Updates in Second-Line EGFR-Mutated Non–Small Cell Lung Cancer

Samantha Conlin:

Hello, and welcome back to JADPRO's roundtable discussion on Updates in Second-Line EGFR-Mutated Non–Smal Cell Lung Cancer. My name's Samantha Conlin and joining me today are my colleagues, Mary Ellen Flanagan and Hailey Hunter. We are thoracic nurse practitioners at Washington University School of Medicine in St. Louis. I'll let you guys introduce yourself.

Mary Ellen Flanagan:

Hi, I am Mary Ellen Flanagan.

Hailey Hunter:

I'm Hailey Hunter.

Samantha Conlin:

Thank you both so much for joining me today. In this final installment of our video roundtable, we'll be discussing another case study, this time with a patient with EGFR-mutated non–small cell lung cancer receiving datopotamab deruxtecan. In this case study, it's a 62-year-old female never smoker who was diagnosed in February of 2022 with stage IV adenocarcinoma with metastasis to the brain and to the pleura. Genomic testing was sent on the pleural fluid revealing an EGFR exon 19 deletion with TP53 mutations. She initiated single-agent osimertinib 80 mg daily in March of 2022. She had a PleurX catheter placed due to the recurrent effusions, and subsequently had that removed 2 months later as the output subsided.

Imaging on that treatment showed a good response. Following, she had progression noted in January of 2024, and we initiated cycle 1 day 1 of amivantamab, carboplatin, and pemetrexed. She did well on that for about a year, until January of 2025 when she presented to the hospital with progressive and worsening low back pain. CT of the chest, abdomen, pelvis showed diffuse widespread metastatic disease throughout the thoracic and the lumbar spine. The MRI agreed with that, with diffuse sclerotic osseous mets involving the thoracic and lumbar spine. Thankfully, there was no pathologic fracture or soft tissue extension noted into the spinal cord.

I attached a picture here, and you can see just the numerous areas throughout the thoracic and lumbar spine, these darkened areas. Many, many mets noted at the time of this progression. We did refer her to radiation oncology for palliative pain control because she was having a lot of pinpoint low back pain.

At that time, we initiated datopotamab deruxtecan, or dato-DXd, and that was in 5 of 2025. We started at 6 mg/kg. Unfortunately, she struggled with that dose. She had grade 2 nausea, she had weight loss up to 6 pounds, so we therefore held treatment and supported with IV fluids weekly. We did a dietary referral, and we also added olanzapine 5 mg nightly to help with the nausea.

She was then reduced to 4 mg/kg with cycle 2. She did seem to tolerate that a lot better, especially with the interventions that we had in place. We did weekly IV fluid support and weekly visits really through cycle 2 to be sure that she wasn't losing more weight and that she was tolerating that dose modification at 4 mg/kg. She did get radiation to her T7 to T9, which was given in combination with the drugs that helped her with that pain that she was having in her low back. Scans after two cycles of treatment showed us a response in the osteometastasis.

Pooled analysis of the TROPION-Lung05 and TROPION-Lung01 data is what led to the approval of dato-DXd. As Mary Ellen spoke about in the first discussion, dato-DXd is a TROP2-directed antibody-drug conjugate. It was approved in 2025 for EGFR-mutated non–small cell lung cancer after prior therapies. This, again, was based on these two trials, the TROPION-Lung05 and the TROPION-Lung01.

The Lung05 is shown here on the left side. I think it's important to note that 56.9% of these patients did have EGFR mutations. We saw a median progression-free survival of 5.4 months and a median overall survival of 13.6 months with an overall response rate of 49.1%. The Lung01, as shown on the right, compared dato-DXd versus docetaxel, and median progression-free survival was 5.5 months versus 3.6 months, with an overall survival of 14.6 months versus the 12.3 months in docetaxel for the nonsquamous histologies.

As far as side effects go, I enjoyed this visual because it shows not just dato-DXd but antibody-drug conjugates in general and the side effects that come along with that, so with nausea, vomiting, being close to number 1, ocular toxicity, pneumonitis, decreased appetite, constipation, fatigue.

Again, it's important to be able to manage these toxicities proactively. As far as stomatitis goes, or mouth sores, we normally do dexamethasone oral solutions, 0.1 mg for prophylaxis four times a day, so that's every day, four times a day. That's not optional. It's something we need to educate our patients on doing as soon as we start the drug. Additionally, ice chips during the infusion of dato-DXd is really helpful because, again, it coats the mouth and the tissue on the tongue and down the throat. That helps prevent those sores from arising. If stomatitis does occur, we increase the frequency of the mouthwash and administer other topical agents for relief.

I'm curious, Hailey, in your practice, is there anything that you guys do different to manage stomatitis?

Hailey Hunter:

Essentially all the same things. It's very important just to have a lot of education with the patients, hopefully before the toxicity even occurs.

Teaching them to avoid acidic foods or things that would normally irritate the mouth just in general. I do a lot of preventative baking soda and saltwater rinses, so I have them put a teaspoon of baking soda in a 16-ounce bottle of water, shake it up and essentially carry that around with them all day and just spit and swish, swish and spit whenever they think about it. That helps keep the acidity in the gum line hopefully so that the patient can avoid the stomatitis.

Mary Ellen Flanagan:

Yeah, one thing I want to add is unfortunately there is a nationwide shortage of the dex mouth rinse right now, and so in my practice we've been having problems locating it and having to utilize a compounding pharmacy. When we do find it and get it, I feel like I'm stressing the importance of what Hailey talked about even more so hopefully they're not requiring and we can really save the dex mouth rinse.

My head and neck colleague, one of our colleagues here, she encourages her patients to buy a cheap spritz bottle. She'll have her patients spritz the dexamethasone mouth rinse in their mouths, and it is able to provide the medication exactly where they want it. It also makes the oral solution go a little bit further because we're concerned about wasting it because of this shortage we're experiencing.

Hailey Hunter:

It's a very thick liquid too, so I think the spray helps it be a little less thicker, thin it down so it gets in more area.

Samantha Conlin:

Yeah, that's a great recommendation, Mary Ellen. I actually haven't heard of that, but it makes more sense, especially when people are on the go. They have it. They don't have to bring the bottle with them.

Mary Ellen Flanagan:

And swig it, yeah.

Samantha Conlin:

It's just a quick easy spritz. I think that's a great recommendation that I'll certainly take forward to my patients. Again, it's a convenience factor, just having it there with them.

Ocular toxicity is also something very common in dato-DXd, so seeing an ophthalmologist prior to initiating treatment is something we always encourage patients to have with, again, a low threshold during treatment, if we do have these visual changes or eye side effects that we are able to lean on them to help us.

Additionally, using the preservative-free lubricating eye drops four times a day as needed to help keep the eyes moisturized and then not to wear contact lens. I feel like that's a really big teaching point that, although I'm the outlier today wearing my contacts, but we all need visual support of some sort. I think emphasizing the no contact lenses is important.

Hailey Hunter:

I think it's interesting to note too, we just put our first patient on the first-line trial of dato-DXd plus osimertinib, and it was very interesting. The sponsor actually sent eye drops to the patient, so that's going to be... moving forward, I think they're recognizing the preventative care is very, very helpful here.

Mary Ellen Flanagan:

Absolutely.

I wanted to ask you ladies, do you have an ophthalmologist of choice or how are you guiding our patients? Because I feel like in our practice we don't have a system in place. We panic and call around to every ophthalmology satellite place to see who can get them in first.

We're so fortunate to have a derm that specializes in oncology. I almost feel like with the rise of these products, we need a ophthalmology team in our back pocket.

Hailey Hunter:

Definitely some food for thought as we start using these drugs more and more. Probably every center would benefit from having these resources in play because there is a lot of toxicity associated with these medicines. It's very helpful to have other providers weigh in as well. Also, make sure there's nothing else going on in the eye with ocular toxicity that may not be from drug but could be confused as a side effect from these drugs.

Samantha Conlin:

Mary Ellen, I appreciate your honesty because I too feel that we do the, okay who can see our patient? I also, when I find somebody that I refer to often, I'll curbside them every time that I have a patient that's having these side effects and oftentimes building that relationship and collaboration with these physicians is helpful because then they can promptly see our patients and get them in. But I agree, I definitely think a specialized oncology-driven with these drugs would be really nice.

Next we'll talk about the proactive management and toxicities associated with dato-DXd in terms of nausea. That was pretty high up on the list of things, and I'd say when it comes to antibody-drug conjugates, as Hailey spoke about in the prior slides, they're designed to deliver the cytotoxic drug, or the payload, to the cancer cells. When this happens, we do still see some damage to the healthy cells as those cells are rapidly dividing. That includes the lining of the digestive tract. What happens there is the serotonin is released from the damaged cell and it goes into the gut, which activates the nerves, which send the signal to the brain, triggering that acute emetic response.

With that being said, how do we manage these toxicities? Making sure patients have their antiemetics at home, the prochlorperazine, the ondansetron, that they're taking them around the clock as needed. I often educate patients on stacking the medications, taking the one first. Four hours later take the other one if we don't see a response, and really trying to utilize those medications to the extent. We also refer patients for dietary consultation to follow along with us. Our dietician is great. She calls our patients at home, talks about different foods and things that would help in the instance of nausea and how to keep that weight up. And then also, as I mentioned, the IV fluid support, which I think is helpful as well to make sure patients are staying hydrated.

I'm curious, Mary Ellen, how does your team manage nausea? Do you guys do anything different?

Mary Ellen Flanagan:

I think we all practice similarly, but one thing that my team does that you touched on is it's really a shared decision-making process. We loop in our dietician and we really lean on our pharmacy staff to look at the current regimen and see how we can make some small changes to it.

One medication that we've been utilizing more and more is olanzapine with these patients. Datopotamab was recently, I believe the hematogenic risk was escalated to moderate because we have been seeing so much. And so in our practice, we've been having our patients take a low dose of olanzapine scheduled at night versus just around treatment. When we first started using olanzapine, we would only use it for about 5 days around treatment, but now we use it nightly. I've had a lot of success with that.

Samantha Conlin:

Mary Ellen, do you give the 2.5- or 5-mg dosing to start?

Mary Ellen Flanagan:

I typically start at 5.

Samantha Conlin:

Hailey, do you guys do anything different in your practice?

Hailey Hunter:

We essentially practice the very same way: alternate your antiemetics, keep it on a very scheduled basis. If that doesn't help with the nausea or they're still having some quality life issues, again, yes, we add the olanzapine. We start at 5 mg. I usually caution once they start the olanzapine, if the nausea improves, let's go ahead and back off some of the shorter acting antiemetics because double dipping and all these can be pretty toxic. Ondansetron can cause constipation, which can cause further nausea. If we can get off some of the acute, the shorter-acting antiemetic medications if the olanzapine is effective, we would typically change over to that regimen.

Ensuring they're meeting their caloric intake needs. It takes quite a bit of calories to be able to gain some weight. If not, just keep their weight stable. I'll often use my mom voice: “Let's not lose too much weight here because if that happens, we are going to have to dose reduce and limit this medication.” Just making sure they're very well versed in high calorie foods or making sure they're getting enough calories every day. Oftentimes, we'll bring them in. We'll do IV fluids weekly if they can tolerate it, and just really helping meet their nutrition goals and feeling better. Because it's really the end goal is good quality of life outside of treatment, so we want to make sure that's occurring for every patient.

Samantha Conlin:

That's a good point, Hailey. I feel nausea is one of those things that can severely impact patients’ quality of life. When you feel terrible and you're sick to your stomach all the time, it makes the living factor a little harder.

I did appreciate the comment too about backing off of the antiemetics. Some patients, as we tell them to do things, they do things religiously until we tell them to stop. And so I think it is important, especially considering the QTC prolongation with some of these medications, to be sure that we're asking patients, again, to back off the short-acting once we get the olanzapine going. That was a great point.

Next on the toxicities I wanted to touch base on was pneumonitis, which we're all too familiar with, I think. Pneumonitis often accompanies dyspnea, a dry cough, sometimes a drop in oxygen saturation, fevers. How do we manage those toxicities? We look at CT scans day in and day out in our thoracic clinics, and so I find that pneumonitis is often caught a little bit earlier because we are looking at these scans. We are looking at their disease. We're looking at other things, and sometimes we can catch these hints of pneumonitis before they become a real problem. Grade 1 toxicities, we would initiate corticosteroid treatment at 0.5 mg per kilogram, and then grade 2 we would escalate to 1 mg/kg with the gradual taper over at least 4 to 6 weeks. And just to note, the patients who have had prior radiation therapy, they're obviously at higher risk for developing these pneumonitis. Again, the education, the being proactive on catching these I think is really what's important. Here I just have a picture of-

Mary Ellen Flanagan:

It can be really, really difficult in our patients with lung cancer and other comorbid conditions like heart failure, COPD. They've had thoracic radiation. Trying to tease out is this disease progression, or do you have a pneumonia, or is this a heart failure exacerbation? Should we treat you for a COPD exacerbation? When do we escalate and get a CT?

It's an incredibly difficult situation to be in as an advanced practice provider, I think, with working with these drugs with this added risk.

Samantha Conlin:

Absolutely. Mary Ellen, do you see a lot of pneumonitis in your practice?

Mary Ellen Flanagan:

We do. I'm glad you touched on the fact that I feel fortunate that we get imaging of the chest often. As I was discussing this with a colleague in the melanoma department, and this colleague was overwhelmed with how to catch pneumonitis. I thought, I think we catch a lot of grade 1 and can be more proactive and hold treatment before it escalates to grade 2 and they have symptoms. And so I do think that we've had the opportunity to become experts in looking at these images and finding pneumonitis earlier and hopefully treating it before it becomes a big problem.

Samantha Conlin:

Absolutely. This image I have attached here is just an inflammation that we see in the lungs, or pneumonitis, bilateral infiltrates. We can see this to varying degrees. These little wispy areas that we have to keep an eye on, is that pneumonitis? Is that a pneumonia developing? Again, it can be very hard and very difficult to tease out, as Mary Ellen said, what is causing what.

Hailey Hunter:

Well, a lot of times you have a superimposed pneumonia over the pneumonitis, and you're managing high-dose steroids and antibiotics. It can be a very convoluted picture. Oftentimes for me, I will give high-dose steroids and antibiotics and the patient will improve. A couple of weeks later as they're tapering, they'll get worse again. And then you're like, "Oh shoot, do we go up on the dose of the steroid? Do we give more antibiotics?" And so it can be pretty complex. I think it's going to be even more so as we're adding agents together that both have a pneumonitis toxicity associated with them.

Samantha Conlin:

Yeah, absolutely. I always try to educate patients as they do taper off of these steroids, and I try to, as maybe we all do, go slow over the 4 to 6 weeks. But try to emphasize as they drop from one dose to another that they could see that flare of the shortness of breath, of the dry cough, and to be calling us.

Often we see these patients while they're on the steroid tapers pretty frequently so that we can assess them ourselves as well, but educating them. If you do see as you drop from 20 to 30, do you notice a big difference? Are you coughing more? Are you more short of breath? You need to call us. We go back up by five and then, again, try to titrate back down. Because I do feel the lungs are a little non-forgiving and they respond as we drop the dose. Sometimes that can rebound, and so it can sometimes be challenging.

Hailey Hunter:

Completely agree.

Samantha Conlin:

So what does the future look like for EGFR-mutated lung cancer patients? There are several studies and coming down the pipeline even, as Mary Ellen said prior that, as soon as we turn around there's new things coming. The TROPION-Lung15 is a phase 3 study with dato-DXd plus osimertinib versus platinum doublet chemotherapy again for our EGFR-mutated non–small cell lung patients. And then there's TROPION-Lung14, which is also a phase 3 osimertinib plus or minus dato-DXd as first-line treatment for patients with EGFR-mutated lung cancer. And then we have to think about fourth generation TKIs, as we've gone through several generations thus far and they just keep getting better. And then again, the future of antibody-drug conjugates, which I think we're seeing are another avenue that we can use when treating lung cancer patients.

To wrap up this segment, I think it's important that we as APP providers are understanding the mechanism of action and how these antibody-drug conjugates work and how that affects the toxicity and the management. Again, knowing that these ADCs, how they work with the payload and how to manage the nausea and all the things that come with that. And then again, incorporating dato-DXd as a treatment option for EGFR-mutated non–small cell lung cancer patients.

This concludes our discussion of this case study in dato-DXd. I'd like to thank my colleagues, Mary Ellen and Hailey, for joining me today. For more information and to view our other discussions on Updates in Second-Line EGFR-Mutated Non–Small Cell Lung Cancer, please visit JADPRO.com.