another drug to keep an eye on here.

Enozertinib in Uncommon PACC Mutations

Then finally another drug to keep an eye on for patients with uncommon or PACC mutations is a drug from ORIC Therapeutics called enozertinib. This is another novel EGFR TKI, developed to specifically have activity against atypical mutations here being evaluated based on the PACC designation once again. We can see that at 80 milligrams, the response rate here was 36% with this agent. You can see quite a few tumor shrinkages on the waterfall plot with many of these agents, and especially as we get into the data with exon 20 insertions, we have to keep an eye on the safety profile of these drugs.

This has been a challenge in the development of TKIs for the atypical mutations and for the exon 20 insertions where the side effects related to inhibition of wild-type EGFR have led to more significant safety profiles. Here we are seeing diarrhea, paronychia and stomatitis as the most common adverse events. Relatively few grade 3 or higher events at 80 milligrams and a little bit higher, 14% at 120 milligrams with about 70% of patients at 120 milligrams having to reduce the dose to a treatment-related adverse event.

Again, this is a drug. As we keep an eye on this drug's development, we will have to keep an eye on the safety profile as well.

Exon 20 Insertion Mutations

Moving on to our third category of EGFR mutations. We talked about the classical EGFR mutations. We talked about the uncommon or PACC mutations. The third category are the EGFR exon 20 insertions.

Molecular Landscape of EGFR Exon 20 Insertions

This is a diverse group of insertion mutations that occur across EGFR exon 20. This figure shows the many different exon 20 insertions that can arise. If you take all of these exon 20 insertions together, they are about 10% of all EGFR mutations in lung cancer.

NGS reports have gotten better and better about specifying based on the amino acid structure, that this is an exon 20 insertion, but sometimes it can be confusing to read these NGS reports if they are only using the amino acids here and not specifying the type of insertion. If you have trouble, you can either look at a figure like this and see, okay, exon 20 arises between amino acid 761 and 775, and that is where the insertion is arising. So it is exon 20. Or you can reach out to the molecular pathologist who signed out that report and ask them to help you understand which EGFR mutation it is.

Again, this is less of a problem now, but sometimes we still see reports that do not define an exon 20 insertion and we want to make sure that we are clear on that and that we are identifying these mutations appropriately.

All of these mutations, although they are quite diverse, are treated currently in a similar fashion.

Amivantamab for EGFR Exon 20 Insertions

Right now, the first agent approved for patients with EGFR exon 20 insertions was amivantamab. Again, we already heard about this agent, a bispecific antibody targeting EGFR and MET. But its first approval was actually accelerated approval in 2021 for patients with EGFR exon 20 insertions after progression on chemotherapy.

This initial monotherapy approval was based on the phase I CHRYSALIS trial cohort, where amivantamab had a confirmed objective response rate of about 40% and a median progression-free survival of 8.3 months. This was very important because this was the first approval in the United States, at least, of a drug for patients with EGFR exon 20 insertions. Of course, we later saw the approval of amivantamab in many other settings, but this was the first step forward for patients with EGFR exon 20 insertions.

Trials Targeting Exon 20 Insertion Mutations in First-line Treatment

Fortunately, since then, we have had a lot more drug development and we will talk about the current use of amivantamab in combination with chemotherapy, which was based on the PAPILLON first-line trial. We also have other TKIs being developed here, both in the first and later line setting.

Overall, I would say the goal of all of these trials is to identify TKIs that will be efficacious, that will have good and durable efficacy, but also that will have good safety profiles. We saw with some of the initial TKIs that were developed for patients with exon 20 insertions, such as poziotinib and mobocertinib, that there could be significant challenges when you have a drug that has some activity, but a lot of effect on wild-type EGFR, a lot of diarrhea and skin rash, which led to frequent dose reductions and really limited the efficacy of these agents.

This new generation of drugs has been developed to more potently inhibit the exon 20 insertions and have less of an effect on that normal wild-type EGFR to improve upon the safety profile.

Let us look at these data in a little bit more detail.

PAPILLON: Amivantamab + CT vs CT as 1L Therapy for EGFR Exon 20 Insertion–Mutated Advanced NSCLC

First, probably one of the most important studies in recent years in the EGFR exon 20 insertion space was this study, the PAPILLON study. PAPILLON was a first-line study specifically in patients with EGFR exon 20 insertions. Here patients were treatment-naive and were randomized to a first-line combination of chemotherapy plus amivantamab, building on the observation that amivantamab had activity in the later line setting, but asking whether adding it to front-line chemotherapy would improve outcomes and compared here to chemotherapy alone, which was our old standard of care until just a few years ago for a patient with an EGFR exon 20 insertions.

We did see an improvement in the primary endpoint of progression-free survival here from about 11.4 months with amivantamab chemotherapy, 6.7 months with chemotherapy. This was statistically significant. We also saw significantly higher objective response rates with the chemo-amivantamab combination. All in all, this has been a success. We do not have the final overall survival data from the study.

Based on these results, this is now how we are using amivantamab for most of our patients with EGFR exon 20 insertions as first-line therapy together with chemotherapy for a patient and then thinking about TKI clinical trials down the line.

This was really a practice changing study for our patients.

FURMO-003: Phase II Trial of Furmonertinib in EGFR ins20 NSCLC

Now, as I mentioned, we have a number of TKIs in development for patients with EGFR exon 20 insertions. Let us go through those in a little bit more detail.

We talked about furmonertinib in the setting of the atypical or PACC mutations. This drug is also being developed in patients with EGFR exon 20 insertions. Here are some data that were presented recently looking at furmonertinib in patients with EGFR exon 20 insertions after platinum-based chemotherapy. 71 patients were treated here, and we saw a response rate of about 45% and a median progression-free survival of about 8.3 months.

As you look at these data sets that I will present to you, you will see that all of these drugs seem to be in this range in the post-chemotherapy setting and response rates not quite as high as what we are used to seeing with TKIs for classical EGFR mutations. But certainly a step forward for patients.

Then again, thinking about both efficacy but also the safety of these agents. Let us look at the safety profile of furmonertinib here at the 240 milligram dose. We do see that about 65% of patients had diarrhea. Mostly these were grade 1 and 2. Only 4% grade 3 or 4. As we look at these data, though, I will encourage you to also keep in mind that even grade 1 and 2 diarrhea can have a significant impact on patient quality of life, particularly when they are remaining on TKI therapy for many months. So we have to be very mindful of toxicity management and supportive care for these patients.

Other toxicities, anemia, some creatinine increase in about a third of patients and others as you can see here. But only about 13% of patients require dose reduction and about 6% of patients discontinued due to treatment-related adverse events, which is encouraging.

Trials Targeting Exon 20 Insertion Mutations in Second-line Treatment

Now, if we look at the additional agents that we are going to talk about, including sunvozertinib and zipalertinib, these have thus far largely been developed in the second-line setting. There are ongoing first-line studies of all of these agents for patients with EGFR exon 20 insertions. The data that we have thus far is largely in the post-chemotherapy second or later line setting.

WU-KONG1: Global Phase II Sunvozertinib (DZD9008)

Taking first, sunvozertinib. Now, this is an important drug to be aware of because in the United States, this actually has accelerated FDA approval for patients with EGFR exon 20 insertions following progression on a standard of care chemotherapy. This is approved at the 200 milligram dose level in the United States. It is also approved in China at the 300 milligram dose level. However, I will say that in the United States, this drug, although it has been approved since last July, it is not yet currently available on the marketplace because of the drug production and distribution issues.

While this is approved, it is not actually available, at least in my practice and those of my colleagues to our patients yet, we hope it will be soon, but we are still waiting for it to become available.

Let us look at the data for sunvozertinib. This was tested in a global phase II study called WU-KONG1. Here, patients with EGFR exon 20 insertion positive lung cancers who had progressed on prior platinum-based chemotherapy were randomized to two dose levels, the 200 milligram and 300 milligram dose level. When we look at the efficacy across these, we can see that the confirmed objective response rate was quite similar across these two, as was the median progression-free survival.

So really these look to be quite comparable. I will say that they looked at a small cohort of patients who had had prior amivantamab. Remember, for most of our patients, that is now the context that we would be thinking about using a second-line agent, getting chemotherapy and amivantamab first and then reaching for TKI. When this study was done, amivantamab was not widely available worldwide. So only a small number of these patients had prior amivantamab.

We did see that in this small cohort of patients, at least at 200 milligrams, the response rate seemed to be a little bit lower, but these are still exploratory analyses of a small number of patients. We do not have specific intracranial activity here, but we can see that among patients with baseline brain metastases, the systemic response rate seemed to be a little bit higher at 300 milligrams than 200 milligrams, again, small numbers here.

WU-KONG1B: Treatment Related Adverse Events

When we look at the safety profile of sunvozertinib. This is a very busy table. I will highlight for those of us who are watching from the United States, that the 200 milligram dose level on the left here is the one that is approved. The most common side effect that we see with sunvozertinib is diarrhea. We see that similarly to other agents, but with sunvozertinib at 200 milligrams, we see diarrhea in about 68% of patients.

The majority of these are grade 1 events, about 17% grade 2 and a lower rate of grade 3. Notably, at the 300 milligram dose level, the rate of diarrhea does seem to be higher, but overall diarrhea is the most common side effect with sunvozertinib. We do see others, including CPK increase and some rash and dermatologic toxicities as well in about 40% to 50% of these patients.

REZILIENT1: Zipalertinib in EGFR ex20ins–Mutated NSCLC After Prior Platinum-Based CT ± Amivantamab

We also have another TKI being developed for patients with EGFR exon 20 insertions called zipalertinib. This has been developed over a few different studies. Here we wanted to highlight the REZILIENT1 trial, which was a phase I and II study looking at zipalertinib in patients with EGFR exon 20 insertion positive non-small cell lung cancer who had had prior second or later line. They could have had prior chemotherapy alone, or they could have also had other exon 20-directed agents, including amivantamab and other TKIs.

In each of these cohorts, the patients received zipalertinib 100 milligrams twice daily, which is the approved dose.

REZILIENT1: Zipalertinib Activity After Amivantamab

What the analysis here really focused on was the activity of zipalertinib after a prior amivantamab. Once again, keeping in mind that for patients in our current practice, most patients are getting chemotherapy and amivantamab as first-line therapy. With all of these novel TKIs, we are really interested in what their activity is in that post amivantamab setting.

What we saw with zipalertinib was that in patients who had had chemotherapy alone, the objective response rate was about 40% and those who had had a prior amivantamab and prior chemotherapy for the vast majority, the response rate was 30%, interestingly, if patients had had amivantamab and other EGFR exon 20 TKIs.

Some of these patients had mobocertinib when it was briefly on the US marketplace or have participated in other clinical trials of exon 20 TKIs. We saw that the response rate to zipalertinib was lower. It was 14%. This suggests that likely many of the drugs that are currently in development, zipalertinib, sunvozertinib, furmonertinib will have some cross resistance. Even if we have multiple in the market, using them sequentially would not be as effective and likely resistance to one will confer resistance to the others.

Looking at zipalertinib safety, the most common side effect with this agent have been dermatologic, including paronychia, rash and dermatitis, and dry skin. These have again largely been low grade, grade 1 and 2. Again, like with diarrhea, we have to keep in mind that even grade 1 or 2 skin toxicities can have a significant impact on quality of life for patients, and they require careful monitoring. We see diarrhea in about 22% of these patients and again largely low grade.

Phase IIb REZILIENT1: Efficacy Among All Patients and Specific Subgroups

This is the efficacy looking at specific subgroups once again, and including those patients who had had prior chemotherapy and no prior exon 20-directed therapies where the confirmed response rate was 40%. Then once again looking at patients with baseline brain metastases. So here, we are looking at systemic response rate in patients with baseline brain metastases not directly intracranial efficacy. But we see a confirmed response rate of 31%.

Now in another data set that was just recently presented by my colleague Dr. Yu at ESMO this year, we did see that in a small dedicated cohort of patients with intracranial metastases, the intracranial response rate to zipalertinib seem to be similar to the systemic response rate in the 30% range. So it does suggest that this drug does penetrate into the CNS and can have some activity.

We need more data about the intracranial efficacy of all of these different TKIs that are in development for exon 20 insertions.

Enozertinib in EGFR Exon 20 Insertions

Then lastly, enozertinib. We talked about this drug in the uncommon mutations. This is also being developed for patients with EGFR exon 20 insertions. We are seeing in the later line setting a response rate of about 45% at 80 milligrams daily. A little bit lower actually at the higher dose level, likely owing to high levels of dose reduction. But in the first-line setting, we saw an impressive response rate of 60% at the 120 milligram dose. We saw a small number of patients with brain metastases where we saw five out of seven responses. This is a drug to keep an eye on. This is one of the newer exon 20 drugs in development.

Here again if we look at side effects, diarrhea, skin toxicities are the most common side effects. We can see about 40% of patients having grade 3 skin toxicities at the 120 milligram dose level. This is a drug where we will have to see what the longer term follow-up shows in terms of efficacy and safety.

Datopotamab Deruxtecan (TROP2 ADC) in EGFR-Mutant NSCLC

Then finally, we talked about ADCs and the classical mutations, just to highlight that the approval of datopotamab deruxtecan for EGFR-mutant non-small cell lung cancer was based on a study that did not focus just on classical mutations, but actually included all of the different EGFR mutation subtypes. As you can see here, small numbers of patients, but there were patients with uncommon mutations and exon 20 insertions included here.

Datopotamab deruxtecan is an option for our patients with both exon 20 insertions and uncommon mutations who have exhausted other standard of care therapies and who may not have access to some of these exciting TKIs that are in clinical trials. It is something that you can think about for all of the different EGFR mutation subtypes based on the current FDA label.

Conclusions

With that, I will just again highlight that for our patients with EGFR exon 20 insertions, today, still first-line therapy is a chemotherapy-based regimen, which I hope will change in the near future, chemotherapy plus amivantamab. In the United States, sunvozertinib is approved in that post chemotherapy setting, but we are waiting still for its availability. There are ongoing first-line studies of sunvozertinib, furmonertinib and zipalertinib combined with chemotherapy, all as first-line therapy.

Our standard of care is likely to change in the coming years. Hopefully, we will be using a TKI first-line for these patients.

Conclusions

Then for our atypical mutations, again, this is a heterogeneous group, so the nomenclature can be challenging. It is important to really look at the data for the specific mutation that you are dealing with. Currently, afatinib is currently the only approved TKI in the United States, but we do frequently use osimertinib when we can get it off label. Amivantamab and lazertinib is also something to keep in mind for these patients.

Again, here new agents are in development. We have a phase III first-line study of furmonertinib ongoing. Other drugs that are looking quite promising. We hope that this landscape will change in the near future.

Experts Address Hot Topics in EGFRm NSCLC: Current and Future Perspectives

Experts Address Hot Topics in EGFRm NSCLC: Current and Future Perspectives

Maybe we will move to our questions here and then we will do the post-test. Nicolas, this is for a discussion with us both. An important question to start off with and then we can also check in the Q&A here. We talked about different combination approaches for classical mutations. How are you deciding between them?

Dr. Girard: That is a very good question. I believe that we have a PFS benefit. We have an OS benefit with osimertinib plus chemo and amivantamab plus lazertinib. These are the new standard of care options versus osimertinib as a single agent. My way of thinking is, okay, I will do chemo plus osimertinib or amivantamab plus lazertinib. If the patient is not eligible, elderly patients not amenable to chemotherapy, maybe I will consider osimertinib monotherapy.

Then between these two options, chemo-free versus no chemo-free depends probably also on the presentation of the disease. Maybe patients with more aggressive disease, CNS disease. We can go with osimertinib plus chemo. For all the other patients, amivantamab-lazertinib is my preferred option.

Dr. Piotrowska: Yes. My approach sounds very similar to yours. I would just highlight when we are using amivantamab-lazertinib, there has been a lot of work. You have led a lot of these efforts to think about how we can support patients with these regimens. The COCOON regimen has really improved outcomes, has really improved the patient experience. It helps with the skin toxicities.

Now we have subcutaneous amivantamab available in the United States, which helps with the infusion reaction. So taking advantage of all of these different supportive care models that we have can be really helpful to improve patient experience when we are using amivantamab and lazertinib. It has really been great to see how much effort has been placed on toxicity management with that regimen.

Let us see here. Maybe before we answer this question, just in the interest of making sure we are involving the audience, we have two questions in the Q&A from the audience. Maybe I will tackle the one about exon 20 insertions and then I will ask you to talk about progression after osimertinib.

So Timothy Quill asks, what is your go-to-treatment after amivantamab for EGFR exon 20 insertions? If sunvozertinib becomes available, what is your recommendation to manage diarrhea?

I will say that this is a really challenging question in the United States right now, because we do not have a good option after chemotherapy and amivantamab today. I hope that that is going to change very soon. My answer is a clinical trial unfortunately or thinking about datopotamab deruxtecan if you do not have another option because currently that is our only real approved option for these patients in addition, of course, to later line chemotherapy.

I do think that diarrhea management will be really important. This is going to be, similar to many of our other drugs where diarrhea is frequent. Careful counselling. I do not know that I would use Imodium loperamide prophylactically, but I would counsel patients to have it on hand and really to call the clinic quickly if they are having diarrhea.

Just seeing these patients frequently after the start of therapy can be really helpful to manage side effects. Nicolas, what is your practice for exon 20 insertions in Europe?

Dr. Girard: Well, first-line with the PAPILLON regimen. Then we do not have access to the TKIs outside of clinical trials. So, obviously, clinical trials are key for these patients. With regards to the management of diarrhea, I really feel that proactive management, as you mentioned, is the key. Education, checking how patient's nutrition and so on is very important as well.

Dr. Piotrowska: Great. Let us see. Another question in the chat. For patients who are progressing on osimertinib alone, which still is a lot of our patients in my practice at least. How do you decide between the next options for patients?

Dr. Girard: I feel that most of the patients in my practice go to the MARIPOSA-2 regimens, so chemotherapy plus amivantamab. In Europe, we do not have access to Dato. Clinical trials, I think is a very important thing to consider in those patients. Most of the trials are in the second-line setting and not beyond. So there will be always an opportunity to use amivantamab, maybe later in patients who are eligible to a clinical trial.

Rebiopsy is something that we do for most of the patients to identify some of the biomarkers and resistance mechanisms, which may drive to one option or the other.

Dr. Piotrowska: I totally agree. Still we can sometimes find MET amplification and think about targeting that histologic transformation. So I do think rebiopsy is still an important step to consider.

An interesting question and then we will move to our post-test questions. As someone asks in the chat, I have a newly diagnosed patient with EGFR L861Q mutation and T790M. What would be the treatment? Would osimertinib and chemotherapy be effective? Nicolas, how would you approach a patient like this?

Dr. Girard: Well, quite a complex situation. Yes, but it is combined mutation. Probably in such a patient, I would go with amivantamab plus lazertinib, because this patient has an EGFR dependency. So having a dual targeting of EGFR is probably something to consider in such patient.

Dr. Piotrowska: Yes. I would also say osimertinib plus chemotherapy would be reasonable as well for a patient like this. The osimertinib should cover the T790M. So adding osimertinib-chemo would also be a good option.

We touched on most of these questions. Do you have Dato-DXd available to you, Nicolas, in France?

Dr. Girard: No. Unfortunately, no. But we have some clinical trials ongoing and open with Dato plus osimertinib first-line, second-line. This is a way to access to Dato in patients.

Dr. Piotrowska: How have you managed the unique toxicities of Dato-DXd?

Dr. Girard: Well, these are quite similar to those observed with Dato in the second-line setting. So stomatitis is the most frequent side effect, probably less a problem in patients who are never smokers and young patients. You may manage the indication of the patients and say the clinical monitoring of these patients. One point to pay attention to is probably the ILD which may be more frequent in combination with the TKI, but this is part of clinical trials so far. So something to look at in the future.