Managing HER2 and TROP2 ADC Adverse Events: Advanced Practice Providers Case Discussions Highlighting the Critical Roles in Patient Care

I am going to provide a brief overview of the structure of ADCs for anyone not familiar. Basically, the antibody drug complex is composed of 3 parts, the antibody, the linker, and the cytotoxic payload. The antibody is a monoclonal antibody. It targets tumor-specific antigens that are abundant on tumor tissues and minimal on normal tissues. The linker is stable in plasma to prevent premature release of the payload, and then the cytotoxic payload is actually the chemo agent attached to the antibody via the linker. This is a molecule that is 100 to 1,000 times more potent than our traditional small-molecule chemo agents.

[00:10:20]

ADC Mechanism of Action

ADCs are given intravenously. Once in circulation, the ADC binds to the tumor antigen on the surface of the cancer cell, forming the ADC antigen complex. After binding, the ADC is internalized by the cell and targeted for destruction. ADC is then processed within endosomes and lysosomes, releasing the ADC payload. This cytotoxic payload leads to cell apoptosis by any number of mechanisms. Even if the cancer cell dies, that chemo payload is still within that cellular microenvironment. If that tumor cell has membrane permeability, that cytotoxic payload can actually cause destruction of the adjacent cancer cells. This is what makes an ADC unique compared to our traditional chemotherapy. You do not necessarily have to have the tumor antigen expressed on all of our cancer cells for it to be effective because of this bystander effect. Lastly, the antibody component may engage with the patient's immune system to trigger an anti-tumor immunity. There may be some activation of the immune system related to administering these ADCs.

[00:11:44]

TROP-2 Overexpression in Solid Tumors

TROP-2 is 1 of our common tumor antigens that we target with ADCs. As you can see, TROP-2 is overexpressed in many solid tumors, including breast and lung. We also see it in thyroid cancer, gastric cancer, cervical, urothelial, prostate, and colon cancer. Within breast cancer specifically, which is what I will be talking to, about 64% of all breast cancer cancers express TROP-2. Nearly 80% of triple-negative breast cancers have TROP-2 expression. This is not something that we have to specifically test for. It is so common within breast cancer that we are able to just initiate treatment without specific TROP-2 testing.

[00:12:31]

TROP-2-Directed ADCs: Sacituzumab Govitecan and Dato-DXd

In the context of breast cancer and the TROP-2-directed ADCs we are going to be focusing on are sacituzumab govitecan, and datopotamab deruxtecan or Dato-DXd. These are very similar in structure. They are both TROP-2 IgG monoclonal antibodies, and they both have a topoisomerase I inhibitor attached. For SG, this cytotoxic payload is SN-38 or camptothecin derivative. Similar to irinotecan but significantly more potent. The drug-to-antibody ratio for SG is 7.6:1, so there is a high drug-to-antibody ratio. For Dato-DXd, the topoisomerase I inhibitor payload is the exatecan derivative. The drug-to-antibody ratio is 4:1.

[00:13:26]

HER2: A Key Targetable Biomarker in Cancer

We are also going to be talking about HER2-targeted ADCs. As we know, there is a high incidence of HER2 gene amplification or protein overexpression in many solid tumors, including breast and lung. We also see high rates of gene amplification in gastric cancer, bladder, cervical, and endometrial cancer. HER2 is a very popular target in this space.

[00:13:54]

Trastuzumab Deruxtecan: HER2-Targeted ADC

Specifically, I am going to be focusing on trastuzumab deruxtecan or T-DXd. This is a monoclonal antibody directed at HER2. It has the same amino acid sequence as trastuzumab. It also has a T-DXd payload. Again, a topoisomerase I inhibitor with a high antibody drug ratio of 8:1. The blue box on the right here just shows all of the FDA-approved settings for trastuzumab deruxtecan, including metastatic breast cancer, but also HER2-positive gastric cancers, HER2-mutated non-small cell lung cancers, and other HER2-positive solid tumors.

[00:14:54]

ADC Indications in Breast Cancer

This is our current indication for ADCs in breast cancer. We will talk about some recent updates very soon. For T-DXd, this is approved. Metastatic HER-2-positive breast cancer is currently in the second-line space after anti-HER2-based treatment in the first-line setting. We are also giving this in hormone receptor positive HER2 low breast cancer, which is defined as HER2 IHC score of 1 or 2 plus that is FISH negative. It is also indicated in HER2 ultra-low breast cancer, which is an IHC score of zero but has membrane staining. These are indicated after at least 1 line of endocrine therapy in the metastatic setting, and at least 1 line of chemotherapy in the metastatic space.

Trastuzumab emtansine is our tried but true ADC in breast cancer. This is still relevant these days. Now, we are giving it typically third line in the metastatic setting or beyond. We are also using it in the early breast cancer setting for patients who have residual disease after neoadjuvant taxane and trastuzumab-based therapy. For SG, this is approved for patients with inoperable or locally advanced metastatic triple-negative breast cancer after at least 2 lines of systemic therapies, 1 of which was administered in the metastatic setting.

For hormone receptor-positive HER2-negative breast cancer, we can also give SG in this space. Patients should have received endocrine therapy and at least 2 lines of systemic therapy in the metastatic setting. Our current approval for Dato-DXd is in HR positive HER2 negative metastatic breast cancer in patients who have received prior endocrine-based therapy and chemotherapy for unresectable disease.

[00:16:51]

Trial Summary of ADCs in Breast Cancer

This slide just lists the various trials that led to the approval of ADCs within breast cancer. As you can see, all of the ADCs in this space led to an improvement in median progression-free survival compared to the comparator arm, which was our usual chemo of choice or other standard therapy. I would say the most impressive data that we saw was in the metastatic HER2-positive space in the DESTINY-Breast03 trial with T-DXd, which led to an almost tripling of median progression-free survival compared to trastuzumab emtansine. We also see some really impressive approvals in the HER2 low and HER2 ultra-low space, which we will talk about just a little bit later.

We have some updated information about sacituzumab govitecan. The ASCENT-03 trial was recently presented, which looked at SG in combination with pembro for PD-L1-positive metastatic breast cancer in the first-line setting. Look for some updates about that. That was a positive trial. Also, we have recent data from the TROPION-Breast02 study that was just presented at ESMO over the weekend, looking at frontline Dato-DXd in PD-L negative, triple-negative breast cancer. That showed a very impressive improvement in median progression-free survival.

[00:18:33]

Treatment Algorithm for mBC

This is our current treatment algorithm for when to implement ADCs within metastatic breast cancer. When you have hormone receptor-positive breast cancer and the patient has progressed despite adequate endocrine therapy, in terms of deciding what to do next, we want to look at what is our HER-2 status. If we have patients with HER2, IHC zero, no membrane staining, we can give SG or Dato-DXd after chemo in this space. If they have HER2 low or HER2 ultra-low, my first-line systemic therapy might be trastuzumab deruxtecan or chemotherapy followed by SG or Dato-DXd.

In the hormone receptor-negative space, similarly, we want to check for PD-L1 status in this population. If the patients are PD-L1 positive, currently, pembrolizumab plus chemotherapy is our first-line agent, and then check our HER2 status for that population. If HER2 is zero and no membrane staining, I would give SG second-line. If I have HER2 low or ultralow, then you can give SG or T-DXd subsequent to that.

[00:19:57]

DESTINY-Breast09: PFS (BICR)

The DESTINY-Breast09 study was recently presented. This is the first study to challenge first-line THP in metastatic HER2-positive breast cancer. This is a really exciting study. There were actually 3 arms to this study, but we only have data on the first 2 arms, the T-DXd plus pertuzumab compared to THP. The T-DXd plus placebo has not yet reported out. In the T-DXd plus pertuzumab arm, we are seeing an improvement in median progression-free survival of 40 months compared to about 26 months in the THP arm. This benefit was shown across all subgroups, including hormone receptor status, PIK3 mutation status, and presence of brain mets. This is really exciting data. We are looking forward to seeing the outcomes of just the T-DXd alone arm compared to THP, but this could very well take over the first-line setting.

[00:21:03]

TROPION-Breast02: Frontline Dato-DXd vs CT in mTNBC

Just over the past weekend, we heard about the TROPION-Breast02 results. This was a phase III randomized controlled trial in PD-L1 negative, triple negative breast cancer compared to investigator's choice of chemo. This was a positive trial. It did improve median progression-free survival to about 10 months compared to 5 months with traditional chemo. There was a benefit in overall survival of about 24 months with Dato-DXd compared to about 18 months with chemo. This is very likely to take over first-line metastatic triple-negative space for those who are PD-L1 positive or cannot receive pembrolizumab.

[00:21:49]

Understanding HER2-Low/Ultralow

This is just a graphic in terms of how to understand the concept of HER2 low and ultra-low. Basically, with any weak or faint membrane staining for HER2 IHC, that is still considered HER2 ultra-low. These patients have been shown to benefit from getting trastuzumab deruxtecan in the DESTINY-Breast03 trial. Do not discount your HER2 IHC zero scores.

[00:22:25]

Interactive Case Study 1

We are going to start with a case study. Tammy is a 72-year-old woman with metastatic HER2-positive breast cancer to the lung and liver, who is currently on second-line T-DXd for the last 3 months. Her past medical history is significant for hypertension, hyperlipidemia, and obesity. She calls the office complaining of fatigue, worsening cough, and new shortness of breath. She lives 80 miles from the infusion center, so having her come in for an evaluation is difficult, but she is able to take her vitals at home. Her blood pressure is 128/79. Heart rate 105. Temperature 99.9°F. Her oxygen saturation is 91%. Just think about what your differentials might be for this patient.

[00:23:13]

Common AEs Associated With ADCs

What are our common AEs associated with ADCs and trastuzumab deruxtecan specifically? You will see nausea across the board, pretty much with all of these, and pretty significant rates of nausea with T-DXd specifically. All 4 agents cause fatigue. The big differences here is with T-DXd, there are higher rates of ILD or pneumonitis compared to our other ADCs in this space. This is something we have to be constantly checking and monitoring our patients for. With SG, nausea is quite common. Neutropenia, diarrhea are also things that we will frequently be encountering with this drug. Then, uniquely with Dato-DXd, we actually see more of stomatitis, mucositis, and ocular events, which we do not see with some of the other ADCs.

[00:24:15]

Common (in ≥30%) and Dose-Limiting/AESI Toxicities Associated With T-DM1 and T-DXd

This graphic just is another way of depicting some of our most common AES related to the HER2-targeted ADCs, T-DM1 and T-DXd. T-DM1 specifically carries a black box warning for hepatotoxicity and cardiac toxicity. Also, we see moderate rates of thrombocytopenia and hemorrhage. That is something we always have to be looking out for, as well as peripheral neuropathy. Hepatotoxicity is also quite common with T-DM1. It is 1 of our dose-limiting toxicities. Something we need to be monitoring for regularly. With Dato-DXd again, we have a black box warning for ILD/pneumonitis, so frequently I am monitoring for this. There are also fairly significant rates of neutropenia and thrombocytopenia. We still need to be monitoring for left ventricular ejection fraction decrease because this is a HER2-targeted agent. It has also a fairly high rates of nausea. Up to 80% of patients describe some degree of nausea on this type of treatment.

[00:25:30]

Interactive Case Study 1 (cont'd)

Returning to our case. Again, we have a 72-year-old woman, HER2-positive metastatic breast cancer and T-DXd. Past medical history of hypertension, hyperlipidemia, and obesity. She is presenting with cough, fever, and dyspnea. She has a low-grade fever, mild tachycardia, and hypoxemia. Her baseline EF was 50% to 55% and her baseline oxygen saturation is 97%. The risk factors I am worried about for her are her known history of lung mets, her preexisting cardiac disease. My differentials are ILD/pneumonitis, left ventricular dysfunction, neutropenic fever, and disease progression.

[00:26:19]

ADC-Related ILD/Pneumonitis

We will talk a bit about the mechanism behind ADC-related ILD or pneumonitis. As we know, lung toxicity is frequent with taxanes, anthracyclines, and all other anti-HER2-directed therapies. We think in the ADC space, the mechanism of pneumonitis may be related to the cytotoxic payload itself. There may be independent uptake of the payload and immune cells. That is then attacking or irritating the lung tissue, particularly in the setting of lung mets. The bystander effect of the released payload may affect some of our normal lung tissue, and thereby disrupt effective gas exchange. There may be damage from the circulating payload after it is released.

The graph on the right just shows the incidence of ILD in clinical trial participants across the drugs that we use within the breast cancer space. You will see the highest rates of incidents with T-DXd in the HER2-positive breast cancer space, including some fatalities. This is something we have to be really mindful of, particularly with a HER2-positive breast cancer patients. Lower to no rates of ILD with SG, and very small incidence of ILD with datopotamab.

[00:27:44]

Managing ILD/Pneumonitis With T-DXd

This is a busy slide, but basically, it goes through the elements of management of ILD/pneumonitis with T-DXd. The big thing is, first and foremost, educate our patients that this is a side effect and a serious one that can be experienced with T-DXd. We want to advise them to monitor for any signs or symptoms of new or worsening respiratory issues like cough, dyspnea, or a low-grade fever. If a patient is presenting with any of these symptoms, we do want to investigate. We do want to start a workup promptly. You can do chest X-ray, but a really high-resolution CT is more sensitive at detecting ILD.

We should be considering other causes like infection, disease progression, or pneumonitis from another agent that the patients are already receiving. In terms of dosing for any grade 1 cases, which is basically radiographic evidence of ILD but no symptoms, we do want to hold T-DXd until the symptoms resolve, and initiate appropriate treatment. For any grade 2 to 4 events, which is a symptomatic pneumonitis to varying degrees, we are going to hold the treatment and then permanently discontinue this. We treat ILD with corticosteroids.

For grade 1 events, you can consider a starting dose of prednisone of 0.5mg/kg. For grade 2 events, we are going to start at a higher level. I would start with at least 1mg/kg of pred for at least 2 weeks, and then taper slowly. When to resume treatment for pneumonitis really depends on how quickly the patient recovers. If they recover with grade 1 event in less than 28 days, we are going to maintain the dose. If it takes more than 28 days, we are going to need a dose reduction. That is included here on the left.

[00:29:52]

Detecting and Managing T-DXd -Related Interstitial Lung Disease: The 5 "S" Rules

This slide is just for your reference in terms of how else can we think about monitoring for pneumonitis. This is the 5S rules: screen, scan, synergy, suspend treatment, and steroids. That might make it easier for some of us to remember.

[00:30:12]

Monitoring Left Ventricular Dysfunction With T-DXd

In terms of monitoring for left ventricular dysfunction, you want to get a baseline echocardiogram or MUGA scan, and then follow this routinely while you are on treatment. If a patient is presenting with new shortness of breath, it is always reasonable to repeat your echo at that point. The dosing modifications and guidelines are listed here.

[00:30:39]

Managing Neutropenia With T-DXd

As far as neutropenia with T-DXd, educate patients of the potential for this to happen, even though usually it is low-grade. We do want to monitor our CBC at baseline. Then, every 3 weeks prior to each treatment, the median time to onset is 16 to 22 days. Typically, this is something we will see within the first cycle or 2. Usually, this is something that we can modify with dose hold or dose reductions. We do not typically need G-CSF, but you can consider using it prophylactically for your patients who have had a prior history of neutropenic complications.

[00:31:15]

Case Study (cont'd)

Returning to our case. Tammy presented to her local ED. She is found to have wheezing on physical exam. Importantly, there is no lower extremity edema. She was sinus tachy on her EKG. Temperature 99°F. Oxygen saturation 91%. Her white count neutrophils were normal, and her CT chest showed bilateral patchy ground glass opacities and peripheral reticulations consistent with drug-induced pneumonitis.

[00:31:43]

Interactive Case Study 1 (cont'd)

This workup confirmed a grade 2 ILD. We initiated prednisone 1mg/kg for 2 weeks and then tapered slowly. Then, we repeated imaging to confirm resolution. We permanently discontinued T-DXd.

[00:31:59]

Managing Clinically Significant Nausea and Vomiting With T-DXd

I am going to go through quickly just some of the other elements of managing toxicity on T-DXd for nausea and vomiting. Recall that a significant number of people experience nausea and vomiting from T-DXd. You do want to premedicate with a 3-drug regimen and provide your patients with antiemetics to take at home.

[00:32:25]

Common (in ≥30%) and Dose-Limiting/AESI Toxicities Associated With Sacituzumab Govitecan vs Dato-DXd

In terms of TROP-2-directed antibody drug conjugates, this slide again just shows some of our most common and dose-limiting toxicities related to these agents. I will point out, both cause alopecia. Dato-DXd, again, ocular events and stomatitis differentiates it from some of our other ADCs. For SG, there is a high rate of nausea and vomiting, as well as clinically significant diarrhea and neutropenia. Those are black box warnings for this agent.

[00:33:02]

Sacituzumab Govitecan and the UGT1A1*28 Genotype

In terms of testing for UGT1A1 genotype, you do not need to do this at the outset with SG. You should consider testing for this if you have a patient who is experiencing prolonged toxicity related to treatment, as these patients with this genotype may be poor metabolizers of SG and actually have increased toxicity from this treatment. It is something just to be mindful of while you are administering it.

[00:33:28]

Managing Neutropenia With Sacituzumab Govitecan

In terms of managing neutropenia with SG, again, monitor your CBC at baseline prior to Day 1 and Day 8 in the directions for holding treatment, given your ANC counts are included here.

[00:33:45]

Management of Additional Toxicities Associated With SG

For additional toxicities with SG, remember hypersensitivity reactions can occur. We do want to premedicate our patients appropriately prior to the first treatment. The first infusion is given over 3 hours. If they do well, subsequent infusions can be given over 1-2 hours. We want to keep the patients in the clinic for at least half an hour after each infusion to observe them.

For nausea, vomiting, again, this is highly emetogenic. Usually, we are using a 3- to 4-drug antiemetic regimen prior to treatment. I am giving people antiemetics to have at home. It is important to tell people that the onset may be delayed. The median time to onset is 8 days for nausea, vomiting with this drug, so they may not experience this right away.

[00:34:34]

Dato-DXd: Key Adverse Events per TROPION-Breast01

I am not going to go into this in too much detail because you will hear about key adverse events with Dato-DXd in Beth's talk for lung cancer. Specifically, though, the main difference is ocular and stomatitis. Lower rates of nausea, but still some, and fewer lab abnormalities in the breast cancer space.

[00:34:57]

Quality-of-Life Considerations With Sacituzumab Govitecan, T-DXd, and Dato-DXd

With that, I am going to skip over this. This is just for your reference. Other key strategies to manage fatigue, alopecia, and symptom burden. I am going to switch it over to Beth.

[00:35:11]

ADCs in Lung Cancer

Beth Sandy: Thank you. Just a reminder, if you want to put questions into the iPad, then we can look out for them and address them as best we can. Let us talk about lung cancer and the ADCs in lung cancer.

[00:35:26]

Currently Approved ADCs in Lung Cancer

There is currently 3 approved antibody drug conjugates in lung cancer, T-DXd, which we just heard from Julia a lot about that. This is approved for adults with unresectable or metastatic non-small cell lung cancer with an activating HER2 mutation, who have progressed on a prior systemic therapy. It is currently approved in the second-line setting, even though it is a targeted therapy for mutation-positive disease.

It is actually also approved for adults with unresectable or metastatic HER2 IHC 3+. Those high IHC patients. This is a pan-solid tumor approval, which does include lung cancer for patients who have progressed on a prior systemic therapy. They say this in the indication, with no satisfactory alternative treatment options. Which, unfortunately, in lung cancer, is most second-line therapies or third-line therapies sadly.

My point is, with this, you have to actually test for IHC. This is not something that is typically being done in our large NGS panels because IHC is an immunohistochemistry stain. This is something now that we are trying to test for in our settings. Dato-DXd is approved for adults with locally advanced or metastatic EGFR-mutated non-small cell lung cancer who have progressed on prior EGFR-directed therapy. This is for EGFR mutation-positive patients, even though it is not technically an EGFR inhibitor. We will talk a little bit about that as well.

Teliso-V or telisotuzumab vedotin, this is the newest antibody drug conjugate that has been approved for adults with locally advanced or metastatic non-squamous non-small cell lung cancer with high c-Met expression, so IHC 3+. Another immunohistochemistry stain that we have to start testing for now in lung cancer, which, again, is not part of an NGS panel. This is for patients who have progressed on a prior systemic therapy. Also, in that second or beyond line setting.

[00:37:22]

T-DXd in NSCLC

We will talk about each one of these.

[00:37:23]

HER2 in NSCLC

Let us start with T-DXd. Again, this is for patients who are HER2 non-small cell lung cancer. Now, when we talk about HER2 in lung cancer and in other cancers as well, I am so lung cancer-focused. There are different ways you can talk about HER2. Overexpression is an immunohistochemistry stain. It is really easy to get your stain tissue. You do not need a lot of tissue. We get the result back very quickly. Amplification would be something that we might see on a FISH test. They use this in breast cancer a lot more than what we would do in lung cancer.

Then there is mutation. That is in the DNA. That is in a next-gen sequencing panel. This is actually a mutation. There are 3 different ways to look at HER2. They are not all the same, and the outcomes are not all the same. If you look at the bottom here, you can see in the DESTINY-Lung01 trial, they looked at the frequencies of where we see HER2 in lung cancer.

The overexpression in both 2+ and 3+ is around 15% to 30%. Where the drugs actually indicated is in that IHC 3+. That only makes up about 2% to 6% of our patients. The gene amplification is 2% to 5%. Currently, there is no indication for any HER2-directed therapies in lung cancer based on amplification. Then the gene mutation is only about 1% to 4%, so less common. This is something you would find on an NGS panel.

[00:38:48]

DESTINY-Lung02: T-DXd in HER2-Mutant NSCLC

It is more common in never smokers, the HER2 mutations. The DESTINY-LungO2 trial is where T-DXd got its approval in non-small cell lung cancer. I will just remind you that T-DXd is this antibody drug conjugate with a cleavable linker. The cleavable linkers are the ones that have that more rapid payload, and thus a higher bystander effect. Remember, there was a question about that. Just saying.

Going forward, what you see here is, there were 2 cohorts to this study. There was a 5.4mg/kg and a 6.4mg/kg. You can see in this table, I put green boxes around the 5.4 because that is the approved dose. This 6.4mg/kg, similar outcomes here if you look side by side but it was more toxic. That is why the 5.4mg/kg got the approval here.

[00:39:46]

ILD Considerations by Disease and Trial

Now, I am not going to do tons on ILD because Julia talked about this very much, but I wanted to compare a little bit and talk about ILD and lung cancer. Because if you see the rates on the DESTINY-LungO2 vs DESTINY-Breast06, they are a little bit higher in the patients with lung cancer. Not tons higher, but a little bit higher. Also, the problem ends up being, with patients with lung cancer, it could be a lot of different things. When they present with acute shortness of breath, it could be disease progression, a PE, a pleural effusion, a COPD flare. It could be ILD from the drug. There is a lot in your differential diagnosis here.

I always say, it is really imperative to get that stat CT of the chest when they are having acute onset shortness of breath. You can figure out what is going on with it. Now, if you look at the second bullet point under lung, this is why the drug got approved for 5.4 and 6.4. There was a doubling of ILD in the 6.4mg/kg. That is why we use the 5.4.

[00:40:48]

DESTINY-Lung02: Toxicity Profile of T-DXd 5.4 mg/kg

The toxicity profile, I am not going to spend a lot of time here. I just show the nausea and neutropenia, very similar to what we saw in breast cancer.

[00:40:57]

Dato-DXd in NSCLC

I am going to move on to Dato-DXd since we already covered a lot with T-DXd. I am going to move on to Dato-DXd and non-small cell lung cancer.

[00:41:05]

Interactive Case Study 2

This is a newer indication. We are going to follow a case study here. This is Barbara. Barbara is a 63-year-old woman who presented with frequent dry cough and back pain. Allergy meds did not help. Chest X-ray confirmed she has a 6-cm lung mass. Pretty big lung mass. CT of the chest MRI shows that she has a lung tumor and some spinal metastases. She has metastatic lung cancer with brain mets. Brain mets are somewhat common in HER2-mutated patients.

I am sorry worrying about EGFR. It is actually really common in EGFR patients. It is actually twice the amount of brain mets that are seen in EGFR-mutated patients, as in regular run-of-the-mill lung cancer. She has an EGFR mutation. She starts to take osimertinib, which is a frontline therapy for EGFR mutation-positive lung cancer with chemotherapy. She does this for 2 years, and then she has disease progression. Her oncologist decides she is a good candidate for Dato-DXd because she has progressed on EGFR therapy and platinum-based therapy.

[00:42:09]

TROP-2 as Therapeutic Target

Let us talk about TROP-2 for a minute. Remember how I said this is for EGFR-mutated patients, even though it is not an EGFR inhibitor. It is a TROP-2 inhibitor. We know that TROP-2 is overexpressed in lung cancers and particularly in EGFR-mutated patients as well. Again, TROP-2 causes that downstream signaling and cell growth, just like a lot of other mutations do in lung cancer. The point I am trying to say is, you do not have to test for TROP-2. We know it is overexpressed. We know it works in this population of patients.

[00:42:39]

TROP-2 Overexpression in Solid Tumors

It is overexpressed a lot in lung cancer, as you can see here.

[00:42:42]

Dato-DXd: Pooled Analysis of EGFRm Cohorts from TROPION-Lung01/05

This was the data. Now, this gets a little bit hairy. Again, it is late in the evening. Bear with me here. Dato-DXd was trialed in all lung cancer, squamous, adenocarcinoma. Then they took different cohorts and looked at the mutated patients. If you see AGA there, that means genomic alterations, something. It is another word for biomarker positive. They pooled the data, P-O-O-L-E-D. They pooled the data from the EGFR cohorts of these studies. There were 2 different cohorts here. The top one was just getting the Dato-DXd at 6 mg/kg. The bottom one was actually a phase III trial, randomizing it with docetaxel. This was not just EGFR in these 2 cohorts, but they took the EGFR patients out of them. You can see that pooled data of 117 patients there in Lung01 and Lung05.

[00:43:37]

Pooled Analysis of TROPION-Lung01 and TROPION-Lung05: Efficacy

That is the data I am presenting to you. It is the cohort taken out of that with the EGFR mutation patients. If you look at the EGFRm pool, the 117, just focus on that line, this is the response rate. 42% of patients responded. You had 4% complete response, but the majority had stable disease and partial responses. The disease control rate was high. It was 86%. The median duration of that response was around 7 months. The median overall survival was over a year. This is, remember, in the second or further setting. That was good to see, that they were living another year plus on average after taking this medication.

[00:44:24]

Interactive Case Study 2 (cont'd)

Barbara is here to start cycle 1 of Dato-DXd. What adverse of effects will you, as the APP, tell her to expect? What can you do to prevent these? Julia, if you had a patient starting on Dato-DXd in your practice, it is the same drug. We see similar toxicities across the board, what might come to your mind?

Julia LaBarbera: I am going to be talking about preventative treatments for both ocular and stomatitis.

Beth Sandy: That is it. Bingo. Those are the 2 that we really want to try to prevent. I think you used the perfect word. Prevention is really the key here.

[00:45:00]

Pooled Analysis of TROPION-Lung01 and TROPION-Lung05: Safety

These are the toxicities. You can see the swimmer's plot here on the left. Stomatitis was the worst and the most frequent. Almost 60% of patients developed it, and even 9% had severe grades 3, 4. You can see the rest of them listed here. Then, in the green box at the lower right is the oral mucositis. Why it did not make the swimmer's plot, I do not know. This was just weird publication. We think that when they collected the data, the ocular toxicities somehow were not enough to get into that swimmer's plot, but they were more than 10%. You can see that any grade was 69%. The majority were grade 1 and 2, meaning they were manageable. We will talk about what they look like.

[00:45:42]

Management of Stomatitis/Mucositis Associated With Datopotamab Deruxtecan

This is the stomatitis/mucositis that prevention is completely the key here. Because once they develop it, there's not tons more you can do that is really helpful outside of dose delaying and dose reducing. The prevention in the green box, take your eyes there. I know it is a lot on this slide. Soft toothbrushes, bland fluoride-containing toothpastes floss. Do not overfloss. If your mouth is sore, do not go nuts on the floss.

Advise. Use a steroid-containing mouthwash 4 times a day. This is 0.1mg per ml of dexamethasone. It has to be compounded by a pharmacy, but most pharmacies will compound it for you. You have to find one that will anyway but it is a compounding pharmacy thing that has to be compounded. They are supposed to do it 4 times a day, swish it around the mouth for 1 or 2 minutes, which is a really long time, and then spit it out.

This is prevention. I really highly recommend that they do that. Using good oral hygiene and hydration. Then cryotherapy comes back. I feel like I have not talked about this in forever, but it is back. Using ice chips in the mouth can reduce the exposure of the drug to the mucosa while you are getting the infusion. Putting those ice chips in the mouth or something cooling in the mouth to try to reduce exposure.

What to look for? Of course, you guys know this. Typically, this is red, irritated mouth. Sometimes there are sores. Sometimes there are not. There are not always sores. It is just red, inflamed, irritated mouth. You can see the grading is over there on the right-hand side, which is vague. One is asymptomatic, which is rare. Usually, they are telling you about it. They are symptomatic and they have some moderate pain. Again, once they experience it, the management is the same. Using the steroid mouthwashes, comfort measures.

Technically, you can use numbing solutions in the mouth, but they are not always that helpful because a lot of them are gels, over-the-counter things that you spot put on. If it is the whole mouth, it can be really difficult. Just make sure that they are, again, good oral hygiene if this happens, using the steroid mouthwash. A lot of times, I do need to hold drug or even dose reduce if this becomes really problematic and painful for them.

[00:48:03]

Management of Ocular Toxicities Associated With Datopotamab Deruxtecan

The ocular. This is typically dry eye and an irritated eye. If you look on the green box, the required eye care is to do an ophthalmic exam. It does not have to be an ophthalmologist. It can be an optometrist. Go initially, just to make sure the eyes are in good shape to start. Then, the recommendation is preservative-free lubricant eye drops 4 times a day.

Prevention. This is not wait until you get dry eye. Preventatively, start these. You guys they are expensive. I do not know if you have gone to CVS or Walgreens lately and bought these, but they are actually expensive. The company have a QR code to help with some free eyedrops. It is nice if you can get that for the patients. I do recommend that they do this.

I put this red stop sign. Thank you for making that in the slide. I wanted to make that very clear. You are not supposed to wear your contact lenses. That is super annoying. I wear contacts, but try to avoid wearing them because then it makes your eyes more prone to dryness. Again, it is typically dry eye, inflamed eye. Not so much crusting and secretions that we have seen with other stuff with keratitis. Again, once it occurs, you are stuck still doing what you were doing.

I will send them back to the ophthalmologist if it is occurring and being problematic despite using the lubricating eyedrops. I will say, this is not 1 of the ADCs where we recommend the vasoconstricting drops. There are other ADCs where you actually use vasoconstricting and steroid drops. This is not 1 of them that we recommend to do that. If I send them to the eye doctor and the eye doctor says do that, I will let them prescribe that. I just do the lubricating drops with this. That is the recommendation here.

[00:49:45]

Teliso-V in NSCLC

Let us finish up talking about telisotuzumab vedotin.

[00:49:50]

LUMINOSITY: Telisotuzumab Vedotin for Advanced NSCLC With High c-Met Expression

This is the newest one. This is for patients with high c-Met expression. I put in the green box here. Remember, this is overexpression, not MET exon 14 skipping mutation. A MET exon 14 skipping mutation is a DNA mutation that is different from this. That has its own set of oral agents that we use. This is c-Met overexpression, which again has to be done on an immunohistochemistry stain. That is the only way to find this. You have to be actually doing that test within your facility to find these patients.

These patients make up around, I think, 16%. This is a little bit more common than you would think. This is something that we have started testing for where I work. Now, again, this is something that they tested in all of lung cancer. Then, when they ended up finding out that this was working really best in those non-squamous patients, they tested a couple of different, 1.6mg/kg, 1.9. What they found is that it was working best in the c-Met high population of patients, which is typically going to be your non-squamous patients. That is where the best data was. I circled the box in green. That is where this indication is for, again, the IHC 3+, the high expressors.

[00:51:07]

Teliso-V: Safety Data

Where is the most common toxicities that we are seeing here? It is peripheral neuropathy, really. It is the thing that stands out the most. The main reasons for discontinuation of drug were neuropathy and ILD, though the ILD was a bit less common with this. The edema was the second most common AE. Any grade 3 is in parentheses there. 7% was grade 3 or higher. The peripheral edema is a class effect of met inhibitors. When you talk about the oral Met inhibitors, it is really a lot of edema. It was not quite as much with this drug, but still some.

[00:51:44]

Teliso-V: Toxicity Management

What do we do? Again, 31% of patients developed peripheral neuropathy with this. It was, like I said, 1 of the main reasons some people had to discontinue. 7% had severe neuropathy. There is no prophylaxis for this. You obviously treat it like you would treat other neuropathies.

Use of medications such as duloxetine or pregabalin. Duloxetine is technically the only 1 FDA indicated here, but we use a lot of pregabalin as well for these patients. Pain medications, wearing protective footwear, even physical therapy can be helpful sometimes. You guys know, peripheral neuropathy is a lot of times something that is very hard to manage and can be really painful for patients.

The peripheral edema, again, in about 16% of patients, was less common to be grades 3, 4 here. Not a lot works for met peripheral edema either. It is really difficult sometimes. Elevation, compression. I do not use a lot of diuretics. You think it is the first thing to go to when you see lower extremity edema. Because of this third spacing fluid, it is not an overload. It is not heart failure. The diuretics do not typically work very well. If anything, they just end up dehydrating you more. We try the elevation and compression. Sometimes, this can be dose-limiting.

[00:53:00]

Conclusions/ Closing Remarks

In conclusion, APPs have a pivotal role in education, in particular the prophylaxis of adverse events, as well as the prompt reporting of ADC adverse effects. In breast cancer, and especially lung cancer, perform the biomarker testing in non-small cell lung cancer. All 3 ADCs are approved, but only for patients who have specific biomarkers.

Remember, the Dato-DXd is for patients with EGFR mutations in the second or third-line setting, and the T-DXd and the met drug, the Teliso-V, those are for IHC, and then the HER2 mutation in T-DXd as well. We have to be doing biomarker testing and immunohistochemistry add-ons now, which, again, cannot be done in that NGS panel.

The knowledge of these new therapies and their indications, many of these were approved only in the past 3-6 months. This field is really changing rapidly. Two out of the 3 drugs I presented here were just approved in the last 3-6 months. I have to keep updating slides. You are going to see, I think, more and more in this field because of the way that the drug is delivered, we get good outcomes. Even though we talked about a lot of toxicities here, relatively not as severely toxic as a lot of the chemotherapy agents that we use.

[00:54:17]

Now, let's go back to some of our questions

We are going to go back to our questions and go through those. We will take any questions that may be coming in from online or from the audience.

[00:54:28]

Posttest 1

When talking with a colleague about using Dato-DXd in patients with advanced non-small cell lung cancer, which of the following is the least likely to be discussed and is not a common adverse event associated with Dato-DXd? Is it

A. Diarrhea;

B. Stomatitis;

C. ILD/pneumonitis; or

D. Ocular (dry eye);

Yes, diarrhea is actually not a common side effect of Dato-DXd. The stomatitis and ocular are the 2 most common. ILD does occur. It is not super common, but it does occur. Diarrhea was really not a big side effect. Very good job there.

[00:55:24]

Posttest 2

Based on the guidelines, how would you manage grade 1 mucositis associated with Dato-DXd?

A. Maintain the dose as it is transient avoiding steroid mouthwash;

B. Delay the dose until resolved and then resume at the same dose;

C. Delay the dose until resolved, then resume at a reduced dose; or

D. Maintain the dose with supportive pain management;

I was just remembering that most of you got this right initially. That is correct. We pretty much stayed the same. Most of you got this right. I did not really address this probably as much as I should have. Anything grade 1, we typically do not hold dose for. We treat through it and try to supportively manage them. It is usually grade 2 where we are going to delay or hold. Good job. You guys got that initially mostly right.

[00:56:24]

Posttest 3

When discussing the unique characteristics of ADCs with patients, which of the following would you tell them about a potential for a "bystander effect?" Is it

A. ADCs with a cleavable linker and high drug-to-antibody ratio may allow membrane permeability payloads to also affect adjacent cells;

B. The cytotoxic payload on ADCs internally affects target cancer cells, preventing bystander effects on surrounding healthy cells;

C. ADCs with a non-cleavable linker and low drug-to-antibody ratio are more likely to result in increased systemic exposure to the payload; or

D. Lower specificity of the ADC to target antigens on cancer cells can prevent potential "bystander effects" by attenuating cell uptake;

Right. Good job. Those ADCs with a cleavable linker and have that high drug to antibody ratio, unfortunately, can also affect the bystander effect there as well. A bit of a trade-off.

[00:57:41]

Poll 4

A couple of last questions, and then we will get to any online questions. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;

2. No; or

3. You are uncertain;

We are not going to show the answer. Be honest. Do not hurt my feelings, though.

[00:58:12]

Poll 5

Oh my. Please take a moment to text in 1 key change that you plan to make. We are going to put you to it.

[00:58:21]

Thank You for Attending

Let us see. Any questions there, Julia?

Julia LaBarbera: I have couple coming in. What are the most common Dato-DXd AEs you see in practice?

Beth Sandy: In my world, it is definitely the stomatitis. I have not seen as much ocular stuff. Maybe my patients are good with. Honestly, I have not used the drug a ton. It has only been approved for a few months but I do have a couple of patients on it. Certainly, 1 definitely has stomatitis. She is doing what she is supposed to be doing. She is already doing the steroid mouth rinses. We are just making sure she is not using any alcohol-based mouthwashes. You always go back to that. Saltwater and baking soda. We are trying to throw a little bit of that in there. I do not know.

Julia LaBarbera: I do actually see some ocular toxicity, mostly dry eye, which is what was reflected in the TROPION studies. We are really, really adamant about using the preservative-free eye drops with our patients. It is pretty manageable. I would say stomatitis is also manageable. We are prescribing dex mouthrinse up front. A lot of our patients are using cryotherapy during treatment.

Beth Sandy: I always think if they are getting it, just make sure you are using at least 4 times a day. Because I am thinking maybe they are not. If they are not having it, and then once they have it, just make sure they are being more aggressive. You can use it more. It is actually 4 times or as needed. They can even use it more often. It does not taste very good. That is the other thing I am told, unfortunately.

Julia LaBarbera: We do have a question. Can you check c-Met on an older biopsy, or is a new biopsy needed?

Beth Sandy: That is actually a really, really good question. You can check it on an older one, but we actually do not. We actually recommend for both the IHC for HER2 and c-Met that you actually try to get new tissue and do it on that, because we can see it not be there in their original biopsy. Remember, these drugs are approved after you have progressed on therapy. A lot of times we have actually seen it not be on their original tumor, the high expression, but on their progressive tumor. Once it is progressing on whatever therapy they are on, then we see it.

That was actually a good point that I did not make in this program it is that we recommend, in the lung space, you try to get more tissue and retest the IHC based on that. We are actually not usually testing it up front. We are trying to test it at the time of progression. In order to do that, you need a biopsy, and you cannot do it on a blood test. IHC cannot be done on 1 of those fancy blood tests that you send for NGS. It has to be in the cells.

Julia LaBarbera: In our last question. In the TROPION trial, where steroids are used as preventative for dermatitis and was cryo used, what are the rates of stomatitis without steroids? What is the reduction with steroids?

Beth Sandy: That is a really good question. I actually do not think it was used preventatively.

Julia LaBarbera: I think it was investigator's choice once the patient developed the toxicity.

Beth Sandy: They definitely did not all get steroid mouthwashes preventatively. That was something that came out as a recommendation in the PI after this because the rates were so high. Now, I do not have numbers for you of exactly what it was before and after, because I think some patients did use it preventatively on the trials, but definitely all of them did not.

Julia LaBarbera: That is it. Unless we have any questions here from the audience.

Beth Sandy: Thank you so much for attending. To claim your credits, you are going to go to this website to access the online evaluation form. You can view and print your certificate upon completion of that online evaluation. I do not know. Can they do that from the iPads right here? No? I am hearing no's from the audience. To claim credit.

Speaker 3: I think we have 1 more question.

Julia LaBarbera: One more question. Do you have experience with utilizing the cryo mouthwash piece vs ice chips? I am not familiar with cryo mouthwash piece. Most of our patients still use traditional ice chips.

Beth Sandy: I found 1 online because somebody told me about this. They said it was on Amazon, but it is not on Amazon. There is this thing. You know the spacer for an inhaler? It looks like a spacer for an inhaler. You put it in your freezer, and then it is a mouthguard, almost. You would wear it for lacrosse or whatever. Mouthguard. It is a mouthpiece that fits in, and then it looks like it has this spacer on the end of it, which is whatever the cooling thing. I do not know if it is air or circulates something in your mouth. It is expensive, but you can buy it. That would be the only alternative.

I did find that there is a total market for it. It is an interesting product. I have never seen a patient use it, but I talked to somebody who had a patient that used it, and they liked it. Outside of that, it is just ice chips in the mouth, which is not super comfortable, as you can imagine.