This is a 67-year-old person with advanced non-small cell lung cancer. He is a man with remote history of smoking but less than 5 pack years, who comes in with persistent cough, weight loss and right upper quadrant pain. Imaging shows a lung mass and unfortunately, liver and bone lesions that are all positive on PET CT.

A biopsy confirms lung adenocarcinoma in the liver. IHC shows TTF-1 and Napsin A positivity. NGS unfortunately just shows a TP53 mutation with a high PD-L1 of 60%. He got standard first-line therapy with a platinum doublet and immunotherapy. After 6 months of response, unfortunately, now with progression in the liver.

He has good performance status, mildly elevated liver enzymes and no other comorbidities. Retesting on the original biopsy shows HER2 IHC 3+ and MET IHC zero expression.

[00:21:17]

          Pretest 2

Which of the following is the most appropriate second-line therapy for this patient?

1. Docetaxel with or without ramucirumab;
2. Disitamab vedotin;
3. Nivolumab + ipilimumab;
4. Sevabertinib or zongertinib; or
5. Trastuzumab deruxtecan.

Thanks for voting.

[00:21:54]

HER2 in Context 

ErbB Family of Receptor Tyrosine Kinases

To put HER2 in context, obviously, those of you who do medical oncology in the general sense have used a lot of HER2 agents in the breast cancer space. I really want to put HER2 into context of this broader family, the ErbB family of receptor tyrosine kinases.

It is not always obvious to a lot of folks that EGFR is in this family too. EGFR, also known as HER1, is one of these 4 receptor tyrosine kinases. These are extracellular ligand-binding regions with a single membrane spanning region and that a cytoplasmic tyrosine kinase-containing domain.

Ligand binding initiates homo or heterodimerization that activates the kinase domain in the cytoplasm, and that phosphorylates tyrosines in the tail of each receptor. The signaling is different. HER3 is an orphan. It does not have its own kinase activity, so it has to dimerize with others. Very important in some resistance settings like EGFR. But HER2, the focus of today are erbB2 for this slide binds any of those erbB ligands and is activated via this heterodimerization with other ligand-bound receptors.

[00:23:05]

HER2 Expression Across Solid Tumor Types

HER2 is really expressed at a different level across different solid tumor types. To the left are the ones that have more expression. And you expect breast endometrial over there, but there number 5 is lung. We see a fair bit of 1+, 2+ and 3+ overexpression in lung. That is what made it a provocative choice for using targeted therapies of various types that we will talk about today.

[00:23:33]

Rationale for Targeting HER2 in NSCLC

Let us talk about HER2 in the non-small cell lung cancer context.

[00:23:37]

What Is HER2-Positive NSCLC?

First of all, what is HER2-positive non-small cell lung cancer? There are actually 3 ways you can think of HER2 as being at play in a lung cancer. First of all, there can be HER2 overexpression. This is detection by immunohistochemistry. This is just a whole bunch of HER2 showing themselves on the membrane of the cell. This is seen in 15% to 30% at a level of 2 or 3 positivity.

However, a subset of non-small cell lung cancer actually has a gene mutation at HER2, and this is an overlapping but not entirely overlapping Venn diagram. 1% to 3% of our patients in non-small cell lung cancer have these actionable HER2 mutations.

Then finally, not so important in lung cancer is HER2 amplification, at least in the targeting sense. Amplification, of course, the FISH is so important in breast cancer treatment decision making, but really does not play a role in any of the FDA labels, though it is amplified in 2% to 5% of our patients. Again, an overlapping but not entirely overlapping Venn diagram here.

[00:24:40]

Clinicopathologic Features of HER2 Mutations in NSCLC

What patients have these HER2 mutations? Well, they are actually seen much more often in adenocarcinoma or in adenosquamous histology. Like EGFR, its sister, tyrosine kinase, it is actually more common in never or those with a mild tobacco history.

Females do have a higher incidence. Unfortunately, HER2 mutations are associated with higher rates of brain metastases and worse overall survival compared to other non-small cell lung cancers.

Now again, even though there is some overlap, HER2 overexpression amplification do not quite have the same epidemiology, broadly speaking. Again, these are patients who are very important to find these mutations to be able to use the best drugs.

[00:25:25]

Mechanisms for Targeting HER2 in Cancer

Now, over the years, there have been various mechanisms for targeting HER2 in cancer broadly stated. Again, many of these involved in breast cancer, but lung has been at the table as well. There are a family of nonselective pan-HER TKIs that basically can hit any of these HER family, including EGFR.

There are some with more selectivity that we will talk about that really are designed by organic chemists to hit HER2 specifically. Then there are monoclonal antibodies that basically grab the extracellular domain, to be able to induce an effect.

Then most recently HER2 antibody drug conjugates, where they latch onto the HER2 but deliver then a payload of sorts that is endocytosed with hopefully a release of payload and effect against the cancer cell.

[00:26:21]

Past Efforts to Target HER2-Altered NSCLC

Now, past efforts in the HER2 non-small cell lung cancer space, we admit, have been somewhat disappointing. Some of these HER2 TKIs, they really have not had very strong response rates, and they are also limited by some of their toxicities.

Afatinib you might recognize as an approved second-generation EGFR TKI, it does have some benefit in HER2, but at a much, much reduced overall response rate. Then, of course, as the monoclonal antibodies and antibody drug conjugates came into being, especially in the breast cancer space, there was borrowing them into the non-small cell lung cancer space.

Here you see the response rates up a little bit. This is a little more compelling and provides the basis on which some of the data we will show today, have led to FDA approvals.

[00:27:10]

HER2 Testing in NSCLC

To take a step back, how do we assess for HER2 testing in non-small cell lung cancer?

[00:27:16]

Reexamine the Absence of Driver Mutations: ESMO/NCCN Guidelines Evolve

Again, as I said at the outset, non-small cell lung cancer just has this amazing proliferation. In my training, we only had EGFR, 2020. We had 4. Now we have almost 10 genetic alterations, mutations or fusions where we have first and/or second-line agents available. HER2 is at this party. We have these second-line options, both ADC and TKIs that we will talk about. So it is important to find these.

[00:27:41]

Reexamine the Absence of Driver Mutations: ESMO/NCCN Guidelines Evolve

What the take-home message of any non-small cell lung cancer talk is that this is something we should be looking at in every adenocarcinoma and actually probably most squamous cells, certainly those when we find that their demographics do not quite jive with the usual squamous cell epidemiology.

Of course, it is also important to look at the quality of our specimens. Are there enough tumor cells collected? We are doing a lot more small biopsies through EBUS, through fine-needle aspiration. Sometimes we get a diagnosis but not many cells to do the next-generation sequencing. So interrogating that report, not just looking at negativity but saying are they actually saying quantity non-sufficient, QNS, the dreaded acronym we see.

And really to be open to the idea of rebiopsy or retest, if necessary. It is not appropriate not to have this answer, and even if it takes some more time, or maybe it leads us to employ liquid biopsy, this is really important for our patients and their outcomes.

[00:28:39]

HER2 Testing Guidelines for Lung Cancer

Just to summarize, there are these 2 different HER2 aspects as I talked about: overlapping but not entirely. HER2 mutations are found as part of broad molecular profiling using next-generation sequencing. Again, this is part of NCCN and other recommendations for all metastatic non-squamous non-small cell lung cancer, or NOS. And we think about it for squamous.

HER2 overexpression, meanwhile, requires its own IHC testing. It can be done upfront. But I would always caution to say prioritize PD-L1 and NGS because that will impact first-line therapy decision-making. You can always do the HER2 IHC later or on a separate sample, but both are very important, just different tests that potentially can be done at different times.

[00:29:23]

Distribution of HER2 Mutations

Now, HER2 mutations come in many varieties, and this is something we are learning with other mutations in other spaces. Just suffice it to say there is a set of extracellular domain mutations, intracellular domain mutations and transmembrane domain.

Now technically, the FDA only approved T-DXd for all of these, but for the TKIs only the tyrosine kinase domain mutations. And we will talk about that later too.

[00:29:47]

Guidance for HER2/ERBB2 Testing in Advanced NSCLC

Now guidance. Generally, FFPE is going to be the way we analyze this. Cytology samples, cell blocks. Cell blocks from pleural effusions can be a very rich source of data for NGS. Of course, peripheral blood, the burgeoning area of liquid biopsies.

For tissue processing, it is important to have a workflow to make sure that small samples are really treated with good stewardship to make sure we do not overuse on diagnostic IHC without doing some of the biomarker testing we need.

NGS assays really should be broad based. We really past the age of doing EGFR, then ALK, then ROS1. It takes too much time, too much tissue. All of us are familiar with these broad NGS testing that we either do in-house or with some of the great vendors that are available.

Again, even though I mentioned some non-smoking female predilection for the mutations, we really should not use these select patients. We really need to get the data. We get surprised. Even in that demographic that is also enriched for EGFR and ALK. Again, it has to be part of this panel where we get this data up front in a timely way to dictate first and second-line therapies.

[00:30:55]

NSCLC Treatment Guideline Recommendations

Again, the treatment recommendation is that, in the first-line, patients with HER2 mutations really should get platinum-based chemo with or without immunotherapy. We will talk about the data in a moment. At subsequent at that second-line, based on really favorable data compared to our old docetaxel/ramucirumab, trastuzumab deruxtecan or the TKIs, zongertinib or sevabertinib really are preferred on NCCN.

Trastuzumab emtansine is another therapy option. Again, really data are not as strong as the ADC trastuzumab deruxtecan. We really do not recommend single-agent therapy with trastuzumab or afatinib in this situation. We have better agents now.

That is for the mutations. I want to stress, however, that when we have the 3+ overexpression, it is just the trastuzumab deruxtecan and it is just for 3+. There are some data in 2+. There is a gradient. But right now the FDA label is only for 3+ overexpression, and the TKIs do not pertain to overexpression, only mutations.

[00:31:57]

Let's Revisit Our Survey and Case

With that, let us revisit our survey and case.

[00:32:00]

          Posttest 1

First of all, which of the following is an indication for trastuzumab deruxtecan in patients with advanced non-small cell lung cancer who have received a prior systemic therapy? Is it:

1. HER2 low/ultralow;
2. HER2 exon 20 mutation positive;
3. HER2 amplified; or
4. HER2 overexpressed at a 2+ level.

Which one actually has the label?

[00:32:34]

          Posttest 1: Rationale

The correct answer is B. This HER2 exon 20 mutation positive is an activating HER2 mutation. That is where the label is. The distracters here were that even if it is 1+ or 2+, it is overexpressed to some extent but not enough for the label.

Finally, in choice C, HER2 amplification does not play a role in any HER2 labels in non-small cell lung cancer.

[00:33:00]

          Patient Case: 67-Yr-Old Patient With Advanced NSCLC

Question 2, related to a 67-year-old gentleman with metastatic lung adenocarcinoma who gets a chemoimmunotherapy initially. Then on retesting for second-line, he has HER2 IHC 3+.

[00:33:13]

          Posttest 2

What should he get second-line?

1. Docetaxel-ramucirumab;
2. Disitamab vedotin;
3. Nivolumab + Ipilimumab;
4. Sevabertinib or zongertinib; or
5. Trastuzumab deruxtecan.

Again, this is IHC 3+, not a mutation.

[00:33:40]

          Posttest 2: Rationale  

I think I made that pretty clear. This is trastuzumab deruxtecan. This is the ADC. The ADC is approved for 3+ IHC. Because this was not a mutation, you are not opting for an sevabertinib-zongertinib. Nivolumab-ipilimumab, disitamab vedotin are not good options here. Docetaxel-ramucirumab is a second-line regimen, but really not the one that you would choose when you have an ADC with a better response rate and better durability.

[00:34:06]

          Discussion  

Just to take a moment. Estela, you work in Florida, the opposite side of the country from me. We have a lot of commonality in our patients. I am wondering, how are you thinking about HER2 testing in your practice?

Dr Estelamari Rodriguez (University of Miami Miller School of Medicine): I agree that the best use of tissue is to do upfront NGS. We do PD-L1 testing IHC in-house. HER2 is something you have to ask for, but we ask for that later on. It is important to get as much information as you can get upfront, so that you know what to do next for your patients.

Dr Gubens: So important. Are you sending it along with MET usually or on its own time frame?

Dr Rodriguez: The PD-L1 we do from the get go and then when people progress, we will do IHC for MET and HER2. One is in-house. The other one is outside. So that always adds some delay.

Dr Gubens: Us too. It is really a struggle because this is evolving in a very rapid way. Even in-house, we had to really clarify with pathologists, “Hey, we use the HER2 gastric scoring, not the breast scoring, which is not intuitive when you think about this.”

I see someone wrote in asking, saying HER2 mutations are pretty uncommon. The question is whether the morphology of the tumor cells were clearly correlated with confirmed HER2 alterations before initiating therapy.

Again, most of this is adeno or adenosquamous. But keep in mind that the mutations are really based on NGS. These were selected based on NGS findings of the HER2 activating mutation. We really were not using this in a broad, nonselective manner like you asked.

Dr Rodriguez: Although the clinical characteristics may point you, there are more women, people that present with brain mets may have HER2 alterations. So we always think of that.

Dr Gubens: Exactly.

[00:35:49]

Brief Review of ADCs: Exploration of ADC Structure and Mechanism of Action

ADCs: Key Principles

Just to whet your appetite, as Estela gets deep into the data that we have, just a very quick primer to remind you, ADCs, how are they built? You have got the antigen. You want to find one that is abundant in tumors, the minimal and normal tissues. These will get internalized on ADC binding. Then there is the conjugation chemistry. How do you link the antigen to the linker to the cytotoxic drug payload?

Then the payload itself, which one do you choose? Because the one you choose, you want to make sure it is highly potent, active at a subnanomolar activity level. There are functional groups for linking and lower hydrophobicity. There is a lot of design elements here that do impact efficacy, but also side effects.

[00:36:33]

ADC Mechanism of Action

Mechanism of action. Of course, the most obvious one is as it is endocytosed, that cell in particular is targeted for destruction. But there is the idea that it is also potentially causing some bystander killing effects. These membrane permeable payloads may act in the neighborhood, if you will, to elicit this effect.

Then there is this provocative area where there might be an antibody component that engages with immune effector cells to get anti-tumor immunity more broadly.

[00:37:02]

3 Drug-Related Components and Patient-Related Variables Relevant to ADCs

I would not belabor this, but just to say there are drug-related components like the payload, like the antibody epitope, like the linker that can be relevant to how these drugs work, but also patient-related variables. How much do they express the epitope in that tumor vs other tissues? You want a specific one.

Also prior or current therapy. If you choose a payload that is related to a drug you have already given, you are going to expect less efficacy. Then some of the biology of the cancer influence is listed here.

[00:37:30]

Adverse Effects of ADCs: A Conceptual Framework

Then finally, as Estela talks about some of the adverse effects, think about the drug matters, the payload matters. These are related to drugs we have used for a long time. Some of them are old school. MMAE causes cytopenias and peripheral neuropathy. DM4, for example, causes ocular toxicity, whereas DM1 we look at liver and thrombocytopenia.

Which drug is chosen affects how we have to follow these patients.

With that, I hand the gavel over to Estela to talk about some of the data we have here.

[00:37:59]

Data on HER2-Targeted Therapies in NSCLC, Practical Applications of HER2-Targeted Therapy, and Management of Treatment-Emergent Adverse Events

Dr Rodriguez: Great. Thank you, Matt. That was a great introduction not only to how we do the testing, but what are the features of the actual drug. Now we are going to dig in talking about the data from the clinical trials. This drug has been in the market now for several years, so we have had some experience understanding who is the best patient, what kind of efficacy we have seen that replicates what was done in the original trials.

[00:38:26]

Let's Consider a Patient Case

First, let us consider a patient case.

[00:38:28]

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

This is a real case from my practice. Is a 65-year-old woman who had relapsed HER2-mutation positive non-small cell lung cancer. We knew the HER2 mutation was identified at the initial NGS. The patient was treated with first-line carboplatin/pemetrexed/pembrolizumab.

She did well for about 7 months when she developed headaches and was found to have new brain metastases. At that point, that was the only HER2 agent that was approved for lung cancer. She was offered T-DXd, trastuzumab deruxtecan at the dose of 5.5 milligrams per kilo.

She achieved a good PR with resolution of the brain mets, which is really a valuable thing that we have seen from these drugs to minimize toxicity. The patient develops some grade 2 nausea and vomiting, and due to refractory nausea, we had to decrease the dose of the drug.

After cycle 12, she developed acute worsening dyspnea and cough. That was an important thing to recognize since the patient had been so stable.

[00:39:33]

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

At a follow-up visit, when she presented with these symptoms, we ordered a CAT scan that revealed this right lower lobe infiltrate. The differential the radiologist reported could be ILD vs an atypical infection. The patient was referred to our pulmonologist and we had to make some decisions for this patient.

[00:39:55]

Pretest 3

First, we will a pre-test question. Which of the following clinical features or diagnostic tests will help you distinguish ILD exacerbation from alternative causes such as infection, pulmonary embolism, and heart failure because our patients can have shortness of breath from many reasons.

1. A bilateral ground-glass opacities on a CST scan. That would be one feature;
2. Elevated procalcitonin;
3. Fever with purulent sputum; or
4. A focal lower consolidation on a CT scan.

Get your answers on that and we will discuss them at the end.

[000:40:42]

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

Now, this patient on restaging high-resolution CAT scan was found to have scattered ground-glass opacities on both lungs. So we have a suspicion of ILD in this case. She is asymptomatic and has normal vital signs and normal oxygenation. This is something that is tricky because this is considered a grade 1 ILD where patients have imaging studies but they do not have symptoms.

With the involvement of our pulmonologist, she was diagnosed with grade ILD after we had ruled out other causes.

[00:41:13]

Pretest 4

The question is, at this time, what would you recommend for this patient with asymptomatic grade 1 ILD? We will have our questions come up. Should we:

1. Continue treatment with T-DXd at the same dose and arrange for close clinical follow-up;
2. Continue treatment with T-DXd and promptly initiate steroids at a dose of 1 mg/kg per day and then taper over 4 weeks;
3. Hold the treatment until resolution to grade 0 and we close clinical follow-up, Consider a steroid initiation of 0.5 milligrams per kilo; or
4. Permanently discontinue the drug and promptly initiate steroids at a dose much higher than 1 mg/kg per day.

If you have had some experience with other drugs that may cause ILD, you may have already have a plan at your institution of how to manage that, but many times these patients are in our clinic and we have to actively decide what to do about the treatment that day. We will go over that data and what the recommendations are.

[00:42:18]

Data on HER2-Targeted Therapies in NSCLC

First, let me talk about why we are using HER2-targeted therapies in lung cancer. What we have seen from the data.

[00:42:23]

Trastuzumab Deruxtecan: HER2-Targeted ADC

Matt described for us very well what trastuzumab deruxtecan is. It is an antibody drug conjugate, first of its kind that has an anti-HER2 monoclonal antibody, this tetrapeptide-based linker that allows the drug to be delivered. The drug is the payload. Understanding all of these components we can understand the toxicity. We heard yesterday about a new FDA approval, but this drug is approved for other solid tumors including breast GI. So you may have had experience managing some of the toxicity from other patients.

[00:42:59]

DESTINY-Lung01: T-DXd in HER2-Mutated or HER2-Overexpressing NSCLC

Now, the first data in lung cancer came from the DESTINY-Lung01 trial. This was a trial that patients that had unresectable or metastatic lung cancer. This cohorts had patients that were HER2 overexpressing or had HER2 activating mutation, and they had relapsed after standard therapy. They could have had prior pan-HER TKI allowed but not directed HER2-targeted therapy. It is 181 patients that were randomized in one cohort to 2 different doses at that point.

[00:43:35]

HER2-Mutated NSCLC Cohort in DESTINY-Lung01: Best Percentage Change in Tumor Size

This is the initial data that we got, where most patients responded, which is a beautiful waterfall curve, just showing you that regardless of where the location of the mutation is, these patients were getting a significant response of over 55%. So better than your second-line chemo, which would have been docetaxel. The median progression-free survival approaching a year, 8 months. Median overall survival over a year at 17.8 months. So really remarkable data for patients that were identified to have these mutations or overexpression.

[00:44:07]

DESTINY-Lung02: Trastuzumab Deruxtecan in HER2-Mutated NSCLC

Then we had data from DESTINY-Lung02. What we learned from DESTINY-Lung01 is that at the dose of 6.4, you can see a higher response, you may see more toxicity. More importantly, ILD was one of these toxicities that are dose-limiting for the drug for patients. This is a trial that tested a lower dose at 5.4 randomized 2:1 to 6.4. Again, similar patients that have been treated previously with 1 more anti-cancer therapy and stable brain mets were allowed on this trial.

Then I guess the hypothesis was just to really find can we find a response with this lower dose?

[00:44:47]

DESTINY-Lung02 Final Analysis: Baseline Characteristics

Just to tell you a little bit about these patients to just think, are these patients like your patients? So the patients with ECOG performance 1 were included. The majority of them had kinase domain mutations. Then about 34% to 44% of patients had CNS brain metastasis at baseline, which is critical that we have data for these patients. Patients had good renal function.

Most of them had more than 2 lines of therapy, which is important, 32%, or 2 lines of therapy, 67%. Then we also get the question of where these patients previously exposed to immunotherapy, and the majority of them, 73% were.

[00:45:28]

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

These are patients that you would have seen in your practice. Again, what we saw that was important for patients that are dealing with these toxicities is that we can achieve an excellent response of about 50% at a lower dose. They were complete responses at 3%, a lot of stable disease and partial responses. More importantly, a lot of these patients had a duration of response that was over close to a year.

This gave the FDA enough data to approve this dose of 5.4 since August 2022. So we have had some experience in our practice if you have identified these patients with this agent.

[00:46:06]

DESTINY-Lung02 Final Analysis: Survival

Now, we have gotten more data, since the trials were started a while back. Now we know that the final analysis for survival showed that the 12-month progression-free survival was excellent, about 45% of patients were progression-free at almost a year. The median overall survival, 19 months. So much better than what we had seen in the initial phase I trial.

At 18 months, 50% of patients were still responding with a median overall survival of 18 months. So really remarkable that at the lower dose, we are seeing these responses that are definitely over a year, very meaningful responses for patients that were previously treated.

[00:46:45]

Pooled Analysis of DESTINY-Lung01 and -Lung02: Intracranial Efficacy With T-DXd in HER2-Mut NSCLC With Brain Mets

Then we wanted to know an important part of this, which is the intracranial efficacy. If you have met patients, especially younger patients that present with brain mets, and in the past we have radiated the whole brain, now we are using more targeted radiation with SBRT and Gamma Knife.

Those patients who get a lot of brain radiation upfront, they do survive cancer, but they end up getting more toxicity. Getting agents that get in the brain with efficacy are critical for these patients quality of life, but also for the longevity. We saw that in the pooled analysis from DESTINY-Lung01 and Lung02, where we have data of patients that have baseline brain metastases, we had complete responses of brain metastases. We had a lot of stable disease and partial responses.

The median intracranial duration of response was 9 months for the patients at this dose that were currently testing of 5.4.

You can see responses on patients that had prior therapy and patients that did not have prior therapy. Just to show the data that these agents are active for patients that you may not have treated if they have stable brain metastases.

[00:47:59]

DESTINY-Lung02 Final Analysis: Safety Summary

The DESTINY-Lung02 final analysis looked at the safety, another one to shift gears. Now that we know that this drug works and it works in the brain, why do we have to deal with in terms of toxicity for our patients. Like Matt mentioned, this is delivering chemotherapy in a more targeted way to cancer cells. So we are going to see some of the toxicities of the drug related to the chemotherapy that is being delivered.

When we look on the right, some of the T-DXd toxicities that have to do with nausea, neutropenia, fatigue, these are toxicities related to the payload. Those were seen 65% of the time. We have to give patients antiemetics from the get go. In the case, we discussed with a patient that required dose reduction for significant nausea.

Grade 3 or greater hematologic toxicity was less than other agents we use. But there are patients that experience neutropenia, anemia and thrombocytopenia. This is given every 3 weeks. You have to monitor patients and may have to adjust doses.

Any grade toxicity was seen 98% of the time because there are other things that patients reported, including fatigue, but leading to drug interruption 30% of the time, dose reduction 18% of the time, but discontinuation was only 14%. Most of our patients that are on these drugs are able to stay on drug with some adjustment of the dose.

The first time you encounter a toxicity, you do not have to move to the next drug, while we have been able to manage patients now for the last 3 years since these drugs have been approved doing dose modifications and managing toxicities.

[00:49:36]

DESTINY-Lung02 Final Analysis: Adjudicated Drug-Related ILD/Pneumonitis

Now I think one of the most critical toxicities that we all have to learn to manage, and if you have used this agent in breast cancer or gastric cancer, you have had probably some experience as well. But in lung cancer, ILD toxicity is critical not only because our patients are already short of breath at baseline, but we are also delivering a drug to a tumor that is right there on the lung.

Matt talked about the bystander effect of these drugs that not only are you delivering this payload to a tumor, but cells around that tumor that are healthy in the lung may get that. That is why ILD in lung cancer, it is important to recognize and address early so that patients can hopefully stay on treatment or that they do not suffer any significant side effects.

Most of the toxicity related to the lung at the 5.4 dose, which is what the FDA has approved, is low. The grade 1 was 4%. The grade 2 ILD, 8.9%.

Those are either patients that have an imaging abnormality that many times gets missed or treated as an atypical infection, or some shortness of breath that does not require significant intervention, does not affect their significant activities of daily living, around 8.9%.

The grade 3 serious ILD toxicities, these lows were only rated at 1%. But these are patients on a clinical trial that have teams of people that recognize these symptoms and are learning to use this faster. It is important that you recognize that.

One thing that I want to highlight here before we move on is that patients that have prior immunotherapy may be more at risk. Patients that had immunotherapy in the last 3 months before they got T-DXd had ILD 20% of the time here as opposed to more than 3 months. Just take that into consideration when you think of patients that have ILD.

Patients without any prior PD-L1 exposure that had ILD were 14%. You can get ILD even if you have not had immunotherapy.

[00:51:40]

DESTINY-PanTumor02: Confirmed ORR

Now the PanTumor02-DESTINY data is really what got the HER2 overexpression approval as a tumor-agnostic biomarker. We saw this PanTumor trial that included other tumor types that are HER2 overexpression, endometrial, cervical, ovarian, bladder. These are tumors that are big area of needs that after platinum-based chemotherapy they did not have options. We found that the IHC 3+ was the one that had the highest response, especially in endometrial at 85%. Really exciting that we have a tumor-agnostic approval for HER2 overexpression.

[00:52:17]

Phase II DESTINY-Lung05 Trial: Response and Survival

Then, in the Lung05 data, we saw that the best overall response rate was also very good. When you use IHC as the marker with responses of 56%, there were also some complete responses and partial responses. The IHC overexpression of HER2 really gives us a potential target for these patients.