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Personalized Treatment in EGFR-Mutated NSCLC: Applying the Latest Clinical Evidence to Address Barriers and Improve Quality of Care

We are going to start out and talk a little bit about some of the genomics.

[00:07:53]

Patient Case 1

When we do this, there is a couple of things. Because we are a broad audience, I hope for those of you that work in the lung cancer space, it is not too insulting. When we look at this, it is easiest to start with a patient and how this happens.

We have got a 45-year-old woman. She presents with a cough, shortness of breath, has some workup, and ultimately, she has got metastatic lung cancer. It is adenocarcinoma. Good news is she does not have brain mets. What is next? We have got the diagnosis. They have got lung cancer.

[00:08:27]

Next-Generation Sequencing

Well, what is next is we really need to do what is called next-generation sequencing, where we can look at a panel of genetic alterations, including our targetable mutations, to figure out what is the best treatment.

There is a couple key things here. We really need to do this upfront. That is what is recommended in the guidelines. It is important because if there is a driver mutation that we can target better outcomes, but it also would mean, and this goes back to our other question, that immunotherapy would not work if this is not EGFR-mutated tumor.

I will tell you this again in a minute. But more toxicity and less efficacy with immunotherapy if they have an EGFR mutation. That is something that we would want to wait. When I say wait, how long does this test take?

This test actually takes up to two to three weeks. The gold standard is to do it with a biopsy sample of tissue. We can do what is called a liquid biopsy. If you read some of these places that do this genetic testing, they say, “In blood, we can find all this stuff. But in the clinical trials it looks like you end up with false negative data from a liquid biopsy somewhere in about the 15% to 20% range.”

The gold standard, you need tissue to make the diagnosis, and even a small biopsy that can be done with bronchoscopy, that is still enough to do the full thing. We do not do PCR sequentially and run out of tissue. We actually do next-gen sequencing upfront. That is also in the guidelines to do that upfront.

[00:10:08]

EGFR Oncogenic Driver Mutations

When we start thinking about mutations and where they are, most of the driver mutations that we can target are in adenocarcinoma. Adenocarcinomas are most common in nonsmokers. That is what nonsmokers mostly get. Also, when we look at what are the mutations, EGFR is the most common targetable mutation that we see. Given this audience, in the Asian population, it is present in up to 40% or 50% of lung cancer in Asians.

In Caucasians and in most of the studies in Europe and in America, we think that rate is closer to, in the adenocarcinoma, maybe 23% or 24%. Two very common mutations. Exon 19 deletion, and then the other one is an exon 21 L858R mutation. Those make up about 85%.

Then we have got some less common mutations that would include our exon 20 insertion that is resistant to our traditional EGFR TKIs until sunvozertinib came out. That is what we are going to talk about is how we differentiate our treatments there.

[00:11:19]

Sample NGS Report

The good news is the companies that do next-gen sequencing give you a very nice report. It will look like this. It will tell you what the mutation is, like this EGFR L858R mutation tells you the drugs that actually have clinical benefit. It does not tell you how. We are going to talk a little bit about the efficacy how we decide on the how and which one we think might be most effective, and how to choose that or differentiate that between our patients.

This is something to look for, is there a next-gen sequencing report? That will probably help you test everybody. Given the efficacy differences between chemotherapy and our targeted precision medicine therapies, it is almost criminal not to do the testing, in my opinion.

[00:12:11]

Importance of Waiting for Biomarker Testing Results

Again, why is it important we wait for this test to come back? Well, a couple of things. If you need to start treatment because they have got some cancer-related symptoms, just give chemo without the immunotherapy because the big thing is if you do immunotherapy, then you find out they have an EGFR mutation and start treatment later, increased rates of pneumonitis as well as hepatitis. Because our immunotherapy again turns on the immune system. That is certainly something we want to do.

Also we do not get very much efficacy, if any, with our immunotherapy if they have the mutation. So we really want to wait until it comes back.

[00:12:50]

Potential Treatments for EGFR-Mutated NSCLC

Key Categories of Treatment for EGFR-Mutated NSCLC

Let us talk about what the pharmacology looks like with the treatments, because we have really got three different treatments that we use for our EGFR-mutated patients. The first is our TKIs, our tyrosine kinase inhibitors. These are generally considered small molecules. They get into the cell and they bind the ATP binding site of the epidermal growth factor receptor. They block the phosphorylation events downstream.

In mutated EGFR, most of the time they are constitutively turned on. They do not need any signal. They are mutated, so they are just always turned on. You block that signal, we get great responses.

The one that we are going to talk about the most today is osimertinib, because that is one of our guideline-recommended or preferred treatments. It is a third-generation TKI for EGFR. The other one that we will talk about is lazertinib, another third generation. Then we are also going to talk about sunvozertinib, our new kid on the block, which is a TKI.

The second group that we have got is our amivantamab. Amivantamab is a bispecific antibody. If you remember when you were in school whenever, maybe they taught you an antibody looks like a Y. You have probably seen pictures of antibodies. They look like Y, and the hands stick to things.

Well, with improvements in technology, they can design antibodies now that they will bind to two different things. Amivantamab binds EGFR on the cancer cell, but it also binds c-MET on the same cell. It turns out c-MET is a mechanism of resistance to EGFR.

If it is upregulated or whatever, it can do an end around if you will. So you are blocking EGFR, but it does not matter because c-MET is driving the tumor. This actually hits both pathways. It is a bispecific. It is binding two different things.

Then last but not least, the newest kid on the block, datopotamab deruxtecan. This is an antibody that binds to TROP1 and it is a Trojan horse-like approach. The antibody binds the receptor. It is internalized, but it is probably not going to kill the cancer cell. Connected to that is this topoisomerase I chemotherapy drug. So it binds, it is internalized and it is designed such that it will release the chemotherapy once it gets in, like the Trojan horse releasing the army once it gets in. That is exactly how this drug works is datopotamab and it actually binds to TROP2. So it turns out that this is also effective in EGFR-mutated lung cancer as second-line. We will talk a little bit about that.

[00:15:36]

Posttest 1

Pick up your clickers for those of you in the room. We are going to have our follow-up post-test question on number one. What best describes the mechanism of action for amivantamab? Is it:

1. Monoclonal antibody that just binds EGFR;
2. Antibody-drug conjugates, our Trojan horse;
3. Bispecific that binds EGFR and MET; or
4. Tyrosine kinase inhibitor.

Beautiful. Somebody is paying attention. Thank you for that. It is a bispecific, amivantamab binds c-MET and it binds EGFR. Perfect. Outstanding.

[00:16:37]

Managing Early-Stage EGFR-Mutated NSCLC

Now we are going to move into treatment and how we make treatment decisions. There is really three populations at a stage level that we talk about now.

We are going to talk about early stage where it is curable with surgery. Then the question becomes, is it worth giving some adjuvant therapy after we do surgery to improve the cure rates or decrease the recurrence rates? Then we are going to talk about locally localized disease, where it is still confined to the chest, but you cannot cut it out because it is going to involve both lungs. What we call is N3 disease.

We have positive lymph nodes on both sides, and it is not really plausible to cut out both lungs. So you cannot really do resection. But we can do radiation. We do chemo radiotherapy as our standard there. We will talk about that group.

Then we are going to talk about our advanced metastatic group. Unfortunately, that still makes up about 52%, 54% of our patients.

[00:17:33]

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

Let us get back to our early stage. This is where we want to do surgery, cut it out. They did the study and they randomized patients to either osimertinib or placebo. Now all patients had an EGFR mutation. Again, most common exon 19 deletion or exon 21 mutation.

[00:17:54]

ADAURA: DFS in Overall Population

When we looked at this study, really, really impressive. What does it look like when you do this adjuvant osimertinib? Well, lo and behold disease-free survival here, you can see an astronomical difference. Has not been reached yet with osimertinib, but placebo is 34 months and a hazard ratio of 0.28. For those of you that do hazard ratios, 28% of placebo chance of actually having a recurrence or dying from the disease. This is very significant. Makes a huge difference and has really become the standard in this setting.

[00:18:31]

ADAURA: DFS Subgroup Analysis in Overall Population

When they look through the different subgroups and different populations to say, does everybody benefit or do some people not benefit as much? What you essentially see is everything on the left means osimertinib is better. Indeed, all comers there, did not matter the mutation type or the stage, Asian versus non-Asian, everybody benefits from adjuvant osimertinib.

If you can cut it out, stage Ib, it is bigger than four centimeters in diameter. That is where really if they have got the mutation, but you have got to test for it. Again, back to that principle of testing. Everybody should get tested if their tumor is bigger than four centimeters.

[00:19:12]

Stage III Locally Advanced EGFR-Mutated NSCLC

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

What about our locally advanced? Again, chemo radiotherapy is the standard. Do that for four cycles. Generally, patients that did not progress on this study actually were then randomized to more of a maintenance osimertinib or placebo.

This is a large phase III trial that was done.

[00:19:36]

LAURA: PFS by BICR (Primary Endpoint)

Lo and behold, guess what? If you have mutated EGFR again after you get done with chemotherapy and radiation, they give them concurrently. At the end of that, unless you have had progression, we would give osimertinib maintenance.

Interestingly, in this trial, they treated until they had a recurrence or progression. What you can see here is again a huge difference. Our hazard ratio here is 16%. Median time to progression 39 months versus 5.6 months. It makes a huge difference more than three years versus six months essentially. So a huge benefit to use osimertinib in that setting as well.

[00:20:17]

Conclusions for Curative-Intent EGFR-Mutated NSCLC

In conclusion, early stage, what I call CTMO, cut the mother out. If you have got lung cancer and you can cut it out, cut it out. If it is bigger than four centimeters, we want to give adjuvant osimertinib if it has EGFR mutation. We see a huge value there. That goes for three years. There is at least one participant here in the room that worked in specialty.

Just keep in mind you are going to see these patients for a long duration of time. They are going to be on therapy for a long time, three years.

In the neoadjuvant setting, we are still trying to see if it is better to try to shrink the tumor and then cut it out. Those studies are ongoing. There is probably some positive data there. Once we get to where we cannot cut it out because it is in both sides, chemo radiotherapy then adjuvant osimertinib for those that have EGFR mutation. Again, even with curable disease upfront, we need to make sure we are doing the genetic testing.

[00:21:17]

Treatment for Metastatic EGFR-Mutated NSCLC (Common Mutations)

Patient Case 1

Let us move to where most of the patients fall. We are going to go back to our original case. This is our 45-year-old female that came in. She was diagnosed. She has metastatic disease, lung adenocarcinoma. They did the NGS next-gen sequencing. Found out she has got an EGFR exon 19 deletion. What treatment would we recommend here?

[00:21:44]

Efficacy from Pivotal Trial

When you look, there is three different treatments listed in the NCCN guidelines. That would be:

• Single-agent osimertinib;
• Osimertinib with chemotherapy; or
• Amivantamab with lazertinib.

First-line treatment, we have got three different treatment options listed in the guidelines. I am just going to briefly go through what these trials look like and the benefit that is seen with each.

[00:22:08]

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

Our first-generation erlotinib and gefitinib were better than chemo. That is what osimertinib came along as a third generation. Is it actually better because it hits some of our resistant mutations that were not affected by erlotinib or gefitinib. T790M was the predominant resistant mutation that it hits. They did that and they looked at progression-free survival. Again, this is in the metastatic setting.

[00:22:34]

FLAURA: Survival

What you see, progression-free survival got 19 months until that treatment failed. They are just taking an oral medicine for 19 months until they see progression versus these first generations was 10. With chemotherapy, chemotherapy progression-free survival somewhere in the ballpark of six months. Maybe as little as three.

So huge improvements there. They allowed some crossover for ethical reasons, but still we saw a survival advantage. Osimertinib de facto, first-line preferred, but we did not cure everybody.

[00:23:14]

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

The next big question that you want to ask is, well, how do we get better? Why is it resistant? The study was done saying, what if we gave four cycles of chemotherapy up front with osimertinib and then just followed with osimertinib as it went forward? Usually, that would be done with maintenance pemetrexed as well.

In this study, they compared that to the standard of just osimertinib, gave it with our traditional chemo, combined it.

[00:23:38]

FLAURA2: Overall Survival

Lo and behold, when you look here, what you see is it is better to give the chemo upfront. This is actually overall survival data. What we are seeing now, almost four years, 49% by giving chemo and osimertinib up front. Now again, all these patients had an EGFR mutation first-line therapy. Now we are talking about overall survival getting out to four years. Just as a historical comparison, we had a study looking at four different chemo regimens that was published in New England back in 2002. Eight months overall survival.

Compared to plain chemo, when I tell you how important testing is, it is critical. Almost four years of survival with this combination in this population with the EGFR mutation. It is better to give it than osimertinib by itself about an 8% improvement when we get out to four years.

[00:24:36]

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

That is great. Any other third generations? We have talked a lot about osimertinib, but what about combining it with amivantamab or bispecific antibody and a tyrosine kinase inhibitor, lazertinib. Lazertinib is a third-generation TKI, just like osimertinib. It maybe has an advantage. It gets into the CNS better, and this population has a high chance of developing brain mets. We think it might be better. We do not have any head-to-head data. We have no idea if that is true.

In this trial, it was tested amivantamab and lazertinib versus osimertinib versus lazertinib. The initial study design was created such that it just compared the standard care osimertinib to the combination and we got that data. That is what is available now.

[00:25:21]

MARIPOSA: OS

In this study, known as the MARIPOSA trial, what you see is a significant difference here. Our hazard ratio hit the p value. What you do not see for overall survival is what the median number is. We know the lower confidence interval though is 42.9 months. So basically 43 months is the lower part of that 95% confidence interval, whereas it is three years for osimertinib by itself.

Now all of a sudden you are like, wow, we are basically out probably to four years, maybe a little more and we have not given any chemo yet. Because once you fail this, then you could give chemo as maybe the next treatment. Certainly an improvement.

[00:26:03]

Frontline EGFR Treatment: Key Considerations When Choosing Treatment in the Metastatic Setting

Again, that is where we have our three things. You could:

• Give osimertinib by itself still;
• Give it with chemo; or
• Give amivantamab-lazertinib.

To make those decisions, we tend to say, Let us think about what is in it for the patient. We want to know how effective the treatments are, how toxic are they? Will the insurance company pay for it? All these drugs are crazy expensive, just like all of our cancer therapies. How about the patient? Are they in good shape? Are they willing to have a little toxicity, potentially for more gain or higher risk of toxicity? What about the tumor? Is it in the CNS? Are bispecific antibodies do not cross the CNS well?

We need to think about that. Maybe lazertinib might be a little bit more beneficial get in there. We do not have good clinical data yet but we think that is probably true from some of the basic science stuff. Not one size fits all. You need to take the whole picture into account how the patient is doing, what do they want, where is tumor as well.

[00:27:08]

Posttest 2

This brings us back to pretest. Which of the following would not be appropriate for our untreated or our treatment-naive patient with non-small cell lung cancer with an EGFR exon 19 deletion?

The one that we do not want to do is the immunotherapy. Again, if we do not wait for the results to come back from our next-gen sequencing and we started immunotherapy, then we go, “Oh, we should change and use an EGFR-targeted treatment.” Higher rates of interstitial pneumonitis and hepatitis. So more toxic. If they have got that driver mutation, they get very little if any benefit from the immunotherapy. That is why we do not want to do that.

I like the other two better than osimertinib, but osimertinib would be the second choice there for sure.

[00:28:29]

Second-line Treatment for EGFR-Mutated Metastatic NSCLC

Let us just change gears a little bit and talk about second-line therapy. We have got our three options up front. What do we do after they fail?

[00:28:37]

Frontline Treatment Management Approach

The chemotherapy data with osimertinib and the amivantamab-lazertinib data is relatively new. We still have a lot of patients out there that are still on monotherapy osimertinib.

What do we do when they fail? Well, you can move them to a platinum doublet. You can give them an antibody drug conjugate. You may want to move them to amivantamab-lazertinib, especially if c-MET is driving the tumor. You might want to give them amivantamab and chemotherapy.

[00:29:05]

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

Let us just talk about some of these treatments and what they would look like. Again, we have got some good clinical data here, MARIPOSA-2 looking at after you fail osimertinib. Can it happen? We are going to see these patients for a while.

What about comparing amivantamab-lazertinib in this group with chemotherapy, amivantamab, chemotherapy minus lazertinib, or just chemotherapy by itself.

[00:29:29]

MARIPOSA-2: PFS (Primary Endpoint)

When we look at the survival curves here, what you see is chemotherapy is the clear loser. Do not have to be a statistician to go, “I do not want to be on that survival line.” Instead, I want to be on one of those two.

Lazertinib may or may not provide much benefit here. The numbers have not been compared statistically, but both groups are better than just chemotherapy. Adding amivantamab second-line after you failed osimertinib is of value.

[00:29:59]

TROPION-Lung01/05: Treatment After Osimertinib + Chemotherapy in Patients With EGFR-Mutated NSCLC

The next thing that we want to talk about is our Trojan horse. Our antibody that is now carrying a bunch of cytotoxins on the legs, if you will. Gets into the cell, then releases our cytotoxic chemotherapy, datopotamab deruxtecan.

This actually came out of two large studies, a phase II and phase III study. They just looked at the mutated EGFR patients to see how they would do.

[00:30:24]

TROPION-Lung01/-Lung05 Pooled Analysis: Efficacy

Second-line historically has been pemetrexed or docetaxel. I have put them down here just to give you progression-free survival for docetaxel and pemetrexed in a comparative study was 2.9 months. Not very long. Overall survival was 8.3 and 10.9 months.

What this graph is showing you here is the size of the tumor zeros where it is at baseline. Then each little line is a patient. You can see that the majority of patients, their tumors shrank. We had overall response rate of 43%. Again, pemetrexed docetaxel, single-digit response rates.

More than four times the response by giving datopotamab deruxtecan. Progression-free survival 5.8 months and overall survival 15.6. Compared down here to our historical, 8.3 and 7.9, a huge improvement to give it more as a directed antibody-guided cytotoxin, if you will. Antibody dependent carrier there.

[00:31:37]

Repeat Testing at Resistance

The other thing we want to note, and this gets back to our genomic testing, what do we do with recurrence? At the time of recurrence, we actually want to do next-gen sequencing again. The reason we want to do that, sometimes things change. They can actually change to a different tumor type. Maybe they have now got small cells. Something has changed. Maybe they have got a different mutation that we could target like BRAF or RET. We have drugs for that or even a KRAS G12C, or maybe they have got a different resistance mechanism, like an exon 20 insertion, something that our current therapy would not be responding to.

[00:32:16]

Treatment for Metastatic EGFR-Mutated NSCLC (Uncommon Mutations)

Landscape of Atypical EGFR Mutations in Advanced NSCLC

When we find that, we find an uncommon mutation that is probably conveying resistance, maybe it was their baseline, maybe not. We can see a number of these, again exon 19 deletion and exon 21 as a point mutation. These are the two most common. Then osimertinib picks up this T790M. Then we get about 85%, 90%.

Next most common is exon 20 insertion. Then we have got some other less common or atypical mutations. I am just going to talk about them in two different groups. We are going to talk about the atypical ones. Then exon 20 insertion a little bit different or separately, if you will.

[00:32:56]

Summary Data in EGFR S768I, L861Q, and/or G719X

This is what the data looks like. Afatinib actually went through the process to get FDA approval for these three uncommon mutations. You can see the response rates here are high, 56% to 100%. Very small numbers. That is what it looked like. They went through the process. They looked at the benefit in terms of overall survival as well. Got FDA approval for a number of these uncommon or atypical mutations. You want to look at that.

Osimertinib has been tested as well. We also see good responses with osimertinib as well. Again, those would be the two workhorse drugs. For those of you seeking financial prior authorization, afatinib might be easier here because they went through the process and are FDA approved as compared to osimertinib.

[00:33:46]

NSCLC With EGFR Exon 20 Insertion

Exon 20 is another one that is not as common, but represents maybe as much as 10% of this population with an EGFR mutation, maybe 15% depending. It can happen. We can find it up front or second-line. How do we do that?

Exon 20 insertion generally means there is a change in the conformation of the ATP binding site. That is what keeps our normal TKIs from getting there and working. We can still bind it on the outside of the cell. And lo and behold, we have amivantamab given with chemotherapy here, and it is FDA approved in the first-line.

In the second-line, same thing, but we can use it as monotherapy. Then this is where sunvozertinib is the new kid on the block, a newly designed tyrosine kinase inhibitor for this specific mutation. And it works. Phenomenal activity. We can talk a little bit more about that. But even second-line, this happened in patients that already progressed on chemo. About 14% or 15% of those patients had amivantamab before. So we can use it after amivantamab.

They had 6% complete remissions with an overall response rate in the 40 percentile range. Again, as you think about pemetrexed or docetaxel or traditional second-line chemo, single-digit response rates. So it is really promising. That is why the FDA went with the accelerated approval for that compound.

[00:35:13]

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

Let us start here with first-line amivantamab chemo versus chemo. Again, huge difference, 12 months. You are seeing almost half the patients have progression-free survival versus 13. So the tumor has not grown. Hazard ratio of about 0.4. So a significant improvement in this population if you see the exon 20 insertion.

[00:35:35]

Conclusions for Metastatic EGFR-Mutated NSCLC With Uncommon Mutations

Just to conclude. This would be one. If we found it upfront, we would give chemotherapy and amivantamab. If we use that second-line, we could still give sunvozertinib. If we did not catch or if we used osimertinib and maybe chemo, second-line we could give amivantamab. It is starting to get a little bit more complex depending on what they got as first-line treatment, but sunvozertinib really looks good here.

Again, after feeling amivantamab, if you gave that first-line, you can now give the oral TKI with the idea that we are probably still going to get some responses. Then afatinib is FDA approved, but osimertinib is also effective against some of these other known uncommon mutations that we see.

[00:36:22]

Posttest 3

Which of the following TKIs is appropriate or appropriate for a patient with an exon 20 insertion?

• Erlotinib;
• Afatinib;
• Osimertinib; or
• Sunvozertinib.

For those of you in the room, if you can pick up your clickers and choose an answer, we have got the countdown box.

At least two thirds of you are paying attention. Sunvozertinib is our new guy. The key is you have to know this is the exon 20 insertion. The good news is that is what is going to show up when you see that next-gen sequencing report. Remember, I showed you that next-gen sequencing report. It will tell you the drugs will be effective. Amivantamab and sunvozertinib will both show up there.

[00:37:26]

Managing Adverse Events With EGFR-Targeted Therapies

Let us talk a little bit about the toxicities and how to manage the toxicities.

[00:37:32]

Patient Case 1

Our 45-year-old lady came in, had the exon 19 deletion. Metastatic disease, was not in her brain. The MRI was negative for CNS mets. What point of care meds would we need to recommend to prevent toxicity?

When we think about this, there is a couple of things that come to mind.

[00:37:55]

Rash With EGFR Inhibitors

Epidermal growth factor receptor. Just like it sounds. It is in our skin. It is mostly dermatologic toxicity that we see and the first dermatologic toxicity we see is rash. It usually shows up first as like an acne like rash. Then the skin tends to dry out, get thinner, and we get some other issues from paronychia and other issues.

When we look at the rates of rash, any toxicity versus grade 3/4. For those of you that do not grade toxicity in the cancer world, it is mild, moderate, severe, life threatening. Grade 1, 2, 3, 4. So 3/4 is severe or life threatening. That is where we need to do something different. That is what we care about.

When you look at the bad actor, osimertinib 1% grade 3/4. That is pretty easy. Amivantamab combined with lazertinib, that is troubling. One in four patients, grade 3/4. This is again from the early study. Now we start trying to figure out this is effective treatment. How do we best manage it?

[00:38:58]

Paronychia: Inflammation Around Nail Beds

I will talk about that in a minute with the COCOON trial, pre-test question. Paronychia is the second one where you can see this infection in the nail bed. Again, it is hard to know is this a drug effect, is this infected, is this staph? This is something where we typically will give topical steroids, but we also will give some systemic antibiotics. Doxycycline tends to be a common choice in this regard.

You can also use a Dakin solution type thing to soak it. There is a number of other things. Chlorhexidine solutions, but really to try to fight the infection.

[00:39:31]

Scalp Rash

The other thing that is annoying, bothersome for patients is they tend to get this rash on their scalp. Again, what can we do here? There is a topical shampoos. We can try to treat it with some dandruff shampoos. Clindamycin. Antibiotics is another option that can be used here. Some steroids also can help with this rash as well. This can be very troublesome, especially if it is symptomatic and a little bit itchy.

[00:40:01]

COCOON: Enhanced Dermatologic Prophylaxis With Amivantamab + Lazertinib

What did we do? This COCOON trial is actually to try to prevent dermatologic toxicity. They did this study. Everybody got amivantamab-lazertinib, both groups. Here they did this COCOON study versus standard management.

COCOON was oral doxycycline or minocycline. Okay. Makes sense. It is an acne looking like rash. Then they gave topical clindamycin as a lotion for the scalp. Chlorhexidine to the nails to try to prevent any paronychia. Then nonmedical, CeraVe[?] as a skin hydration. That is always important in terms of trying to do this over time versus our standard of care.

What this resulted in is here in the bottom. But grade 2, mild, moderate, severe. Moderate or severe or even life-threatening. What you saw was 77% with the standard prophylaxis versus 39% with this prophylaxis. This is something you want to get on because there is benefit to this treatment. You want them to stay on it and not go off because of toxicity.

Certainly something that is worthwhile. This means you got to pay attention when they are on this and give them the tetracycline orally. Give them the topical clindamycin. Make sure that they are staying hydrated and some chlorhexidine for the paronychia.

[00:41:36]

Diarrhea With EGFR TKIs

The other thing that we find is with the TKIs particularly, less the antibodies against EGFR, but the TKIs we can see a lot of diarrhea. Afatinib is really the bad actor here. 96%, 15% grades 3 or 4. That is more than seven loose stools a day, or dehydration to the point you need fluids. That is really bad. When you get down here osimertinib, not as bad, but 2% in all grades were in the 58% to 70%.

Not as severe, but still very common. This is something that you want to tell the patients about. Counsel them about. Make sure they have got some loperamide at home. I work to develop this slide set with a friend of mine at North Carolina, and they use diphenoxylate. We use loperamide where I am at. They are both working things to slow GI motility. This is important.

If it gets bad, we can interrupt therapy, fix the diarrhea, and then restart it with a dose reduction.

[00:42:43]

MARIPOSA: VTE Risk

The other thing that we learned with amivantamab in the MARIPOSA study. High rates of VTE. That is what you can see here. No prophylaxis was about 20%. That is like a hospitalized patient. That is why we give heparin to cut that down, versus with prophylactic anticoagulation, we can cut that rate in half roughly.

In the MARIPOSA trial, 37%, 9% with just EOC. Both patient populations were at risk, but the amivantamab-lazertinib was certainly going to make it much higher. Almost all of these happened in the first four months. What is recommended now, and I will get there. But we get prophylactic anticoagulation for the first four months.

It is not clear which one is best or what we do. We use apixaban where I am at.

[00:43:34]

SKIPPirr: IRR Rate With Dexamethasone Prophylaxis

I am going to skip this one, and I will tell you why. This is to prevent fusion-related reactions. Amivantamab was given IV and it was a step-up dose. Lots of premeds, lots of infusion-related reactions. I am going to show you some data from the PALOMA-3 trial. It is actually got approved to be given subcutaneous.

As a subcutaneous injection, the infusion reactions dropped. They are nothing, but they are very minimal compared to what you are seeing over here in terms of infusion-related reactions.

[00:44:07]

MARIPOSA: Supportive Care Summary

If you give it IV, premed for three days with steroids. This is cumulatively where we are at now with the MARIPOSA. So we can skip this if we give it subcu. We need VTE prophylaxis for four months. We are going to give a tetracycline doxycycline. Topical clindamycin can usually get started later. That is again for the scalp. That generally happens after about 12 weeks on therapy. Nightly cleaning with some chlorhexidine. We are talking about the COCOON trial and then a ceramide-based moisturizer as well just to keep the skin well hydrated.

[00:44:46]

Posttest 4

Based on our COCOON trial, which of the following would be included for our rash or the rash dermatologic prevention with amivantamab-lazertinib?

1. Topical steroid;
2. Oral doxycycline;
3. Topical tacrolimus; or
4. We do not need any prevention for the rash.

The answer is the most common, although not quite a home run. Certainly, we want to give an oral doxycycline. Let me just go back, if I can.

[00:45:44]

MARIPOSA: Supportive Care Summary

There we go. These are all the premeds we want to give with this regimen. Even though it is not chemo, still plenty toxic. VTE prophylaxis. For the rash, this is where we want to give, doxycycline or minocycline. Then topical clindamycin later. Want to make sure for the paronychia some wash, take care of the fingernails and toenails and then make sure the skin stays moisturized.

[00:46:12]

Posttest 4: Rationale

I think we got that.

[00:46:17]

PALOMA-3: SQ vs IV Amivantamab With Lazertinib for Previously Treated Advanced EGFR-Mutated NSCLC

This is the PALOMA-3 trial. This is what I was telling you with the subcutaneous administration, where really that helped a lot. Originally, this was just going to be a pure pharmacokinetic study. This was actually done about two years ago, but just recently approved by the FDA. I have heard rumors, they had some challenges with the chemical or the chemistry of producing this consistently, but regardless, it is finally here.

What they did is they just took subcutaneous amivantamab versus the IV, combined with lazertinib. Large study over 400 patients total. What you can see in terms of efficacy, overall response rate, the IV was slightly higher. Progression-free survival was longer, though, with the subcutaneous. 12-month overall survival was also better. This was actually statistically significant.

It should actually be more effective this way. Infusion-related reactions, 13% versus 66%. So huge difference there where we no longer that SKIPPirr study that I showed you of giving dexamethasone two days before, day before and then the day of treatment. We can probably omit that because it was not done with this study, but we are still going to see it. We still need to monitor these folks. But the infusion time goes from like four to six hours down to about five minutes, 10 minutes.

A huge advantage for those of you that are involved with chair time as well. Looks like it is more effective and it is probably less toxic. This was a huge advantage for this molecule that is very active.

[00:47:50]

TROPION-Lung01/-Lung05 Pooled Analysis: Safety With Datopotamab Deruxtecan

A couple of other things though. I just want to change gears back to our antibody-directed cytotoxin or our ADC. Datopotamab deruxtecan, cytotoxin and the antibody. Here we go.

What we see? A lot of toxicity. The linker, the way they hook the cytotoxic to the antibody, it looks like with this class of molecules, they are actually more effective if we have a cleavable connection there. What that means is it is going to probably hit some of the surrounding cells that maybe it did not bind to in a solid tumor, but it also then would be released and we see a little bit more systemic toxicity.

Indeed, that is true for this drug as well. A couple of unique things though. When we start looking at the amounts of toxicity, the thing that jumps out here is that dark bar represents grade 3 or grade 4. This is stomatitis. So sores in their mouth.

When we look at that, that is really one of the problems. When we look over here, a lot of people are having toxicity grade 3/4 about one in four patients. We are seeing dose reductions or dose delays for the toxicity until it can recover and the patient gets better, we can restart it. The good news is, with this class of drugs, for those of you that work in the breast cancer space, we have trastuzumab deruxtecan. We see interstitial lung disease as a major problem with that molecule. We can also see it here.

Thankfully, no grade 4, grade 5 on our toxicity scale means death. No grades 4, no life-threatening or death related to interstitial lung disease. That is a good thing. But we still need to monitor for it.

The other thing that is weird that popped up, some ocular toxicity. Dry eyes is most common, but we can even see keratitis and blurred vision.

[00:49:42]

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

When we start thinking about what we do here, how do we prevent these toxicities with this drug? Well, the first thing for the stomatitis there you can make a compound even, a steroid containing mouthwash. Swish and spit four times a day.

We also do this with everolimus. For those of you that have used everolimus with neuroendocrine tumors or even in the breast cancer space. This really seems to help a lot. Good oral hygiene. I am a little up in the air with this cryotherapy. You will see this used sometimes. It causes vasoconstriction. You get less drug in that tissue. The half-life of this drug is so long. It has marginal benefits.

We have seen that with some of our other drugs that we try to decrease hand foot syndrome and other things like that. Cryotherapy helps a little bit, but because the half-life of the drugs, I am a little skeptical.

[00:50:45]

TROPION-Lung01/-Lung05 Pooled Analysis: Ocular Toxicities With Datopotamab Deruxtecan

The other ocular toxicity, again with the dry eyes, some lubricating drops, some artificial tears. If you are going to give this four times a day, probably something preservative-free, maybe some refresh eye drops would be common. Some other lubricating drops would be there. But baseline optometrist or ophthalmologist review.

Then if they do not have problems, do not have to do anything, maybe at least an annual checkup though. If they have got contacts, they are having problems, ask them to wear their glasses and take their contacts out until the toxicity resolves. And it should get better over time.

[00:51:23]

Managing/Monitoring Logistical Challenges of Oral Anticancer Therapies

Last but not least, I am trying to stay a bit on time. Hopefully, I did not go too much at laser speed, but just want to touch base on some of the logistical challenges. As you just saw, better drugs, better outcomes. We have got to test to make sure we get there.

The toxicity is significant. Some of those toxicity prevention schemes are pretty significant. Some of them are oral, some are IV. So our specialty pharmacists are going to be involved with all of the osimertinib and lazertinib. The majority of these patients are probably set up to get that.

[00:51:57]

Who Gets Paid to Solve Financial Issues That Can Prevent Patients From Getting Access to Medications?

The question is, who is going to coordinate all of this expensive oral care? Well, I would make an argument, if you do not know your specialty pharmacist, you need to. Specialty pharmacy is really in the middle. At least in my experience, they do our prior authorizations. So they help get the financing to get it paid for. As part of the accreditation, they actually interact also to collect toxicity data from the patient and report that and share that back.

The oncologist, oncology pharmacist, all talk and have a relationship here as well as the patient. Patients get there. They actually solve payment issues. One of the key things for this disease is make sure that your friend is with your specialty pharmacist.

[00:52:46]

URAC Accreditation: Patient Management Requirements

Part of their accreditation documents basically show that they are going to make sure the patient understands, they are counseling them. Those of you that do not know about specialty pharmacy, I am not sure if these numbers where they came from, but I have been told this multiple times and I know Emily well, our specialty pharmacy league in oncology.

She says, “A good specialty pharmacist might counsel or fill 12 scripts a day, but they spend most of their time talking to patients about toxicity, and monitoring that over time. That is part of the accreditation guidelines when you look at it.”

Our specialty pharmacy has access to our Epic server. For those of you that work in a hospital or in a clinic, the EHR needs to be available somehow for the accreditation for a specialty pharmacy. How that is, in our setting, our specialty pharmacy actually logs right on to our Epic, and they can see everything in the health record. That is a good thing.

[00:53:43]

Key Counseling Questions

As we get back to a patient focus, it always comes up, who is talking to the patient? The answer is everybody. Everybody plays a role here. Clinical pharmacists. At Markey Cancer Center, our pharmacists actually counsel all patients before they get chemo, but they are overwhelmed with patients. So follow-up patients frequently they do not talk to everybody. They are just overwhelmed. Do not have a chance.

Well, certainly the nurses do in clinic. They talk to them every time. They are looking for the infusion-related reactions and all of that as well. The specialty pharmacists I just showed you, they have got a huge role here. In the middle, especially for all the oral therapies that we use in this space, managed care pharmacists can be involved. Then ultimately what we are finding is payers and even some of the manufacturers, if they find out patients and who is on it and they are providing some support, they also will follow up and want to know, are you having any trouble here?

There is a number of people here recognize, but good communication throughout the whole system is key to keep these patients on these effective medicines.

[00:54:51]

Conclusions

I am just going to wrap this up and try to go back to our first four objectives, if you will. One, cancer. If it is bigger than four centimeters, next-gen sequencing is essential. I showed you the data. If it is resectable in the adjuvant setting for osimertinib after chemo radiotherapy for locally advanced, where they are getting chemoradiotherapy then maintenance. Then in the metastatic setting, we still need to know and we have got some of those, we need to think about the patient and everything else. But testing is critical.

The TKIs, the bispecific antibodies and the antibody-directed cytotoxic agents, they all play a role there. Sunvozertinib and datopotamab deruxtecan are actually more second-line at this point. But there is clinical trials going on. They are combining it with datopotamab deruxtecan and osimertinib. Are they better frontline?

There is more ongoing studies. More will come out. Certainly things to watch for as we move forward. Toxicities. Even though they are targeted medicines, they have this promise of being less toxic. The way we are starting to use them, there is still significant toxicity, and we need to provide some prophylaxis depending on which regimen is being used. Most of these are going to get some prophylaxis to try to prevent toxicity. Certainly, we need to counsel on it and manage it.

So oral anticancer agents, and I would say all of our cancer agents, it is a team sport. Everybody is talking to the patient and good communication with the patient and other team members is really critical to have successful outcomes.

[00:56:29]

Poll 2

That is all I have got. I am going to ask you guys to pick up your clickers in the room here and answer this poll question. Do you plan to make any changes in your clinical practice based on what you have learned today in this program?

The only answer is 100%.

[00:56:58]

Poll 3

If you have got your phone or something handy, you will want to scan this QR code. What would be that key change that you would make? How has this changed your impression? What would you do? Would you share this information with a patient, with a colleague? Will it be yourself that are ordering some of these things and helping monitor them better? I am just going to leave that up for a second so you can do that and let us know what change or how this may influence you moving forward.

Speaker: For those online, just to note that there is an open chat box. You can just put your answer in that and click Submit. Thank you.

Dr. Adams: We still have a number of phones going on here in the room. For those of you online, stay tuned. We have got another slide for some credit here in a second. The participants here still have their phones up and they are scanning the QR code.

Speaker: Thank you so much, Dr. Adams for that presentation. It was wonderful. Reminder to those online, if you do have questions, feel free to submit them in the Q&A. I do see a couple that have come in already, and I will share those here momentarily. If you do have any additional questions, please add them.

Thank you again for a great presentation, Dr. Adams. We appreciate your teaching and expertise this evening. If you could go one additional slide forward, I believe that will lead us into the QR codes. Perfect. Thank you so much.

[00:58:36]

Go Online for More ProCE/CCO Coverage of EGFR-Mutated NSCLC!

Before I offer the questions here online, are there any questions from the group there that you would like to pose to Dr. Adams?

Dr. Adams: Any questions for me? Anything I can answer?

Speaker: Are there any predisposing factors that make the Asian population higher risk for higher mutation?

Dr. Adams: For those of you online, the question was, is there any known risk factors that make Asians at a higher risk for having this type of mutation?

Quite frankly, we do not know. This is really an observation. It turns out that many of our clinical trials actually accrue Asians, whether they are in the US or overseas. A lot of these are international trials to help them accrue much better. It is a known fact. We do not know why. Most commonly these mutations are in adenocarcinoma and most commonly in non-smokers. That is probably why it is a single mutation that tends to drive the cancer to grow. That is why immunotherapy probably does not work.

Immunotherapy recognizes the cell is formed because there is a lot of mutations and neoantigens on the cell surface. With this driver mutation approach, that is probably why we do not see that. Why Asians is not clear, at least to me. I do not know that.

Any other questions in the room before we go online?

Speaker: At what point you have to retest the patients?

Dr. Adams: Great question. Let me just repeat that question for the audience online is, at what point would we retest the patient?

I would say the most common is, and this is just from the surgeons that I know and what we do. When we see a lesion, the first thing is radiology will generally do a CT scan to try to determine is this metastatic? Because you start with the idea that more than half are metastatic. Find where it is metastatic.

If you do not find it metastatic, then you start narrowing down to a PET scan to see if it is in both sides of the chest. If not, it is a surgical candidate. Then we would make those decisions. When you do that, a common thing to do is try to get tissue to confirm the diagnosis, where did it start? What does it look like? The least invasive way. Commonly endoscopy with ultrasound and EBUS is done. Then they can biopsy the different lymph nodes. That will provide a very small amount of tissue. That is enough tissue to make the initial diagnosis of lung cancer. Tell you the cell type. So is this adenocarcinoma or squamous cell or what it is.

Then it also is enough for next-gen sequencing. That is where we can get a whole panel of genetics instead of trying to do PCR. We treat based on that. That is our gold standard. Then moving forward, when it comes back, we want to test again.

When the tumor starts growing again, that threshold when it is gotten bigger by 20%, it is progressive disease. Once that happens, we would want to test again. With that thought, again, the least invasive way to get it. If they have got a nodule by the skin and you can stick a needle in there and get a biopsy, that is what I would do. If they do not have one that is easy to get to, then probably a liquid biopsy. That is where we tend to use the liquid biopsy where you can find circulating tumor DNA in blood and do that.

In the clinical trials, again, they miss a little bit more. So a little concern. Tissue is really still the hallmark. In recurrence, that tends to be where we get more of our liquid biopsies. Recurrence is the key part for that. Yes. What is that progression.

Any other questions in the audience here? Let me see what we have got online and I can share that.

Speaker: Online, the first question, has there been any preliminary data out using the subcu versus IV AMI?

Dr. Adams: Yes, we have the PALOMA-3 data. We do not have real-world data that I have seen. It may be out there, but the clinical trial data that compared IV to subcu is out. That was the study that I showed you where the subcu actually had a better 12-month survival. It is less toxic. It looks like it is slightly more effective, if not at least equally effective. I think that ultimately that is what I would use every time if I had a choice.

Speaker: Perfect. The next question, what are the biggest challenges in your practice related to the process of physically obtaining and stocking EGFR inhibitors for patients with NSCLC?

Dr. Adams: I am going to answer this with an empty answer. One of my main focuses in life is clinical trials. I would try to find a clinical trial for our patients. That would be my first answer.

Second answer, in the real-world for what would I recommend, and this is a little bit research oriented, among the three in the metastatic setting, I would probably want to see if c-MET is overexpressed. We have some data to suggest that if c-MET is overexpressed with an EGFR mutation, amivantamab is probably going to be better. That would be my go to with lazertinib and amivantamab.

Otherwise, I think it is a toss-up as to whether you are going to go for osimertinib and chemotherapy. If they can tolerate the more aggressive therapies, we know both of those combination therapies are better than osimertinib monotherapy. As patients get older and they do not want the toxicity they cannot tolerate, they have got comorbid conditions, osimertinib monotherapy is still a great option.

Sequencing them. It depends what you do first. That is why I started there, as to then what would you do second or what would you do third? I would try to probably keep chemotherapy for last if all things were equal, because we know it is limited. It is definitely beneficial, but it is limited in what it is going to do.

Speaker: Wonderful. Then I have one more question, which EGFR inhibitor-related AE in NSCLC is the most challenging to manage, and how often do you encounter it?

Dr. Adams: If you monitor carefully, essentially they can all be successfully managed. I am not too concerned about that. The one that concerns me the most is probably going to be the datopotamab deruxtecan molecule with interstitial lung disease. That really is unfair to some degree because it goes back to what we learned with trastuzumab deruxtecan. In that setting, they had a relatively high fatality rate in those breast cancer patients because the interstitial lung disease, because there you are going to stop treatment. That is an intermittent therapy. You are going to give them some steroids to try to manage it.

I think catching that early and making sure you monitor for any dyspnea or shortness of breath is really critical to capture that early to try to minimize that, because if you let that get to grade 3 or grade 4, the chance of it progressing and being fatal is a little bit high. That one probably concerns me the most.