Let us talk about biomarker testing for EGFR mutations.

[00:06:00]

Testing Options for Biomarkers in NSCLC

I always say that you cannot use an EGFR inhibitor in non‑small-cell lung cancer unless you find the EGFR mutation. In order to find it, you have to do 1 of these 2 tests. The tissue testing here on the left really is the gold standard. You have tissue available because, somehow, you made the diagnosis of lung cancer. It is not 100% accurate. Sometimes there is tissue heterogeneity, so technically, if the needle went into a part of the tumor that did not have the EGFR mutation in that small part, you could have an inaccurate test. But generally, this is the best test for this.

It does have a slower turnaround time, so next‑gen sequencing on tissue can take 2-4 weeks or even longer for that DNA sequencing. Tests that use IHC or FISH are faster. However, they cannot detect EGFR mutations because those are DNA mutations and those require the next‑generation or the DNA sequencing panel.

The other way you can test for biomarkers in non‑small-cell lung cancer is to use blood tests, or sometimes they will call it a liquid biopsy, which I joke that it is neither liquid nor biopsy. It is blood test. But you are looking for circulating tumor DNA.

What does that mean? That means that if you have lung cancer, the tumor anywhere in your body, whether it is the primary tumor in the lung, the liver mets, whatever it is, if it is shedding DNA into the bloodstream, then you will find DNA within the bloodstream. Then you can test that tumor DNA for biomarkers. It just requires a phlebotomy, usually to send out to a certain company. It is a quick turnaround time, so usually 7 or less calendar days. It is quick turnaround. It cannot currently detect PD‑L1, which is an expression level. This is really generally for the DNA sequencing tests.

This, though, can miss mutations. It relies on that DNA shedding. For people who have low burden of disease, and they are not shedding much in the bloodstream, we can miss mutations from this. They estimate that this can have anywhere from a 10% to 20% false negative rate.

[00:08:10]

Methods of Tissue Testing in Solid Tumors

The methods of tissue testing, I alluded to this earlier. IHC is immunohistochemistry. It is really quick and easy. This is how we determine PD‑L1 expression. This is staining to determine if a cancer is from the lung or from the colon, but it has a really low sensitivity for actionable biomarkers, so it is not something that we rely heavily on.

A FISH test is quicker than next‑generation sequencing, and it is a little bit more sensitive, particularly for the fusions. We look for HER2 by FISH in breast cancer, and it can detect ALK and ROS1 fusions in lung cancer. Again, it is not as sensitive as an NGS panel, but it is more sensitive than an IHC. It really requires specific equipment. We do not always do FISH on everyone.

Then, the NGS panels, the 2 below are the most sensitive tests. The NGS DNA panel is what you would normally order, and this is the most sensitive test. It can detect everything: fusions, point mutations, insertions, in‑frame deletions. The problem is it takes longer, 2-4 weeks. It requires good cellularity of the tumor because they have to really manipulate that DNA in order to be able to extract DNA in order to run these tests. This can have up to 20% or 30% quantity‑ or quality‑not‑sufficient rate. Which means there was not enough good DNA for them to run the test.

An RNA fusion panel is listed at the bottom. This is new in the last 6-8 years. For patients on a DNA panel in whom they do not find a fusion, most companies are now reflexing to an RNA fusion panel. This will detect the fusion genes. In lung cancer, this is ALK, ROS1, RET. Technically, it can look at MET as well, NTRK; these are all fusions. It is a newer technique. It can also take a couple of weeks, but it is more sensitive to detecting the fusion genes. We do run it if we do not find 1 of those fusion genes on the DNA panel.

[00:10:22]

Principles of Biomarker Testing

The NCCN says that we should be doing this on this broad‑based approach, so not single‑gene testing but the broad‑based approach and do the RNA testing to be more specific for the RNA fusions if we do not find it on the DNA, like I said. It recommends that using peripheral blood or liquid biopsy or the blood‑based testing, that there is enough data to support using that in conjunction with tissue‑based testing. There was always this thing of if I am running tissue testing, insurance will not pay for the blood as well, but really, they do. Upfront in my practice, we do blood and tissue on everyone to make sure we are getting the fastest results and the most accurate results. Because of this language in the NCCN guidelines, really insurances should be paying for it.

Who do we test? We test all patients with adenocarcinoma of the lung. Patients with large cell. Anyone that does not have squamous should definitely be testing. You should also consider testing squamous patients with non‑small-cell lung cancer. In my institution, we do not do every single patient with squamous. Some do. That might be in the future. Only about 5% of patients with squamous non‑small-cell lung cancer will have an actionable mutation, and about half of those are never smokers.

For example, who do I test in squamous? I test patients with never smokers or patients who have had a minimal smoking history. Maybe they smoked for 5 years, 10 years, but they quit 40 years ago. Those are patients I would test. I would test young patients. Why are you getting lung cancer if you are 30 or 40 or even in your early 50s? That is much younger than our average population. Those are patients also with squamous, I would consider testing.

[00:12:10]

Biomarkers in Metastatic NSCLC, Adenocarcinoma Subtype

Biomarkers in metastatic non‑small-cell lung cancer. This is the pie chart. You can see in green that is EGFR, and that is the majority of the actionable mutations that we find. KRAS is the second most common type. Now, we find a lot of KRASes, that is in the navy blue and the light blue there, but the light blue, the KRAS G12C, is the only 1 that is actionable.

Then you see a whole bunch of little ones there. Pretty much almost all listed there are actionable. Now, you might say, "Beth,” I’m trying to find 1 on there, “HER2 is only 3.8%, or ALK fusion is 4%, or ROS1 is only 2%. Beth, I am never going to find 1 of those in my practice." The thing is, if you do the NGS panel, if you add them up: MET 2.5%, RET 2%, ROS1 2%, that is 2, 4, 6%, another 4% for ALK, that is 10%, HER2, BRAF. You start to add them up, it is actually 15%, 20% of patients are going to have 1 of those really rare ones. The target therapy that we match with them is much better generally than a run‑of‑the‑mill chemo immunotherapy would be for these patients. It is important to look for all of these.

[00:13:26]

EGFR Oncogenic Driver Mutations

We are going to drill down on EGFR, which is the topic of conversation today. This is what we find within EGFR mutations. The most common by far is the exon 19 deletion and the exon 21 point mutation that is otherwise known as L858R. You can see in the pie chart on the left in the navy there, that makes up, some quick math, 79%, 80% of EGFR mutations are going to be the common mutations.

Then we see about 12% of EGFR mutations are in something called the exon 20 insertion space. It is less common, but it does have different treatments. The exon 20 point insertions do not typically respond to our regular EGFR therapies, as the other ones do. We have some specialized therapies for that.

Then there is something called the uncommon mutations. These make up about 9% of all EGFR mutations. I listed some of them there in that green square at the middle bottom. A lot of times, they are compounded with a common 1, or they are compounded together, but these are actually actionable as well. Again, they do not respond nearly as well to our traditional EGFR therapies.

[00:14:50]

Barriers to Biomarker Testing in NSCLC

I put some barriers here to biomarker testing. We should be able to do this pretty easily, right? It is not always that easy. Like I said, there is apathy. Doctors say, "I do not think I will ever find a ROS1. Why am I testing?" Just do the full NGS panel. After a while, you will find it.

The tissue. So there is either not enough, then what do you do? Do you go back and rebiopsy them? Sometimes the answer is yes. Sometimes, if we can get something on liquid biopsy and we feel confident that it is the right result, then we do not need more.

The other thing is getting it from a facility. I work at the University of Pennsylvania, but a lot of my patients may have had a biopsy done somewhere else. It is like, "I need to get it from that facility, but that facility is dragging their feet." At our institution, we have a tissue navigator, who just works all day long for the cancer center, procuring this tissue from the other institutions.

Complex reports. Have you guys tried to read 1 of these? They are really hard to understand sometimes. Oftentimes, I will need to call molecular pathology to figure it out.

The timing. I alluded to this earlier. It can take 2-3 weeks. Patients and doctors do not want to wait for the results, so they just hop on a different treatment. It is important, really, that we wait.

Then the administrative barriers. This might sound so silly, but I cannot find the report. Is it like stuck on the fax machine? Is it in my EMR, but in some crazy tab that I cannot find it? In my practice, they used to embed this report in the original pathology, which sometimes, when I go back to look, could have been several months ago. It is important administratively to figure out where these reports are and consistently putting them in the same place in the EMR.

[00:16:35]

Importance of Waiting for Biomarker Testing Results

It is really important to wait. It is unsafe to give EGFR tyrosine kinase inhibitors after initiation of immune checkpoint inhibitors. There are really high rates of pneumonitis and hepatitis if you give an EGFR inhibitor right after immunotherapy. We really recommend that you have all of those biomarker reports back before immunotherapy. The chemotherapy is fine. If you needed to start them right away, really fast, and you gave them chemo, okay. But once that immunotherapy is in, you cannot take it back. It has a really long half‑life, and the EGFR inhibitors are not safe to give directly after immunotherapy.

People who get their first line targeted therapy to match their biomarker disease have longer survival than those who receive non‑targeted therapies. Again, if you have an EGFR mutation and you get chemo first as opposed to your EGFR‑mutated therapy first, you will have a shorter survival. You want to get that first‑line biomarker‑directed therapy first.

Immune checkpoint inhibitors have very little, if any, efficacy in patients with EGFR mutation lung cancer. It is very rare that we use them. They just do not work well in this population.

[00:17:48]

Key Categories of Treatment for EGFR‑Mutated NSCLC

What are our treatments of choice for EGFR‑mutated lung cancer? There are really 3 classes of treatment. One is what we have had around the longest, tyrosine kinase inhibitors. These are things like osimertinib, which is our preferred frontline treatment. Then there are several others. I listed 4 other drugs down there that we used to use in the past, but we do not really use them much anymore. Osimertinib is the preferred frontline therapy.

Then there is a bispecific antibody now, called amivantamab. This is an antibody that binds to both EGFR and MET. MET is a resistance mutation that we often find with patients getting EGFR therapy, so this drug is unique because it actually blocks both EGFR and MET. This is approved as monotherapy or in combination with lazertinib for the common mutations or in combination with chemotherapy for the exon 20 insertions. We will talk about that.

Then the third type is an antibody drug conjugate. Datopotamab deruxtecan or dato‑DXd is now approved in second‑line therapy for these patients. We will talk about that as well.

[00:18:57]

Managing Early‑Stage EGFR‑Mutated NSCLC

I am going to start with early stage and move to metastatic.

[00:19:01]

Case 1: Patient With Resectable NSCLC With EGFR Exon Point 21 L858R Mutation

Early‑stage non‑small-cell lung cancer. This is a case study of mine. This is a patient with resectable non‑small-cell lung cancer with an EGFR exon 21 point mutation. This is 1 of the common mutations. This was an actual patient of mine. He's a 65 year old male never smoker. He presented with shortness of breath. He had got a chest X‑ray that showed a right upper lobe mass. On the CT, it was 4.7cm, and he had enlarged hilar lymph nodes. His bronchoscopy showed that it was adenocarcinoma, and he had a level 11 right lymph node. He was staged as stage 2B.

This is a patient we would take to surgery, but as you might know right now, all the rage is to give neoadjuvant, prior to surgery, chemo/immunotherapy because we have really good outcomes when patients get their treatment upfront prior to surgery. But remember, I just told you that immunotherapy does not work well for patients with EGFR mutations, so we really always want to get biomarker testing in these patients before just giving them chemo/IO.

This guy was like, "Oh my gosh, I do not want to wait 2, 3, 4 weeks to start neoadjuvant treatment or to go directly to surgery." I called molecular pathology. I said we need to prioritize this guy. We need to get this really quickly. I actually single‑gene tested him for just EGFR, ALK and ROS1. What we ended up doing was we put him on the OR schedule, thinking that he might have a mutation because he was a never‑smoker. We thought we will take him off the schedule if he does not have a mutation. Four days later, I did get the result that he had the EGFR mutation, so we cancelled chemo/IO. He never got it. We had him on the schedule, but he never got it, and proceeded directly to surgery. Because we knew chemo io in the neoadjuvant setting would not help him.

[00:20:51]

Poll 2

What would be the following treatment for this patient post‑surgery? He goes to surgery. He has this EGFR mutation. What are we going to do now, following surgery for adjuvant treatment in this patient? Would it be:

1. Immunotherapy plus chemo;
2. Amivantamab plus lazertinib;
3. Datopotamab deruxtecan;
4. Osimertinib; or
5. None; adjuvant treatment has not been shown to be advantageous for EGFR‑mutated lung cancer.

Education Host: The poll is open. Please vote. We will give everybody a few more seconds to submit the response. Beth, here are your results.

Beth Sandy: The majority of you said osimertinib, and this is the correct answer. I am going to show you.

[00:22:03]

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

This is the ADAURA trial. This is giving adjuvant osimertinib to patients after complete resection for early‑stage lung cancer. These patients were allowed to get chemotherapy, so they could get 4 cycles of platinum‑based chemotherapy, which we know was the standard of care up to this time. Then, after surgery, these patients were randomized to either get osimertinib 80mg once a day, which we already knew worked well in the metastatic setting, vs placebo. They did this for 3 years, so they took this for 3 years post surgery, whether they got adjuvant chemo or not first.

[00:22:41]

ADAURA: DFS in Overall Population

This is what we found. The disease‑free survival. Disease‑free survival means that my cancer did not come back. I do not want my cancer to come back. You can see at 4 years here, at 48 months, 73% of patients did not have their cancer come back, as opposed to only 38% on placebo. This is really exciting. Hazard ratio, super low 0.27. We rarely see that. Based on this, this was approved.

[00:23:09]

ADAURA: DFS Subgroup Analysis in Overall Population

You can see every subgroup benefited to the left of this line on the forest plot. Every subgroup benefited a lot to the left of that forest plot line. This is something that we are doing now in the adjuvant setting.

[00:23:23]

Stage III Locally Advanced EGFR‑Mutated NSCLC

What about stage III disease? Post‑concurrent chemoradiation.

[00:23:25]

LAURA: Osimertinib After Definitive Chemoradiation in Unresectable Stage III EGFR‑Mutated NSCLC

This is still a curative intent setting, and these patients with stage III are not resectable but still curative. It is localized to the chest. These patients would get concurrent chemoradiation, which is the standard of care, and then similar they were randomized to either get osimertinib 80mg daily vs placebo.

Now, the interesting thing in this study is that they just stayed on the osimertinib until progressive disease or toxicity that they could not manage. The weird thing about that is, is this was curative intent therapy, so how long do you stay on it? We do cure patients with stage 3 lung cancer all the time. Do you stay on it for 3 years, 4 years, 5 years? I think that remains to be seen. I do not know that I would give it to somebody forever for the rest of their life. In this study, they did not name an end date, just because it was a higher‑risk cancer.

[00:24:27]

LAURA: PFS by BICR (Primary Endpoint)

This was the progression‑free survival. Again, progression here would basically mean your cancer came back because at the end of chemoradiation, we treated it definitively. And again, you see a huge gap here. At 2 years, 65% of patients did not have their stage III lung cancer come back as opposed to only 13% on placebo. This was a wildly positive study. This is somewhat still early data, and these numbers are still coming back but I think you can really see here, even at 3 years, even at 48 months, these curves seem to be very far apart. We will continue to watch data on this and kind of decide how long to keep patients on this. Chemoradiation is still what you should do for curative therapy in these patients. Radiation is the curative intent modality here.

[00:25:18]

Conclusions for Curative‑Intent EGFR‑Mutated NSCLC

Conclusions for curative intent or early stage with locally advanced is that early stage non‑small-cell lung cancer, you must test for EGFR mutation, because those patients we would not give neoadjuvant chemo IO. We would take them right to surgery and then give them osimertinib for 3 years post surgery with or without 4 cycles of platinum‑based chemo in that post‑op setting. There is a study in clinical trials right now looking at neoadjuvant osimertinib; giving osimertinib for a few months or so before surgery. So that is ongoing right now and we do not have any data yet for that. We now use osimertinib after chemoradiation for these patients with EGFR mutations. Again, it is unclear for how long. 80mg daily, but the clinical trial did not have an end time.

[00:26:05]

Treatment for Metastatic EGFR‑Mutated NSCLC (Common Mutations)

All right. Let us move on to the metastatic setting. We have a lot to talk about here.

[00:26:11]

Poll 3

We will first start off by talking about the common mutations. In your practice, this is a polling question: which of the following would not be an appropriate treatment for a patient with first‑line metastatic non‑small-cell lung cancer with an EGFR exon 19 deletion mutation? Is it:

1. Amivantamab and lazertinib;
2. Immunotherapy and chemotherapy;
3. Osimertinib; or
4. Osimertinib plus chemotherapy.

Which is not appropriate?

Education Host: The poll is open. Please vote. Just a few more seconds for incoming responses. Here are your results. There you go.

Beth Sandy: 68% of you got this right. Immunotherapy and chemotherapy is not something we would give to patients with EGFR mutations. All the other 3 are appropriate frontline therapies for this, so we have a choice. Let us talk about what those choices are.

[00:27:24]

FLAURA: First‑line Osimertinib vs Erlotinib or Gefitinib for EGFR‑Mutated Advanced NSCLC

This is the original FLAURA trial. We already knew, when you have metastatic EGFR‑mutated lung cancer, that EGFR TKIs were better than chemo. When osimertinib came along they did not trial it up against chemo. They knew it would be better. They trialed it up against the 2 other EGFR TKIs at the time that we were using, which was either erlotinib or gefitinib, depending on what part of the world you were in. These are patients, again, who were randomized, 550 patients randomized to either osimertinib in the front line or erlotinib or gefitinib, which at the time of this study, I was using erlotinib in the frontline setting.

[00:28:08]

FLAURA: Survival

You can see that osimertinib was better than the comparator EGFR. On the left is the progression‑free survival, and on the right is the overall survival. I will tell you in that overall survival on the right, it does seem like the curves separate and start to come back together at the end. What I will tell you is that those patients on the orange, on the comparator, they were able to cross over and get osimertinib in the second‑line setting when they progressed. Even though they crossed over, they still on average, lived longer than the patients who had the comparator. You can see the median progression‑free survival was increased by 7 months. This is where osimertinib got its frontline indication. I will tell you, if you guys remember, if you are as old as I am, those earlier EGFR inhibitors were also much more toxic. The rash was significantly less with osimertinib. That was something that was also nice.

[00:29:09]

FLAURA: PFS With or Without CNS Metastases at Study Entry

The other thing we saw is that it was better for patients with brain metastases. You can see both the progression‑free survival with and without brain metastases. The patients did very well if they had brain mets, they had a significant improvement in the progression in their brain. For Osimertinib, on average, it took 15 months for their brain mets to progress. That is without any radiation. As opposed to the other ones were not nearly as active. It took only 9 months for their brain mets to progress on average.

[00:29:40]

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

Then they said, they are just taking this pill once a day. This is great. What do you think if we add platinum‑based chemotherapy to the osimertinib? Not immunotherapy, because we know that does not work well, but we will add chemo plus the osimertinib in the frontline setting. Will this be better?

As you can see here, it was. The progression‑free survival was significantly improved by adding chemotherapy, almost by 10 months. If you see there the median progression‑free survival was over 2 years as opposed to 16 months with the osimertinib. Then with patients with brain mets, they did even better. Their hazard ratio was 0.47. So their median progression in the brain was 25 months, as opposed to the osimertinib 13 months. This was significant.

[00:30:30]

FLAURA2: OS

Then this is brand new. This just came in World Lung Conference 3 weeks ago. This is hot off the press information. This is the overall survival. This is really what we wanted to see, that adding chemotherapy to osimertinib is better than osimertinib alone. Sure enough it is. At 4 years, 49% of people still alive vs41% on the osimertinib‑alone arm. Hazard ratio of 0.77. The median overall survival 47.5 months, so almost 4 years is the median overall survival for osimertinib plus chemo vs osimertinib monotherapy. Osimertinib monotherapy was 37 months. That is just slightly over 3 years. So almost a year, basically 10 months, improvement in median overall survival. That is pretty long.

I think the question here is, do you want to add chemotoxicity to osimertinib? Is this for everyone? What they get is they get 4 cycles of pemetrexed and carboplatin and start the oral osimertinib. Then, after 4 cycles, they drop the carboplatin and they can stay on pemetrexed every 3 weeks. On average they stayed on it about 8 months in this study.

Chemo can catch up with you after a while. You have to come back every 3 weeks for it. This is a discussion that we have with patients. I think originally it was like, "Do I want to add chemo?" Now the numbers are convincing. A 10‑month improvement in overall survival is fairly convincing. This is definitely something that we offer to patients.

[00:32:06]

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

Then the third option for patients in the metastatic setting in frontline is amivantamab plus lazertinib. Amivantamab, remember, is that bispecific antibody. It is not a T‑cell engager, so it is not the CRS and all that stuff, but it is a bispecific antibody that targets EGFR and met. That is in combination with lazertinib, which is an oral TKI similar to osimertinib but a different drug. This was a trial looking at the amivantamab lazertinib vs osimertinib. There was a third lazertinib single arm at the bottom, but that was control. The main thing that they were looking at here was the amivantamab lazertinib vs the osimertinib. Again, looking for progression‑free and overall survival.

[00:32:51]

MARIPOSA: Intercranial PFS

For whatever reason, on this slide deck, we started off with intracranial PFS because patients with EGFR lung cancer have twice the amount of brain mets that normal run‑of‑the‑mill lung cancer has. There is a lot of brain mets here. We want to make sure these are working well in the brain. These drugs do work well in the brain. We can see here at 3 years, 36% of patients on amivantamab lazertinib did not have their brain mets progress, vs only 18% with osimertinib. The median progression‑free survival was only off by 3 months, but in favor of the amivantamab lazertinib arm.

[00:33:26]

MARIPOSA: OS

This is the overall survival. This is the big 1 that again we are looking at. This was somewhat similar to the FLAURA2 data. The median overall survival has not been reached yet, which is great; people are living. At 42 months, so this is 3 and a half years, 56% of patients are still alive as opposed to 44% on the osimertinib.

[00:33:48]

OS in FLAURA 2 and MARIPOSA

What I did was I put these 2 together. These are the 2 most aggressive regimens for frontline EGFR. The 1 on the left is chemo plus osimertinib. The 1 on the right is amivantamab plus lazertinib. The 1 on the right, MARIPOSA, there is no chemo, but there are challenges with amivantamab. We are going to talk about that. It is given weekly for the first 5 weeks and then you go every other week. There is logistical challenges there. There is some side effects we will talk about.

The FLAURA2 does not have the antibody side effects and is less frequent, it is once every 3 weeks, but it is chemo. So then you are exposing someone to platinum‑based chemo.

The numbers look fairly similar. The data cutoffs are slightly different: 48 months vs42 months here. The data looks fairly similar. What we do know is that definitely both of them have a 10 to 12 month improvement in overall survival vs single‑agent osimertinib. A lot of food for thought there on what we can do with these patients.

[00:34:52]

Posttest 1

This is the post‑test question for you to vote on. Which of the following most accurately describes the mechanism of action of amivantamab? Is it:

1. A monoclonal antibody that binds to mutated EGFR;
2. An antibody drug conjugate targeting EGFR for selective drug delivery;
3. A bispecific antibody that targets EGFR and met, or;
4. A kinase inhibitor that preferentially binds to EGFR mutations.

Education Host: The poll is open. Please vote. A few more seconds for incoming answers. Here are your results.

Beth Sandy: 45% of you got this right. It is a bispecific antibody that binds to EGFR and MET.

[00:36:00]

Second‑line Treatment for EGFR‑Mutated Metastatic NSCLC

What do we do in the second‑line treatment after patients have progressed on frontline EGFR therapy?

[00:36:07]

TROPION‑Lung01/‑Lung05 Pooled Analysis: Datopotamab Deruxtecan for EGFRmut mNSCLC

Right now, we only have 1 drug technically approved in this space, and that is datopotamab deruxtecan, or dato‑DXd. Now, dato‑DXd is an antibody drug conjugate that targets TROP2, so it is technically not even an EGFR inhibitor. This drug was trialed in all non‑small-cell lung cancer. They took patients with mutations, they took patients without mutations, and they trialed everybody against docetaxel. What they found was in the general population of lung cancer, it was not that much better than docetaxel. It did not get its indication there.

But when they pulled out the data from the EGFR patients in 2 different cohorts, they did find that there was a significant benefit. You can see that on this forest plot, the top 1 where it says absent of EGFR mutations, it comes really close to crossing that middle line favoring docetaxel. But in these 2 cohorts where there was an EGFR mutation present, they did a lot better.

[00:37:09]

TROPION‑Lung01/‑Lung05 Pooled Analysis: Efficacy

These are just single‑arm because this is just pooled data from these trials. You can see median progression‑free survivals here, 5.8 months, 6.8 months, and overall survivals being over a year. This is starting from the start of second‑line therapy, so this is not first‑line. This is once you have started the second‑line therapy after progression on frontline therapy. These numbers were pretty good, and these were reasonable enough for the FDA to say, "I think this is something that we can approve in the EGFR setting where it was significantly better than docetaxel."

[00:37:44]

Conclusions for Metastatic EGFR‑Mutated NSCLC

Our conclusions for metastatic EGFR‑mutated non‑small-cell lung cancer: 3 main options for frontline. Single agent osimertinib, and then the other 2, which we know are better than osimertinib alone, osimertinib plus chemo or amivantamab and lazertinib. It is important to decide which toxicity profile and logistics are right for your patients. We generally will talk about all of these things with our patients.

Then, in the second‑line setting, the datopotamab deruxtecan has just been approved in the past few months as a second‑line indication here.

[00:38:19]

Treatment for Metastatic EGFR‑Mutated NSCLC (Uncommon Mutations)

I have to talk about toxicity because there is certainly a lot of toxicity associated with these drugs, but I am going to touch on the uncommon mutations briefly.

[00:38:26]

Landscape of Atypical EGFR Mutations in Advanced NSCLC

These are less common. Again, I showed you this slide in the beginning.

[00:38:30]

Summary Data in EGFR S7681, L861Q, and/or G719X

These are some summary data, and you will have access to these slides. I am not going to go through it a whole lot. For these really rare mutations here, afatinib is the only drug that is actually FDA approved in this setting. It probably does have the best data overall. The downside of afatinib, if you have ever used it, it has a lot of diarrhea and definitely has a lot more rash than osimertinib. If you are purely going on data, it probably has the best data here.

Then, osimertinib has a couple of studies as well in this setting. Again, there are low numbers of patients because they are uncommon mutations, but they have data as well that is pretty good. It would be a less toxic option. Insurances are generally covering it because the data is there, even though it does not technically have an indication.

[00:39:18]

NSCLC With EGFR Exon 20 Insertion Mutations

Then, for patients with EGFR exon 20 insertion mutations, so this makes up about 10% of our EGFR mutations in general. This 1 does not respond to the traditional EGFR TKIs, the orals. It does not respond to them. It does respond, however, to amivantamab, the bispecific antibody we just talked about. Now, we do not give it with lazertinib in this setting, that is for the common mutations. In this setting, it is approved in combination with carboplatin and pemetrexed chemotherapy in the first line. It is approved as a single agent in the second line as well if you did not give it in the first line.

Then there is a new drug again just approved in the past few months called sunvozertinib. This is an oral and this is approved for patients who have progressed on front‑line platinum‑based chemotherapy. This is our first oral drug that is approved for the exon 20 insertion space.

[00:40:13]

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

This is the data. I do not want to spend too much time here because I really want to get to the toxicities.

[00:40:18]

Conclusions for Metastatic EGFR‑Mutated NSCLC vs Uncommon Mutations

Again, for EGFR exon insertion, you have the amivantamab plus chemotherapy, and now this new drug called sunvozertinib. Those are the 2 that are approved there.

[00:40:33]

Posttest 2

This posttest question. A patient with newly diagnosed metastatic non‑small-cell lung cancer, which of the following EGFR mutations detected with NGS would be a candidate for first‑line amivantamab plus carbo pemetrexed chemotherapy? Is it:

1. Exon 19 deletion;
2. Exon 20 insertion;
3. S768I; or
4. L858R.

Education Host: The poll is open. Please vote. Just a few more seconds for incoming answers. Here are your results.

Beth Sandy: 48% of you got this correct. It is the exon 20 insertion, that less common one, where amivantamab chemo is approved.

[00:41:32]

Managing Adverse Events With EGFR‑Targeted Therapies

Let us talk about the adverse events, because I said, we have all these choices of regimens upfront.

[00:41:35]

Case: Rash Prevention With Amivantamab + Lazertinib

This is a case study, a 46‑year‑old male, never smoker, presented with shortness of breath and cough, not improving with antibiotics. He gets a mass on his chest X‑ray. He gets a biopsy. He has brain mets, and it is found that he has an EGFR exon 19 deletion. That is 1 of the common EGFR mutations. He wants to be aggressive in treating his disease while preserving his quality of life and being able to go to work and be around his friends and family. He decides to be treated with amivantamab and lazertinib, a chemotherapy‑free regimen.

[00:42:12]

Pretest 4

Based on data from the COCOON study, which of the following could be included as an optimal approach for rash prevention with amivantamab and lazertinib?

1. A topical steroid;
2. Oral doxycycline;
3. Topical tacrolimus; or
4. Rash prevention was not recommended; only to treat it if the rash appears.

Education Host: This poll is open. Please vote. Just a few more seconds for incoming responses. Here are your results.

Beth Sandy: This is a little bit all over the board. The correct answer is actually the oral doxycycline. The same amount of people said that rash prevention is not recommended. Honestly, that used to be the right answer, but amivantamab lazertinib has a high rate of rash.

[00:43:23]

RASH With EGFR Inhibitors

I did this table here just to show you all the EGFR inhibitors on the market, and you can see any grade rash and then grade 3/4 rash. Grade 3/4 rash is pretty bad rash. You can see that the amivantamab lazertinib, 26% of patients can have grade 3/4 rash, so we really were looking at clinical trials to reduce that, because it was a problem for patients.

[00:43:42]

COCOO: Enhanced Dermatologic Prophylaxis With Amivantamab + Lazertinib

This is the COCOON trial that looked at giving enhanced dermatologic management, which was oral doxycycline or minocycline twice a day. Topical clindamycin lotion for the scalp, and this chlorhexidine solution for the nails, and then using a moisturizer as well. You can see at the bottom that grade 2 or greater dermatologic adverse events were reduced from 77% with doing nothing vs39% with the enhanced prophylaxis. This is something that we are definitely doing now, and I can tell you from experience, this basically reduced it by half. These patients definitely do much better with that oral doxycycline on board, with having rash.

[00:44:36]

Paronychia: Inflammation Around Nail Beds

I just wanted to show you a couple things. Paronychia is an inflammation around the nail beds. This is something that for MARIPOSA, the amivantamab lazertinib trial, they recommend chlorhexidine solution to bathe your nails, your toenails and fingernails in this a few times a day to prevent paronychia. This was some information from a paper I was part of many years ago. There is a lot of different things. These can be really annoying. That redness around the nail bed can be really annoying and difficult to treat.

[00:45:09]

Scalp Rash

Scalp rash also can be a problem. This is something that they recommend the topical clindamycin for the scalp for patients on amivantamab and lazertinib. Moisturizing shampoos that are selenium‑based are good. There is also fluocinolone solution. That is a nice thin solution if you have a lot of hair. Because it can be hard to get like a lotion or a gel into your scalp when you have a lot of hair, sometimes this dermatologist told us to use fluocinolone solution, which is a steroid solution. It is very wet, and then just put that on your scalp.

[00:45:45]

Diarrhea With EGFR TKIs

Diarrhea is common with the EGFR TKIs. You can see the rates here; the afatinib is very high, like I told you before. Osimertinib about half of patients, but only 2% severe grade 3/4. Sunvozertinib is that new 1 in exon 20 space, that has a lot of diarrhea with it as well, but mostly manageable. Again, we use over‑the‑counter loperamide and diet control. Not anything earth‑shattering here as far as diarrhea goes, but just something to note that can happen. I will say that actually, the amivantamab and lazertinib did not have significant diarrhea associated with it.

[00:46:24]

EGFR TKIs and ILD/Pneumonitis

Also, ILD/pneumonitis. This is an inflammation of the lungs. It is a drug toxicity. It is uncommon, but it is a class effect of all the orals, EGFR inhibitors, and it ranges between 1% and 4%. It can be fatal. It is uncommon, but it can be severe. For those patients who are acutely short of breath, you do want to get a CT of the chest to figure out what that is. We do not rechallenge patients if they get pneumonitis from the TKI; it is a permanent discontinuation.

The big word of caution here, and this was 1 of your pretest questions, was if you give osimertinib in short time frame after immunotherapy, basically within 6 months, there is significant increased rate of severe pneumonitis. We do not recommend that. This is why you should not give immunotherapy before you know the biomarker status. Because once you have given it, you cannot take it back. Then, if they have an EGFR mutation, you cannot give them the osimertinib for at least 6 months; you can, but you are risking severe pneumonitis. It is really important to make sure they do not have an EGFR mutation before you start that immunotherapy.

[00:47:33]

MARIPOSA: VTE Risk With Amivantamab + Lazertinib

Other important things to talk about with toxicity. A lot of this is the amivantamab and lazertinib. There is also a significant risk for venous thromboembolism. I put the grading here because it is really weird, what they say what the grading is; basically, a grade 2 we consider medical intervention indicated, which is generally a DVT. Grade 3 is generally a PE. Just think of it that way. Patients on amivantamab lazertinib, you can see 25% had DVTs, plus 10% had PEs. So 37% of patients had some form of VTE as opposed to only 9% on osimertinib.

[00:48:18]

MARIPOSA: VTE Risk

What they recommend, if you are going on the MARIPOSA regimen, which is the amivantamab lazertinib, is that you take an anticoagulant like a DOAC for the first 4 months of therapy to reduce this risk. When they trialed this, the patients who were on anticoagulation only had a 11% risk of DVT or PE, as opposed to 20% if they were not on prophylactic anticoagulation. We do that. We start our patients on blood thinners if they are not already on them. Some of them are already on them for other reasons, but if they are not, we will start that for at least the first 4 months of their therapy.

[00:48:57]

Amivantamab: Guidelines for Monitoring Infusion‑Related Reactions

Other things that happen with amivantamab is infusion reactions. Now, this only occurs usually on the first dose. The first dose of amivantamab is split between Day 1 and Day 2. They give half the dose Day 1 and half the dose Day 2 of the weekly dose in the beginning, because a lot of patients typically will have an infusion reaction because it is a bispecific monoclonal antibody. We do recommend that patients are premedicated.

[00:49:26]

SKIPPirr: IRR Prophylaxis With Amivantamab

They did a trial called SKIPPirr, which was looking at reducing the infusion‑related reactions because they were in the 60% or more range in that first 1.

[00:49:36]

SKIPPirr: IRR Rate With Dexamethasone Prophylaxis

The very first day what you do is you give dexamethasone before the first day. Two days before, they get 8 mg BID. I know it says dexamethasone 4 mg. I do not know why the schema looks like this, but it is 2 pills. It is 8 mg BID. The 2 days before, the day before, and then the morning of. In addition then, they get 10 mg of IV dexamethasone prior to the amivantamab. That is how that should look.

With that, you can see on the right‑hand side there was a significant reduction. 67% without the 2‑day lead‑in, but only 22% of patients had reactions with that 2‑day lead‑in of dexamethasone. I know it is a high amount. 8 milligrams BID is a lot, but it really reduces the infusion reaction rate so we do that as well. You only have to do it on the first treatment. After that, they do not react. They really only react on with that first treatment. Usually, the reaction is very manageable. Usually, we can just give them steroid or diphenhydramine. They typically do not have severe, life‑threatening reactions.

[00:50:52]

MARIPOSA: First Onset of Key AEs for 1L Amivantamab + Lazertinib

If you look at amivantamab lazertinib, all these, like rash, paronychia, the venous thromboembolism, they generally occur in the first 4 months. Then you can see 5-12 months, and greater than 12 months, those rates really go down to 10% or less. Most of this is in the first 4 months.

[00:51:10]

TROPION‑Lung01/‑Lung05 Pooled Analysis: Datopotamab Deruxtecan Safety

Let us move on and talk about datopotamab deruxtecan. Now, this is the antibody drug conjugate that just got approved in the past few months in the second‑line setting. This is an antibody drug conjugate. This is totally different. It is not targeting EGFR. It targets TROP2. Three things that I want to talk about are the oral mucositis; the ocular events, so the dry eye; and then ILD can occur as well. The stomatitis or mucositis occurred in about 60% of patients or more. You can see even 9% of it was grade 3 or higher. Then the ocular events occurred in 32% of patients, 3% of which were grade 3. They refer to the ocular events as mostly dry eye or blurred vision or inflamed red eye.

[00:52:04]

TROPION‑Lung01/‑Lung05 Pooled Analysis: Datopotamab Deruxtecan Stomatitis/Oral Mucositis

What do we do? For the stomatitis, which was, again inflamed mouth; not necessarily seeing mouth sores just painful sore inflamed red mouth. Our management recommendations on the right‑hand side there are to use daily prophylactic mouthwash, actually 4 times a day. The mouthwash is dexamethasone 0.1mg per ml, and it has to be compounded by a pharmacy, but they do that 4 times a day, swish and spit. Definitely do not use alcohol based mouthwashes. I just saw a patient with this the other day, and I was like, you can use salt water, but the dexamethasone mouthwash is really the best thing to prevent it. Really, it is the best to prevent this if we can.

The other thing is cryotherapy. Using ice chips or ice water in the mouth throughout the infusion to reduce the exposure of the drug to the oral mucosa. Someone was telling me they found something on Amazon that is a frozen mouthguard that people can hold in their mouth. Maybe then the ice chips will not stick to the inside of their mouth. I thought that was something that was good.

[00:53:25]

TROPION‑Lung01/‑Lung05 Pooled Analysis: Datopotamab Deruxtecan Ocular Toxicities

For the ocular toxicities with dato‑DXd, so again, this occurs around 32% of patients, we recommend that you not wear contact lenses while you are on this therapy at all. Use lubricating eye drops 4 times a day to prevent this. Again, prevention is better here. And baseline eye exam with an optometrist before you start, and then at least once a year or more as needed while you are on the treatment, so that they can make any recommendations based on your baseline eye exam.

[00:54:00]

Conclusion

In conclusion, I know a lot, it is 82 slides. We still have to get our post‑test questions in. But basically test for the biomarkers using either blood or tissue or both. I recommend both. There are several therapies available for first and second line for EGFR‑mutated lung cancer. They range in oral TKIs, bispecific antibodies, antibody drug conjugates. The toxicities really vary. We really have to keep up on our knowledge about how to manage and prevent these side effects.

[00:54:28]

Posttest 4

All right. Let us finish out by just answering our post‑test questions. Based on the data from the COCOON study, which of the following could be included in an optimal approach for rash prevention with amivantamab and lazertinib? Is it:

1. A topical steroid;
2. Oral doxycycline;
3. Topical tacrolimus or;
4. Rash prevention is not recommended, only treated if the rash appears.

Education Host: The poll is open. Please vote. We will give everybody a few more seconds to submit their responses. Here are your results.

Beth Sandy: 100% everyone. Oral doxycycline. Correct. Great job.

[00:55:33]

Posttest 3

Then, which of the following adverse events associated with osimertinib can be significantly increased in severity in patients who had immunotherapy before they took the TKI? Is it:

1. Atrial fib;
2. Pneumonitis;
3. Rash; or
4. Stomatitis.

Education Host: This poll is open. Please vote. Just a few more seconds for incoming responses. Here are your results.

Beth Sandy: Correct. 77% of you got this right. Pneumonitis is the risk. You are at high risk for pneumonitis if you take osimertinib after getting an immune checkpoint inhibitor.

[00:56:36]