Now some of the practical applications that I want to cover with Matt is really discussing, Matt, what are the best practices for sequencing now these agents? T-DXd or other therapies that are now in the market.

Dr Gubens: Yes, for the overexpression patients, it is an easy case. Because we only have the ADC. That is a clear cut second-line, absent patient factors like maybe cardiac issues might be difficult based on compromised heart function at the beginning to start. Really it is ADC until there is a compelling reason not to.

It is harder. I will be curious your thoughts on this in terms of sequencing, now that we do have some TKIs that we will talk about because they are both approved after first-line therapy.

Either sequence is reasonable. Both of them tend to do better before the other, but they both have efficacy after the other one. As we will talk about at the end, there is going to be a move to make some of these first-line agents, too. So it is going to get even more complicated over time.

I have a conversation with my patients. Some do choose the oral therapy when it is a choice just for convenience, knowing they can do the IV later. It really is a shared decision-making situation. How about you?

Dr Rodriguez: Yes. Obviously, the new oral drugs just got approved in the last 3 months, so we do not have as much experience. We are learning and we have more experience with T-DXd, especially because it is approved broadly.

I do agree with you. There are patients that T-DXd is working and they should be continued and they should be managed well. There are patients who do not want to come as often, and having an oral option is great, but I do will caution you from the first patients I have treated, some of these oral drugs cause significant GI toxicity and liver toxicity, so it is not toxicity free, oral chemo. You have to cover that well with your patients.

It is a great thing for patients to have options. We are not waiting for clinical trials for these patients. Now we have 3 drugs in the market. We hopefully will get patients that if they progress, all of these drugs are showing efficacy in the brain, whereas most of these drugs have failed. So really exciting. We will learn more how to manage and sequence based on the patients and toxicity.

[00:54:47]

Management of Treatment-Emergent Adverse Events

Workup for Suspected ADC-Related ILD

In the last 10 minutes, let me just cover some of the treatment-emergent adverse events that hopefully you will leave this discussion with more information.

ILD, which I cover, is rare, but it is very important to know how to recognize and manage. In lung cancer, the most important thing is to hold the drug. If you have a patient that comes with new onset cough and shortness of breath and they are receiving T-DXd, until you figure out what is happening, the safest thing to do would be to hold that drug for that patient until you get some imaging information to rule out other things. It could be a PE, it could be an infection.

Some of these things take time to sort out. I think you have that time to sort that out and make the right decision for your patient.

[00:55:31]

Guidelines for Management of ADC-Induced ILD

There are some clear guidelines on how to manage this. We have learned this from the clinical trials. The case that we were talking about that was grade 1, where the patient has an imaging study, just an imaging change, but they are feeling well. Actually that is grade 1 and you have to interrupt the dose.

If the AE resolves within a month, you can resume at the same dose. But if it is taking more than a month, you should consider lowering the dose just because of that imaging change may take longer to recover. Hopefully, you can find a pulmonologist who is experienced and can help you make these decisions about which patients get steroids.

One thing that is critical here, we used to overflow patients with steroid. Some of the patients do not need that much steroid. At the grade 1 level, you can get away with 0.5 mg/kg of prednisone. Once you get to grade 2, you have to permanently discontinue T-DXd. Patients have hypoxic. You have rule out every other possible causes of hypoxia and this just ILD and grade 3 as well.

These patients are symptomatic because of this drug. It will be very hard to get them to that drug and really rechallenge them.

Just understand that dose reductions, 5.4, you can go to 4.4 and 3.2. Once you do that, if you will discontinue the drug. We do not dose escalate again. If you dose reduce, they add a dose that you dose reduce.

[00:56:56]

T-DXd: Common and Notable AEs in NSCLC (Any Grade)

Now some of the common side effects, and I always tell my patient what is commonly to happen and less likely to happen, but important for us to talk about.

Commonly to happen, you are getting chemo payloads, so alopecia, fatigue, anemia, some GI side effects like constipation and nausea. All those things can commonly happen and our patients should be counseled on how to manage that.

Now, less likely to happen, but important to recognize ILD. We talked a lot about diarrhea and neutropenia. Obviously, some patients may require dose interruption or growth factors with those toxicities. Since this is chemo, we all have more experience.

[00:57:40]

Monitoring Left Ventricular Dysfunction With T-DXd

Now left ventricular dysfunction is interesting because it is lung cancer. It is not breast cancer when we do it all the time. You may miss this, but this is a drug like trastuzumab is there. So you have to at least have a baseline echo to evaluate the ejection fraction and understand that if the ejection fraction is more than 45%, you can continue treatment but monitor patients if they have small changes.

Now, once you get less than 45% and you have any absolute decrease of more than 10% from baseline, you have to really reassess these patients, have a cardiologist on board. It is safer to hold the drug and reassess at 3 weeks. Some of these patients definitely can be rechallenged, if they recover, and we have done it in the breast cancer space. But it is important to recognize, especially in your older population. Obviously, patients have heart failure symptoms, these patients will be discontinued.

[00:58:32]

Managing Neutropenia With T-DXd

Then neutropenia. We will go through it really fast because it is really managing neutropenia from chemo. We educate patients about recognizing neutropenic fever. We monitor patients in clinic. We tell our staff to know that this can happen and then we will hold doses if they have ANC less than 100. We can discontinue after a third dose reduction, consider growth factors and growth factor prophylaxis for patients that have baseline low counts. This we have a lot of experience with.

[00:59:01]

Let's Revisit Our Case

            Patient Case: 65-Yr-Old Woman With Relapsed HER2-Mutation-Positive NSCLC

Let us revisit our case in the last minute here. This is a patient that had relapsed HER2-mutation positive lung cancer, progressed after chemo immunotherapy, received T-DXd. After being on treatment for several months is when they developed dyspnea and shortness of breath. This could happen later on. It does not have to happen immediately like it is for this patient.

[00:59:22]

          Patient Case (cont’d): 65-Yr-Old Woman With Relapsed HER2 Mutation-Positive NSCLC

This patient was feeling with some shortness of breath. They definitely had a little bit of more symptoms on follow up. The differential included ILD. We did testing. We got a pulmonologist on board.

[00:59:37]

          Posttest 3

The question was, which of the following clinical features or diagnostic tests will help you differentiate ILD vs other causes of shortness of breath on cancer patients?

1. The bilateral ground-glass opacities on a CAT scan;
2. The procalcitonin;
3. The fever with purulent sputum; or
4. The focal lower consolidation on CT scan.

I will let you answer that. Hopefully we all got the same thought. It will come on your board here.

Yes, you got it right. Bilateral ground-glass opacities that are a known feature of ILD, where fever and focal consolidation will be more consistent with pneumonia.

[01:00:25]

          Patient Case (cont’d): 65-Yr-Old Woman With Relapsed HER2 Mutation-Positive NSCLC

Let me get to the next question. On restaging CAT scan, the patient has a scattered ground-glass opacities, consistent with ILD. She is asymptomatic. This patient has a good oxygenation and does not have symptoms. This is a grade 1 at this point.

With the involvement of the pulmonologist, she is diagnosed with ILD.

[01:00:50]

          Posttest 4

Our question here has to do with management. What would you recommend for this patient?

1. Continue treatment with T-DXd at the same dose and just follow;
2. Continue treatment with T-DXd and promptly initiate steroids at 1 mg/kg;
3. Hold the treatment until resolution to grade 0 and closely follow and consider steroids at a lower dose of 0.5 mg/kg per day; or
4. Permanently discontinue T-DXd.

We have 2 answers where continue treatment, one was to hold, the other one was to permanently discontinue for this grade 1 ILD.

Okay. Everybody was listening. Great. We are going to hold T-DXd because it is grade 1. It is important to hold it when you do not understand the shortness of breath. But this is a patient that could be followed and rechallenged with treatment because it was a grade 1 ILD.

[01:01:51]

          Posttest 4: Rationale

That is the answer for you guys, like I explained. We will Matt for future directions.

[01:01:55]

Future Directions and Research

Beamion LUNG-1: Antitumor Activity of Zongertinib (HER2 TKI) in HER2-Mutated NSCLC Cohort

Again, this is really a burgeoning space. We really focus today's talk mostly on the ADC. The fact is, in lung cancer, if you close your eyes for a couple of minutes, you got 3 new approvals in this space. We wanted to highlight a couple of really exciting advances in this space as well.

Zongertinib is an oral TKI against HER2. Beamion LUNG-1 was a study of this drug in the HER2-mutated population. Various cohorts, as you can see, but the most important one in terms of the FDA label is the pretreated non-small cell lung cancer subset.

What you see here is, again, a smallish subset, but 75 people, a response rate in pretreated patients, 71% response rate with a median PFS of 12.4 months. Back in August, this led to the FDA giving accelerated approval to zongertinib, specifically in the HER2 tyrosine kinase domain activating mutation space. Not IHCI, but specifically mutations and who have already had prior systemic therapy, which can include, of course, the chemoimmunotherapy but can also follow the ADC we have been talking about.

[01:03:05]

Beamion LUNG-1: Safety in Patients With Pretreated NSCLC With HER2 TKD Mutations (Phase Ib)

In terms of the side effects, as Estela mentioned, these do not come cost free in terms of toxicities. It is just a different suite of side effects. What you see here is that some of the side effects are things we expect from the EGFR family, diarrhea and rash, some liver enzyme abnormalities, dry skin pruritus and some cytopenias.

Most of these are grade 1 or 2. Only 3% had to discontinue. Notably, the ongoing Beamion LUNG-2 study is looking at this in the first-line therapy against chemoimmunotherapy. So we will see if this gets promoted to the first-line.

[01:03:39]

SOHO-01: Antitumor Activity of Sevabertinibin HER2-Mutated NSCLC (Cohort D)

Then just last month, less than a month ago, sevabertinib as tested in SOHO-01, another HER2 TKI was looked at in a similar subset of patients, cohort D, in HER2-activating mutations without prior targeted therapy, but with prior other therapy, including chemoimmunotherapy. Again, a response rate 64%, a median PFS of 8.3 months, and a similar toxicity profile. Again, only 5% of patients had to discontinue based on the gravity of these symptoms.

This led to the approval of this drug on November 19th. Again, this is happening so quickly. Now I do not know how to use these in sequence. I think of them as fairly similar, both exciting, maybe a little Coke and Pepsi action going on. But as we have talked about, sequencing will become a greater issue. It is a great problem to have that we have these different mechanisms of action.

[01:04:31]

Future Directions in NSCLC: Phase III Trials Targeting HER2 With ADCs as Monotherapy and in Combination

That is a nice lead into some of the trials that are looking at that maybe in future CME events we will be able to talk about. First of all, there is a bunch of monotherapy. I mentioned the Beamion trial, but here is SOHO-02. There is DESTINY-Lung04. These drugs that are for HER2 currently in the second-line and beyond setting, they are being assessed against platinum doublet IO in the first-line to try to see if we lead with our best targeted foot forward, can we get better results, as we have in the EGFR space, the ALK space, and many others in the targeted areas.

There is also other work happening here among other companies and pharmaceutical sponsors. BL-M07D1 is another HER2 targeting ADC. SHR-A1811 is a HER3-directed ADC. Again, HER3 plays a role in HER2 resistance and EGFR resistance.

Then combinations. Can we safely add these 2 drugs like in DESTINY-Lung06 pembrolizumab and see if that does better in the first-line compared to chemo and pembrolizumab.

[01:05:35]

Future Directions in NSCLC: Select Early Phase Trials Targeting HER2 With ADCs

Then here are some other thoughts in monotherapy. Here is a study that is looking specifically at patients with brain metastases and trying to really evaluate in a numeric way what the brain result is. We are so excited to see these ADC effects in the brain. Let us quantify them. Let us help get some data to undergird how we decide how to sequence radiation approaches to systemic alone approaches.

Here is SHR again, looking not just in the mutation but in the overexpression amplification and mutation space. Then a bevy of other combinations, including upcoming ADCs with or without immunotherapy.

Just it is a wide open space as many of these targeted spaces are. So there will be a lot of data coming hot and heavy in the next couple of years. But it is an exciting time for our patients because it speaks to the idea that we will be able to do more sequencing over time.

I am curious, Estela, what are you most excited about in this HER2 space?

Dr Rodriguez: Well, that data for the understanding the brain activity and how to introduce radiation is critical. I am interested about how can we combine this and use it upfront. We hopefully will get longer responses for patients that way.

Dr Gubens: It seems it has worked that way in every other targeted space. It makes sense, such as we have to have the data. We cannot just pull out T-DXd in the first-line quite yet. But we are hoping DESTINY-Lung04 and some of these first-line TKI trials show us that same principle at play.

Again, over time, we will also get more real-world data about how the sequencing works. Again, definitely some evidence on some of these trials and various cohorts that people who have previously seen the ADC get benefit from TKIs and vice versa. Again, really a rich opportunity for sequencing.

Of course, with the design of ADCs, how do we incorporate different payloads, different structures, different combinations to improve our outcomes? Really a lot of exciting stuff coming down the field, even aside from what has FDA approved today.

[01:07:30]

Conclusions

With that, what I will do is just conclude by saying HER2 really is important and actionable. The thing is, we cannot act on it if we do not find it in our patients. It can be mutated that we find that by NGS, which hopefully you are doing right out of the gate when you diagnose a metastatic or advanced patient.

It can also be overexpressed, and that is a separate test, an IHC test. We use gastric scoring, not breast scoring. That is a separate test that can be done upfront. Or if you are trying to save tissue, you can always do it later.

ADCs are a novel class of agents that can deliver targeted chemo to cancer cells and maybe the neighborhood around, and maybe engage the immune system. More to come on that. T-DXd specifically, trastuzumab deruxtecan has good clinical activity in HER2-mutated and overexpressed non-small cell lung cancer at a level of 3+, and is approved in this setting in both the EU and the US. Of course, further clinical tests are ongoing, including a first-line registrational trial.

Of course, toxicities are important here. ADC-induced ILD is an issue. We have to be very mindful of that. Even when it is asymptomatic, you have to hold and work it up.

CHF is also something we have to monitor for with serial echos. Neutropenia is important. As with all our drugs, patient and caregiver education is so important for preventive and timely management.

Then really excitingly some small molecule inhibitors of HER2 are also approved for some HER2 mutations. All these are in play, alone, in combination, first-line, subsequent line. Really an exciting space for our patients.

[01:08:57]

A Final Survey

With that, what I will do is hand it back to Kemi for a final survey before we take some questions from everybody.

Kemi Obajimi: Thank you very much, Dr Gubens and Dr Rodriguez. Before we go to our Q&A session, we have 2 more polls.

[01:09:11]

          Poll 3

Do you plan to make any changes in your clinical practice based on what you have learned in today's program?

1. Yes;
2. No;
3. Uncertain.

Please vote.

[01:09:38]

          Poll 4

Please take a moment to text in one key change that you plan to make in your clinical practice based on this education. Please type in.

With that, I will hand over back to Dr Gubens for the Q&A session.

[01:09:56]

Q&A

Dr Gubens: Great. Thanks so much, Kemi. Again, this is a whirlwind tour, so we are wide open for questions. Estela, it looks like we have a question from Sheila[?] about whether the hold for grade 1 ILD, is that specific to lung cancer patients or any of the HER2 tumors for which this drug is approved?

Dr Rodriguez: Yes, it is drug-specific. It is more riskier in lung cancer patients. But if you exceed grade 1 ILD in any tumor type, you will manage it similarly.

Dr Gubens: We have learned this from the breast teams, because they have had experience with this and they are very conservative. Any hint of radiographic pneumonitis, they will hold and hopefully watch through to resolution and restart of drug. They took that very seriously given some even grade 5 events. This is not something to be trifled with.

Again, as Estela said, it is so much more ambiguous in a lung cancer setting, is not it? Because COPD emphysematous patients, you have infections. You have so many other pathologies potentially at play even more than breast.

What are other questions people have?

Dr Rodriguez: I will give you a hard question. Patients that had immunotherapy and had pneumonitis from immunotherapy, I do not think we know the answer to that. I just would caution that anyone who you think could be at risk from ILD for whatever reason, because it is an autoimmune chemo-related side effects, you should monitor very closely. I do not think that in some of the trials, they were excluded if they had prior pneumonitis.

Dr Gubens: That is a really important point. That is where the luxury of having different mechanisms of action involved. Might give us a chance if you did have pneumonitis on a first-line chemo immunotherapy regimen. I think I would preferentially choose the TKI as the next line. I would not rule out the ADC forever, but maybe give some space for the lungs to heal. Not that TKIs do not have their own pneumonitis risk, but now we are talking 1% to 3%, not the numbers that Estela showed us before. That is an opportunity to craft a treatment plan based on the patient's specifics and priors.

Dr Sahni[?] suggested a really good question. That is a tough one for Estela. Maybe I will start with HER2-mutated cases. Do you think there is efficacy to immunotherapy? We have learned the hard way that immunotherapy, at least our PD-1, PD-L1 inhibitors really are useless in the EGFR and maybe the ALK and ROS1 space. If you know someone has HER2-mutated tumors, are you inclined to give immunotherapy first-line? I am curious.

Dr Rodriguez: That has been an evolving thought process. These patients were included in the trial, not a small amount of them. A lot of them were included. The data about toxicity when you go to T-DXd, if it has been in the last 3 months that you had immunotherapy and went to that drug, and also the sub-analysis of these patients, they do not get the same responses to immunotherapy.

Yes, I am evolving on this point. I think that I will give people chemo IO because that is our best treatment upfront, but I have hold immunotherapy on patients that I was concerned may need T-DXd sooner than later. I have done both things. It is evolving.

Dr Gubens: That is fair, but Dr Sahni, your question is well taken and I do suspect it is a lower efficacy in these patients, at least again in the mutated patients. In the IHC, it is probably more of an open field. It is a much more heterogeneous patient population.

Layla asks about HER2 TKIs after immunotherapy pneumonitis. My take on that is that, again, there is still a risk of pneumonitis with any of the TKIs in lung cancer, but it is much lower than an ADC, so it is obviously a judgment call. When the incidence is something like 1% to 3%, I probably would feel comfortable with a lot of caution with very careful follow-up in initiating a HER2 TKI, even if the patient is just coming out of immunotherapy-related pneumonitis.

That is a patient, they are counseled for symptoms. They have a pulse oximeter at home. We make sure they do. Maybe I am imaging them a little more quickly when I initiate therapy. But I have less reservations starting a HER2 TKI, even after.

Dr Rodriguez: The other point I would make there, because we have learned the bad way, is that if you taper people from steroids like it happens in immunotherapy-induced pneumonitis, you may get a rebound shortness of breath. It is important to really partner with a good pulmonologist and take your time to taper steroids on patients that have true ILD.

Dr Gubens: Definitely. I was going to make a point. You were talking about toxicities. Obviously, ILD is the one we talk about the most. I wanted to make a point. I have had a couple of just stellar responses to T-DXd, who are really in the 2 to 3-year range and counting. I will say both of them I have managed at full dose, but with growth factor support.

They never had febrile neutropenia, which might have changed my calculus a bit, but we have shared decision-making but not a huge amount of data. Me talking, phoning a friend to my breast cancer colleagues. We did decide to keep them at full dose, but to use in this case pegfilgrastim to be able to sustain their counts. Again, 2 to 3 years of anniversaries and birthdays. It is really gratifying. They were 2 of my first patients when the drug came on the market. They have just done beautifully. Obviously outliers, but fantastic response, fantastic quality of life. With this tweak that we have had to look at, but important to say.