This is a global survey on biomarker testing in lung cancer that was conducted by the IASLC in 2024, looking at physicians’ perceptions regarding biomarker testing. Obviously, the vast majority of thoracic oncologists believe that biomarker testing significantly impacts the outcomes of patients.

Two thirds of these estimated that more than half of the patients with lung cancer do receive biomarker testing. There is a lot here, but at the end, maybe not 100% of the patients receive this testing, and it is actually quite frequent that we may treat patients prior to obtaining biomarker testing results.

Probably here we have two situations. The late stage majority of patients receiving testing. Earlier stages, well more complex maybe and not all the patients do receive a genomic profiling.

Real-world Biomarker Testing Patterns Among Patients With mNSCLC in the United States

Also very interesting to see that over the past 15 years, the number of patients receiving biomarker testing has increased from only EGFR, ALK testing to a more comprehensive assessment with new biomarkers, predicting the efficacy of targeted agents and higher access to targeted therapies.

Options for EGFR-Mutated NSCLC Tumors

Today, we are discussing about EGFR-mutated non-small cell lung tumors, but at the end, this is a very heterogeneous group of patients. We have the common EGFR mutations, and we will discuss the management of patients with exon 19 deletions and L858R. We have the more uncommon mutations quite heterogeneous group, and we have the exon 20 insertion mutations.

2025 SOC Updates per Disease Setting

Let us start with EGFR common mutations. Here we have different groups of patients. Targeted therapies have been made available not only for metastatic disease but also for non-metastatic disease.

Evidence Prompting Challenges in First-line Therapy Selection for EGFRm NSCLC 

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

I will start with these patients. Patients with stage I to stage III EGFR-mutated lung cancer, common EGFR mutations. Here we have data for patients with resected or resectable lung tumors. The ADAURA, the ADAURA2 trials, NeoADAURA as neoadjuvant, and LAURA which is conducted in patients with locally advanced EGFR-mutated non-small cell lung cancer.

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

ADAURA. ADAURA is the assessment of adjuvant osimertinib after complete resection for stage IB to IIIA EGFR-mutated non-small cell lung cancer. The study was conducted in nearly 700 patients, randomizing patients after surgery after adjuvant platinum-based chemotherapy to receive osimertinib or placebo for three years. This study was conducted from stage IB with a cut-off at three centimeters diameter, so we still have in the new TNM classification some patients with stage IB tumors eligible for this strategy.

ADAURA: Results in Overall Population

ADAURA trial demonstrated the benefit with adjuvant osimertinib. In terms of disease-free survival for these patients, it has a hazard ratio of 0.28, so 70% reduction in the risk of disease recurrence. We have a benefit in overall survival, so again reduction by half in the risk of death with adjuvant osimertinib. This is now a standard of care for this patient population.

ADAURA: DFS by Subgroup (Overall Population)

We see that the benefit is observed in the predefined subgroups, Asian, non-Asian patients. The magnitude of benefit is a little bit higher with exon 19 versus L858R. We see that also in metastatic stages. We see also a benefit in patients with or without adjuvant platinum-based chemotherapy.

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

For patients with more advanced disease, locally advanced non-small cell lung cancer not amenable to surgical resection, so mostly patients with stage III disease, we have the LAURA trial, which is osimertinib after definitive chemo radiotherapy, again for these patients with common EGFR mutations.

Here we have the concurrent or sequential chemoradiotherapy. Then patients were randomized to receive osimertinib or placebo. Please note that here there is no predefined duration of osimertinib. This is osimertinib until toxicity or disease progression.

LAURA: PFS and OS

Here again, we see a major benefit with consolidation with osimertinib. This is moving from a PFS of six months to 39 months median with osimertinib. So major benefit with consolidation osimertinib, and we have a trend towards a long-term overall survival benefit in those patients.

Obviously, these patients have more aggressive disease and frequent recurrences after chemoradiotherapy. Here clearly, we have a protection against disease recurrences, especially CNS disease, which is a major change in the evolution of the disease for these patients.

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

This was for non-metastatic disease. We see that osimertinib adjuvant consolidation is now part of the standard of care.

Moving to metastatic patients. Again, common EGFR mutations. We have here more options than historically. Osimertinib, which is a historical standard of care based on the FLAURA trial and now more intensive regimens with FLAURA2, combination of osimertinib plus chemotherapy, and MARIPOSA, which is Amivantamab plus Lazertinib. I will go through these clinical trials and the data that we have.

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

In the FLAURA trial, osimertinib third-generation EGFR TKI was compared to first-generation EGFR TKIs, erlotinib or gefitinib in those patients with metastatic disease. Osimertinib, which is covering the T790M resistance mutation associated that is emerging after gefitinib or erlotinib, is demonstrating a benefit. We move from 10 months median PFS with the first-generation EGFR TKIs to 19 months median with osimertinib.

FLAURA: PFS and OS

This translates into an overall survival benefit. We may expect 39 months median overall survival with osimertinib. This is why osimertinib has been considered as a standard of care for many years now after the release of the FLAURA study.

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

Now we have seen data that are assessing more intensive regimens that were compared to osimertinib. First, we have the FLAURA2. FLAURA2 is osimertinib plus platinum-based chemotherapy. So platinum plus pemetrexed plus osimertinib, four cycles, followed by a double maintenance with osimertinib plus pemetrexed. This was compared to osimertinib.

This is again in patients with common EGFR mutations. The primary endpoint is progression-free survival.

FLAURA2: PFS (Primary Endpoint)

We see a benefit with the combination of osimertinib plus chemotherapy versus osimertinib, moving from the 17 months that we had in the FLAURA trial to 25.5 months, so 26 months median PFS with the combination of osimertinib plus chemotherapy. This hazard ratio of 0.62 is statistically significant. Clearly the combination is doing better than osimertinib.

Obviously the cost here is the toxicity and we are combining the side effects of osimertinib quite limited, mostly rash and diarrhea, with those associated with platinum-based chemotherapy. So mostly hematological and digestive tract toxicities.

Very interesting to see that the benefit with the combination, chemotherapy plus osimertinib, is striking in patients with more aggressive disease, including the patients with baseline brain metastasis, moving from the 14 months with osimertinib to 25 months with the combination. We see also a benefit in other subgroups of patients with aggressive disease, including patients with multiple sites of metastasis in this study.

FLAURA2: Final OS (Key Secondary Endpoint)

Finally, this benefit in terms of PFS is translating into an overall survival benefit. We have here a hazard ratio of 0.77, moving from the 38 months median with osimertinib to 48 months or four years median overall survival with the combination. We see that here escalation and combination is clearly doing better for these patients.

The other point here that is very important is that we know that it is very important not only to get a PFS benefit, but also an overall survival benefit. In this disease, metastatic EGFR-mutated non-small cell lung cancer, we know that the efficacy of subsequent lines is more limited, and Dr. Spira will discuss this data later. The better and the more prolonged will be the first-line, the higher is the chance of getting an overall survival benefit.

It is also true that in clinical practice, many patients do not receive subsequent lines because of rapid degradation of the general condition or a CNS disease, meningitis, which is quite frequent in this patient population. Being more aggressive and more intensive in the first-line setting makes sense in patients with EGFR-mutated non-small cell lung cancer.

FLAURA2: PFS With or Without CNS Metastases

In FLAURA2, we see this magnitude of benefit in patients with aggressive disease, as I previously mentioned. Here in patients with CNS disease, we clearly see this benefit. It is true that in patients with less aggressive disease, for example, patients without CNS disease, the magnitude of benefit with the intensification with the combination is a little bit lower.

TOP: 1L Osimertinib ± Chemotherapy for Advanced NSCLC With Concurrent EGFR and TP53 Mutations

In the TOP study recently presented at the ELCC meeting, we focus on the patients with TP53 co-mutations. So patients with common EGFR mutations plus TP53 co-mutation. We know that TP53 co-mutations are associated with a lower efficacy of single-agent osimertinib. Here, this study is assessing the combination of osimertinib plus chemotherapy in this subgroup of patients.

TOP: PFS (Primary Endpoint)

Here again, we see a major benefit in favor of the combination.

TOP: Interim Analysis of OS (Key Secondary Endpoint)

This translates into an overall survival benefit.

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

Chemotherapy plus osimertinib is a way to intensify first-line treatment for these patients. The other way to do that is to use a combination of a third-generation TKI, which is Lazertinib, quite similar to Osimertinib plus Amivantamab, which is a bispecific EGFR MET antibody. This is a chemo-free regimen and a dual-targeting of the EGFR. Amivantamab is also covering MET, which is a pathway that is activated in many patients after the failure of osimertinib. Again, protecting against the emergence of MET-related resistance.

In the MARIPOSA trial, Amivantamab plus Lazertinib was compared to osimertinib.

MARIPOSA: PFS

We see a benefit in terms of PFS moving again from the 17 months to two years, 24 months median PFS with the combination. Again, we see a benefit with the intensification of the treatment.

MARIPOSA: OS

This translates into an overall survival benefit median not reached in the Amivantamab plus Lazertinib arm, but hazard ratio that is actually quite similar to that observed in the FLAURA2 study. MARIPOSA, FLAURA2 probably quite similar results if we cross compare these two studies. We clearly see that intensification versus osimertinib is doing better not only in terms of PFS, but also in terms of OS. This is quite a new standard of care for the patients.

In the MARIPOSA trial, looking at the subgroup analysis, we see that the majority of patients are actually benefiting not only the patients with aggressive disease, but also the patients with less aggressive disease with a similar magnitude of benefit in terms of PFS.

MARIPOSA: Mechanisms of Amivantamab + Lazertinib Resistance

Also with MARIPOSA, we are changing the mechanisms of resistance after the disease progression to Amivantamab plus Lazertinib because we are covering the MET. Here we do not see that much of MET activation after the failure of Amivantamab plus Lazertinib, which is expected given the mechanism of action of Amivantamab.

This is what we have, and now we have more options for the patients. We probably need to better stratify the patients based on the aggressiveness of the disease, based on the patient's comorbidities, with regards to the delivery of chemotherapy and also looking at the molecular data. For example, TP53 co-mutations which are associated with a major benefit with the FLAURA2 regimen.

Posttest 1

Here is a posttest one question. This is a 62-year-old Asian woman. No smoking history, presenting with worsening respiratory symptoms. We have a CT scan showing multiple pulmonary nodules, adenopathies and hepatic lesions. No CNS disease. This is adenocarcinoma. EGFR exon 19 deletion, PD-L1 10%. We are in the setting of first-line treatment.

Based on the latest FDA approvals and phase III clinical trial data, which of the following is the most appropriate first-line treatment option? Is this:

1. Amivantamab plus carboplatin plus pemetrexed. Well, I did not talk about this combination;
2. Osimertinib monotherapy;
3. Carboplatin/pemetrexed plus pembrolizumab; or
4. Amivantamab plus lazertinib.

You may vote now. Okay, maybe we can look at the responses. Majority stated Amivantamab plus Lazertinib. Yes. Again, we have a benefit in terms of PFS and OS versus osimertinib. Clearly, with Amivantamab plus Lazertinib, the efficacy will be higher. The point will be the safety. With Amivantamab plus Lazertinib, there is a need for a more intensive management and proactive management of the side effects because rash is more frequent. It is occurring in the vast majority of patients.

There is a proactive dermatologic management that is required, including doxycycline, moisturizing, dermatologic monitoring to avoid severe cutaneous side effects. With Amivantamab subcutaneous formulation, the reactions to the first infusions are getting less frequent, and there is also a need with Amivantamab plus Lazertinib to cover the higher risk of thrombosis with anticoagulants.

So versus osimertinib, we have a higher efficacy, but we have more side effects. This is also true with chemotherapy plus osimertinib, where we are adding the side effects of chemotherapy with a higher risk of neutropenia.

Maybe now we can move to the second-line setting.

Speaker: Dr. Girard, there are a couple questions in the chat real quick.

Dr. Girard: Sure.

Speaker: One is, what is the explanation for improved PFS for osimertinib in the neoadjuvant setting without significant overall survival rather than a trend of improvement?

Dr. Girard: In the neoadjuvant setting, we have data that I did not presented with osimertinib or chemotherapy plus osimertinib. It is a way in selected patients. There is no approval for osimertinib in this situation, but in some patients with EGFR-mutated non-small cell lung cancer, stage III, not amenable to upfront surgical resection, it may be a way to obtain a downstaging not only of the primary tumor, but also of the lymph nodes. Here chemotherapy is the standard of care.

Combination of chemotherapy plus osimertinib is probably the way to go. We do not see at this time PFS, OS improvement as compared to historical data, but at least we gain in terms of downstaging, which is a prognostic factor in this patient population.

Speaker: One last quick question. On the last posttest, there was a question as to whether or not the FLAURA2 regimen would be an option for that patient.

Dr. Girard: Yes. For sure. Yes, FLAURA2, as I discussed is also an option in this case.

Maybe we can move to second-line. Alex, I give you the floor.

Common EGFR Mutations in Advanced, 2L+ Treatment

Dr. Spira: Thank you, Nicolas. Today, I am going to be talking about common EGFR mutations in advanced second-line and beyond treatment.

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

There is a lot of different studies that are ongoing shown here: MARIPOSA-2, TROPION-Lung05, datopotamab. Some of these are older. SAVANNAH looking at the MET positivity, as well as ORCHARD, COMPEL. A lot of these have read out already as well. A lot of different approaches depending a lot again on mutational status.

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

We will talk a little bit about COMPEL. COMPEL is osimertinib plus platinum-based chemotherapy in EGFR-mutated advanced non-small cell lung cancer after osimertinib. Again, asking a very simple question right now is, these are patients who have locally advanced or metastatic EGFR-mutated lung cancer with or without metastases. They are stratified by CNS metastases with the presence or not.

As you can see here the randomization. Randomized to either osimertinib versus chemotherapy or placebo. Basically asking the question, does the continuation of osimertinib improve outcomes?

Primary endpoint being PFS and key secondary endpoints, of course, looking at brain metastases.

COMPEL: PFS and CNS PFS

Very interestingly here, what you saw in the COMPEL study is that when you left people on osimertinib, they actually did better. Progression-free survival was 86% versus 65% with a median PFS of 8.4 months versus 4.4 months.

Looking at some of the time points here at six months, 64% versus 32%, six-month progression-free survival. One of the thought processes about leaving people on osimertinib is does that help prevent brain metastases? Because we know osimertinib versus chemotherapy has a much higher CNS penetration. That was seen.

If you look at six months, it was 87% versus 63% with the median CNS progression-free survival of nearly 16 months versus about 8.5 months. Again, based upon this, and this is something people have been doing off label for quite some time, even people on osimertinib with the addition of chemotherapy in that second-line setting.

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

Now we look at MARIPOSA-2. MARIPOSA was frontline. MARIPOSA-2, second-line. These patients were randomized as chemotherapy and Amivantamab/Lazertinib with chemotherapy or Amivantamab with chemotherapy in the second-line setting. These again are patients who got osimertinib with the classical EGFR mutation in the frontline setting.

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

What we will look at here, you can at the two arms: Amivantamab/Lazertinib/chemotherapy and Amivantamab/chemotherapy. Both of these did better than chemotherapy by itself, 8.3 and 6.3 months versus 4.2 months. It does look like that the Amivantamab/Lazertinib/chemotherapy combination had a lot of toxicity, so I want to focus people really on the Amivantamab/chemotherapy part versus the Amivantamab/Lazertinib/chemotherapy part.

As you can see here, overall survival on the right was significantly improved at a 12-month landmark 70% versus 63% and 18-month landmark 50% versus 40% overall survival. This is the second overall survival analysis, so it is going to be very mature.

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

TROPION-Lung01 and 05 is looking at Dato-DXd in the previously treated patient population EGFR-mutated non-small cell lung cancer. These are both complicated studies. The phase III TROPION-Lung01 study randomized patients with AGAs, who received platinum-based therapy, as well as docetaxel with Dato-DXd versus docetaxel, as well as some patients with TROPION-Lung05 study with phase II. These are really grouped together for this analysis, and pulled together a total of 117 patients overall from both studies.

TROPION-Lung01/-Lung05 Pooled Analysis: Efficacy

As you can see in the EGFR-mutated population, median overall survival was 15.6 months with progression-free survival of 5.8 months. Response rates of about 43%, significantly better than historical numbers from both pemetrexed and docetaxel. Again, this led to FDA approval combining these two drugs.

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

One of the newer ones is OptiTROP. This is looking at Sac-TMT. This is a TROP-2 ADC, randomized phase III study. These patients were randomized versus chemotherapy. They were randomized to Sac-TMT versus chemotherapy. Again, chemo-naive patients randomized to either Sac-TMT versus chemotherapy. Again, this is a TROP-2 ADC. Standard endpoints here PFS by Blinded Independent Central Review.

OptiTROP-Lung04: PFS

As you can see here, Sac-TMT versus chemotherapy. Again, this is versus platinum-based therapy, so very exciting here because most commonly as you look at the TROPION study that was compared versus docetaxel in the frontline setting, this is right up versus chemotherapy, significantly improved outcomes here. As you can see, overall survival 8.3 versus 4.3 months and 32 versus 7.9 month progression-free survival at month 12 here.

Again, there has been a lot of thought about the TROP-2 is highly expressed on EGFR-mutated cancer cells. What we are seeing here in OptiTROP study.

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

Now look at ORCHARD. ORCHARD is very different. This is a biomarker-directed study. These are patients who had EGFR-mutated lung cancer with osimertinib. This is a non-matched biomarker. So patients received osimertinib/Dato-DXd in two different doses, primary endpoint of overall response rate. Again, randomized study with just two doses of Dato-DXd with osimertinib who progressed on osimertinib.

ORCHARD Module 10: ORR

As you can see, the response rates here. Really impressive, 43% versus 36% with two dose levels, slightly lower at the higher dose level, but probably not significant. Patients did respond very quickly as well. Again, it does look very promising. There is some caveats here about who might have had greater target lesion shrinkage, etc.. Nevertheless, clear efficacy of Dato-DXd in the second-line setting in this dose randomization study.

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

SAVANNAH. As we know, one of the nice things about Amivantamab is that it covers MET and helps prevent mutations or amplification. Here the SAVANNAH study was looking at a very similar topic, but these are patients who are already on osimertinib only, and they were found to have MET overexpression either by IHC or amplification. They need to have essentially confirmed and a very complicated study design here, but randomized patients to savolitinib and osimertinib and several different doses.

Here, focusing on the overall endpoints. We can look at the right side. These patients were randomized to savolitinib to osimertinib 2:1 versus the savolitinib by itself. There was crossover as well.

Again, really looking at the population post osimertinib developed MET amplification either FISH or IHC.

SAVANNAH: ORR and DoR

As you can see here, efficacy is fairly pronounced, with response rates more than 50%, either 56 or 55, depending on investigator-assessed or central. Almost all PRs. Duration of response between seven to 10 months, 7.1 to 9.9 months, and median time to onset is really the first step. So usually given about six weeks.

Clearly, the addition of the MET therapy in this genomically selected population does improve outcomes.

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

Now we will look at a different study. These are very similar patients. This is randomizing savolitinib-osimertinib in this MET-amplified, FISH-amplified patient population after osimertinib, but now comparing with this chemotherapy. So a traditional way to get an FDA approval. Again patients with EGFR mutation post osimertinib randomized to either savolitinib-osimertinib or platinum-based chemotherapy in a randomized manner.

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

As you can see here, both by investigator-assessed on the left, as well as independent review committee on the right. Progression-free survival significantly better in the savolitinib-osimertinib arm versus chemotherapy. Median PFS of 6.9 versus three months. Similar numbers in the Independent Review Committee as well. Again, clear evidence of activity in the ITT population for those who progressed on EGFR TKI, looks like it is better than chemotherapy in patients with MET amplification done by IHC.

SACHI: Response and OS

Looking at response rates, as you can see here, 50% response rate, disease control rate 89% with a relatively impressive duration 8.4 months, only three months versus chemotherapy. It looks like the beginnings of overall survival improvement as well, 22 versus 17.7 months. Not really mature enough to get to that at this point and reminding everybody that a lot of these patients in the control arm ended up crossing over as well. That enhances the [inaudible].

Agents in Development for Uncommon EGFR Mutations and PACC (G719X, S768I) Mutations

We will now look at uncommon mutations as well. This is furmonertinib. I call it furmo, because it is easier to say. Looking at two different dose levels here right now. As you can see in patients with a typical first-line PACC mutations. PACC mutations typical one was G719X versus or S768I. There are some other ones as well. As you can see response rates depending on the dose 50% versus 80% with significant number of complete responses and impressive PFS as well.

Now there is a first-line, the ALPACCA study done for registration comparing furmo versus investigator choice, either Osimertinib or Afatinib.

Similar studies, Silevertinib, formerly known as Black Diamond’s drug BDTX-1535. Preliminary dose escalation results. This is a very complicated protocol, but a lot of these patients also had atypical PACC mutations as well and did show improvements.

Also as you can see, some very reasonable waterfall plots here. We await some data that can come out each year for more robust data set.

Now I will pass it back to Nicolas to talk about exon 20 insertions.

Exon 20 Insertion Mutations

Dr. Girard: Sure. Exon 20 insertion mutations, again very different subgroups of patients as compared to the other ones. No efficacy of the EGFR TKIs such as gefitinib, erlotinib or osimertinib in this group of patients. Then a lower survival historically in those patients.

Molecular Landscape of EGFR Exon 20 Insertions

First, this is a very heterogeneous group of patients. There is a challenge regarding the identification of EGFR exon 20 insertion mutations. These are highly diverse, and we need NGS to identify all the patients with those exon 20 insertions. Ultimately, this is about 10% of all EGFR mutations.

Amivantamab for EGFR Exon 20 Insertions

Amivantamab has demonstrated efficacy for this group of patients. Here we have the data from the CHRYSALIS phase I study, 80 patients. We see a response rate across all the subgroups of patients around 40% in the late-line setting. This is clearly a signal of high activity. Median duration of response, 11 months. Median PFS, eight months. Clearly higher than what we get with docetaxel or single-agent chemotherapy.

Clearly, in the second-line setting, later line setting after the failure of platinum-based chemotherapy, Amivantamab is an option in those patients.

Trials Targeting Exon 20 Insertion Mutations in First-line Treatment

We also have data in the first-line setting with Amivantamab.

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

This is the PAPILLON study, which is Amivantamab plus chemotherapy versus chemotherapy for the first-line treatment of these patients, a study which randomized more than 300 patients. We see a doubling of the median PFS from 6.7 months with chemotherapy to 11.4 months with Amivantamab plus chemotherapy. We also see a higher response rate, 73% in this patient population, and a tendency towards a PFS2 and overall survival benefit.

Clearly, Amivantamab plus chemotherapy is a current standard of care for the first-line treatment of these patients with exon 20 insertion mutations.

PALOMA-2 Cohort 1: 1L SC Amivantamab + Lazertinib in EGFR-Mutated Advanced NSCLC

We also have data from the PALOMA-2 study in this setting with subcutaneous Amivantamab.

PALOMA-2 Cohort 5: 1L SC Amivantamab + Lazertinib in EGFR-Mutated Advanced NSCLC

Here are some data in the first-line setting for common EGFR mutations. We clearly see the similar efficacy of IV versus subcutaneous Amivantamab. This was the PALOMA-2 trial.

PALOMA-2 Cohort 5: Safety and Key Takeaways

PALOMA-2 is also associated with a different safety profile, so subcutaneous Amivantamab. Here we have probably a lower rate of cutaneous side effects. It is also true that in this study, the investigators have been more used to the management of patients with Amivantamab more globally, and we clearly see that we have a quite low rate of grade 3 or higher side effects.

We also see that there is a reduction in the risk of infusion-related reactions with a subcutaneous administration of Amivantamab, and now the subcutaneous Amivantamab has been assessed not only in the first-line setting based on the MARIPOSA trial, together with Lazertinib, but also in the second-line setting based on the MARIPOSA-2 study, in combination with chemotherapy and also in the first-line setting in combination with chemotherapy for EGFR exon 20 mutations.

Posttest 2

Now we have a post test. Which statements best reflects the findings from the PALOMA-2 trial evaluating subcutaneous versus IV Amivantamab in this patient population?

You may vote now.

Okay. We have majority answered. We have fewer infusion-related reactions, obviously shorter visits at the hospital and the efficacy is similar to intravenous Amivantamab.

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

We have other options in the EGFR exon 20 insertion mutation space, furmonertinib which is a TKI. Here we have data with furmonertinib 240 milligrams in patients refractory to platinum-based chemotherapy, 71 patients. We have a response rate that is actually quite similar to that reported with Amivantamab in the CHRYSALIS study, 44%. Median PFS, 8.3 months. The safety is more like that of a TKI, diarrhea being the most frequent side effect with this agent.

WU-KONG1: Global Phase II Sunvozertinib (DZD9008)

We also have data with sunvozertinib, another TKI targeting EGFR exon 20 insertion mutations. These are data from a global phase II study with this drug, the WU-KONG1 trial. Again, we see a confirmed response rate higher than 40%. This is a strong signal of the efficacy of this drug. We see complete responses. The median PFS was around eight months, which is again a strong signal of efficacy in this late-line setting. Furmonertinib, sunvozertinib are obviously promising agents in this group of patients.

WU-KONG1B: Treatment-Related Adverse Events

Safety, again with these agents is mostly related to diarrhea, which is quite frequent with these drugs. At the next ASCO meeting in a few days, we will see phase III data with sunvozertinib compared to chemotherapy, so WU-KONG28 phase III trial with sunvozertinib.

Posttest 3

Posttest three. You are considering a patient with advanced non-small cell lung cancer with EGFR exon 20 insertion, who has experienced disease progression after Amivantamab plus chemotherapy not considering a treatment with sunvozertinib. The patient asks which are the most frequent adverse events in this setting.

Based on the clinical trial data, what would you tell him is the most common adverse events associated with sunvozertinib?

1. CPK elevation;
2. Diarrhea;
3. Paronychia; or
4. Rash.

Okay. The answer is diarrhea. There will be a need to have a proactive management of diarrhea in those patients. Diarrhea is obviously frequent. Usually it occurs very quickly after the initiation of the treatment. Here the objective is to maintain diarrhea with a grade 1 using loperamide having obviously a concealing of the patients regarding diet and then managing the patients to maximize the observance of the track.

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

Zipalertinib is the third one. Again, it is a TKI targeting EGFR exon 20 insertion mutations. Here we have data after PAPILLON, after platinum-based chemotherapy either alone or combined with Amivantamab. This is REZILIENT1 study with Zipalertinib 100 milligrams BID.

REZILIENT1: Zipalertinib Activity After Amivantamab

Again, we see a strong signal of efficacy in this patient population. After PAPILLON, we have a 30% response rate. 40% response rate in patients without prior exposure to Amivantamab. Again, this is a strong signal of efficacy. After PAPILLON, to me, it is quite compelling to see that we can continue to have this targeting of the EGFR exon 20 mutation.

Zipalertinib safety, mostly cutaneous side effects. Diarrhea less frequent as compared to the furmonertinib, sunvozertinib data. I feel that this is manageable side effects.

Phase IIb REZILIENT1: Efficacy Among All Patients and Specific Subgroups

We have here a table summarizing these data. The duration of efficacy is around eight, nine months. Again, in this second-line, late-line setting, we see that this is clinically meaningful.

Enozertinib in EGFR Exon 20 Insertions

Obviously, we have other TKIs in this setting. Zipalertinib is currently being tested in the first-line setting in combination with chemo versus chemotherapy. We will have to look after this data.

Enozertinib, another TKI, again, in the late-line setting with a response rate around 40%. The intracranial efficacy is also an important endpoint in those patients with EGFR exon 20 insertion-mutated non-small cell lung cancer. Obviously, it may be a way to differentiate one option versus the other.

These are the data for EGFR exon 20 insertion mutations. Many drugs with expected new data to further discuss in this subgroup of patients.

Final Polling

Now we can go to the final polling, Alex.

Poll 3

Dr. Spira: Great. Do you plan to make any changes in your clinical practice based on what you learned? I hope the answer is yes. Otherwise, we did not do our job.

Speaker: For these final demographic polls, we will not be showing the results.

Dr. Spira: Move on again.

Poll 4

Then the one key change you plan to make. I will give everybody 30 seconds to a minute here.

Speaker: Yes. For this one we can leave the poll up and advance the slide, I believe.

Thank You for Attending

We can move on to the next slide there. Please just go online and use the link on the screen to claim credit. I want to thank our speakers today.

Q&A

There is one question in the chat that we have not answered yet on. I do not know if either of you can see it, but otherwise I can read it, which says, with an arsenal of therapy in the second-line, what are the main factors that will affect our decision in selecting therapy and why savolitinib failed in MET-driven RCC, whereas got success in NSCLC.

Dr. Spira: All really good questions, and especially EGFR is getting very complicated. There is lots of different options. Patients have lots of different choices to make. Physicians have lots of different choices to make. It will somewhat be biomarker driven. We did not even talk about C797S that much today, but there is new drugs for that. Lots of different choices.

It is going to come down to level of comfort and where you want to go. Renal cancer is a very different malignancy than EGFR-mutated lung cancer. These are patients with a specific driver developed as a mechanism of resistance. It also goes back to the day of what is called MetMAb which failed miserably in gastric cancer a long time ago. This is just a very unique situation where we know a specific pathway for resistance.