A Practical Framework for Clinical Integration of ADCs Into Individualized Treatment Plans for Patients With NSCLC

Let us start with our discussion about HER2.

[00:08:21]

ErbB Family of Receptor Tyrosine Kinase

ErbB is a family of receptor tyrosine kinases, and we have 4 members of this family of receptor tyrosine kinases. We have EGFR, which is the epidermal growth factor receptor. Then we have ErbB2 or HER2, and then ErbB3 or HER3, and ErbB4 or HER4. The typical receptor tyrosine kinases have an extracellular ligand binding region, single membrane spanning region, and then a cytoplasmic tyrosine kinase containing domain. The ligand binding initiates homo or heterodimerization and activation of this cytoplasmic kinase domain and phosphorylates tyrosines in the tail of each receptor.

The specific signaling for each member can differ. For example, with ERBB3, it has impaired kinase activity, and it is activated only upon dimerization with another receptor, whereas ERBB2 or HER2 binds any of the ErbB ligands and is activated via heterodimerization with other ligand bound receptors. Why this is relevant is how we can target this and use these as potential therapeutic strategies for patients.

[00:09:33]

What Is “HER2+” Lung Cancer?

HER2+ lung cancer is seen in non-small-cell lung cancer as well as in other solid tumors, as is shown on the right. In non-small-cell lung cancer, the mutations are seen in about 1% to 5% that you can see here in this table. So you identified the HER2 mutation in NGS, either in the tissue or in the liquid biopsy. The most common HER2 mutations in lung cancer are in the tyrosine kinase domain. These are HER2 mutations exon 20 insertions. The YVMA is the most common one.

You can also see other less common mutations that are actionable, including the ones cited here and others that are not on the kinase domain. Contrary to breast and gastric cancers, overexpression does not always co-occur with amplification. We will talk about this as well, but we can also identify protein overexpression by IHC or immunohistochemistry in 59% of cases of non-small-cell lung cancer.

We can see IHC 2+ and 3+ in about 15% to 30%, and we can see IHC see 3+ plus in 2% to 6%. Importantly, we will talk about that because both HER2 mutations can be an actionable target as well as the HER2 overexpression IHC 3+. Amplification identified by FISH is seen in 2% to 6% of cases. This is not yet actionable. However, we do see amplification as a potential mechanism of resistance as well in other solid tumors with actionable driver mutations.

[00:11:16]

Past Efforts to Target HER2-Altered NSCLC

There have been multiple past efforts to target HER2-altered non-small-cell lung cancer, and here targeting HER2 mutations in the past. We tried TKIs or tyrosine kinase inhibitors, many of the ones that you see, like dacomitinib and neratinib and afatinib were actually pan-TKIs that also targeted HER2 mutations. These are small studies, but what you can see here is that there is very modest efficacy with these pan-TKIs, or TKIs that also hit EGFR wild-type, leading to significant toxicities.

We also explored the use of antibody drug conjugates like T-DM1 targeting HER2. As you can see here in small studies, T-DM1 in a small number of patients, you can see that there was an efficacy signal there with response rates in the 40% range. This still is included in the NCCN guidelines.

Additionally, T-DM1 has been explored for HER2 amplification and then trastuzumab/pertuzumab for HER2 amplifications are overexpressed but these have not been approved by the FDA.

Really, I think these studies were very important for us to understand that HER2-altered non-small-cell lung cancer was, in fact, a subtype of lung cancer with a target. However, we still had not found the drug to target HER2 alterations.

[00:12:49]
Trastuzumab Deruxtecan HER2-Targeted ADC

Trastuzumab deruxtecan is a HER2-targeted antibody drug conjugate. As you can see here, the trastuzumab deruxtecan has the payload which is a topo 1 inhibitor. It has an IgG1 anti-HER2 monoclonal antibody with a tetrapeptide-based linker with a tumor-selectable cleavable linker.

The DXd payload has a short systemic half-life and also leads to bystander killing effect. Trastuzumab deruxtecan has been approved in multiple tumor types, as is shown on the right, including HER2+ metastatic breast cancer, HER2 low metastatic breast cancer, HER2+ gastric/GE junction adenocarcinoma, HER2-mutated non-small-cell lung cancer, and then in a tumor-agnostic approval for advanced solid tumors with HER2 IHC 3+ with prior therapies.

[00:13:51]

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

Let us review the data for T-DXd in HER2-mutated non-small-cell lung cancer to begin with. This was the DESTINY-Lung01 trial, an international, open-label, multicohort, phase II trial that included patients with unresectable metastatic nonsquamous non-small-cell lung cancer. Here I am going to focus first on the cohort of patients with HER2 mutations.

The primary endpoint was overall response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and then disease control rate and safety.

As you can see here in DESTINY-Lung01, 2 doses were used both T-DXd at 6.4 as well as 5.4 mg/kg.

[00:14:36]

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

What we saw in DESTINY-Lung01 was significant activity of T-DXd in patients with previously treated HER2-mutated non-small-cell lung cancer. We saw responses observed across HER2 mutation subtypes, and the overall response rate here was 54.9%.

On the right in blue, what you are seeing is the kinase domain mutations, which are the most common ones. We also saw activity of T-DXd in patients with extracellular domain mutations. Importantly, the median PFS was 8.2 months and the median overall survival of 17.8 months in this heavily pretreated population.

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DESTINY-Lung 02: Trastuzumab Deruxtecan in HER2-Mutated NSCLC

There was then the subsequent study DESTINY-Lung02, looking at dose optimization of trastuzumab deruxtecan in patients with HER2-mutated non-small-cell lung cancer with 1 or more previous anti-cancer treatment, including platinum-based chemotherapy, measurable disease, stable brain mets permitted at baseline, and good performance status.

152 patients were randomized 2:1 to T-DXd at 5.4 mg/kg every 3 weeks, and T-DXd 6.4 mg/kg IV every 3 weeks, with a primary endpoint here of overall response rate.

[00:15:55]

DESTINY-Lung02: Response by BICR

What we saw in this study is that T-DXd at 5.4 mg/kg led to a response rate of 50% and at 6.4 mg/kg, 56%. Median overall survival of 19 months and 17.3 months, respectively. Median duration of response of 12.6 months and 12.2 months, respectively, and a median PFS of 10 and 12.9 months, respectively, with a follow up of approximately 16 months. In this study, T-DXd showed strong and durable responses.

[00:16:28]

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

We also saw a pooled analysis that was exploratory in nature of both DESTINY-Lung01 and Lung02. As we previously mentioned, these patients had stable treated brain metastases, but we did see in both cohorts of 5.4 and 6.4 that there was a reduction in brain lesion size in both cohorts. 85% experienced reduction in brain lesion size at the 5.4, and 78% experienced reduction in brain lesion size at the 6.4 mg/kg.

The intracranial overall response rate in patients with prior brain metastasis treatment in 32 patients was 25% at the 5.4, and at the 6.4 was 18.5%. Showing here some durability of that response, with the median intracranial duration of response of 9.2 months in the 5.4 and 4.4 months in the 6.4 mg/kg, suggesting here activity of T-DXd in patients with previously treated brain metastases.

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Trastuzumab Deruxtecan: Tumor-Agnostic Approval

T-DXd also received a tumor agnostic approval, and this was based on the pool analysis of patients in the DESTINY-PanTumor02, the DESTINY-Lung01, as well as the DESTINY-ColorectalStudy02.

What we are seeing here in this pooled analysis of 192 patients is activity of T-DXd in patients with metastatic HER2+ identified via IHC or immunohistochemistry 3+. The response rate in the DESTINY-PanTumor02 trial was 51.4%; in the Lung01, 52.9%; and in the DESTINY-CRC02, 46.9%. This data led to the approval of T-DXd in this patient population in patients previously treated.

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DESTINY-Lung03: Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC

To further explore the activity of trastuzumab deruxtecan in HER2-overexpressing non-small-cell lung cancer, DESTINY-Lung03 is an international, open-label, phase Ib study evaluating T-DXd combinations in patients with unresectable locally advanced nonsquamous, non-small-cell lung cancer with HER2-overexpression IHC 3+ and 2+ and good performance status.

As you can see here, the part 1 dose escalation with enrollment complete investigating T-DXd plus durvalumab plus platinum. Then in the part 1, the T-DXd monotherapy, and then also there is a dose confirmation expansion looking at T-DXd with volrustomig which is a bispecific CTLA-4 PD-1 antibody plus/minus carboplatin.

Then the last 1 in part 4 is with rilve, which is another bispecific targeting PD-1 and anti-TIGIT. The key secondary endpoints here are investigator-assessed overall response rate, duration of response, disease control rate, progression-free survival, and overall survival.

[00:19:24]

DESTINY-Lung03: Efficacy of T-DXd Monotherapy in HER2-Overexpressing NSCLC (Arm 1D)

In DESTINY-Lung03, the efficacy of T-DXd monotherapy was seen in patients with HER2-overexpressing non-small-cell lung cancer. As you can see here, the overall response rate in patients with HER2 IHC 3+ was 56%, in HER2 IHC 2+, 35%. They also had patients at a prior EGFR TKI with a response rate of 68% in about 13 patients, and in patients with no prior EGFR TKI of 17.6%. Again, as you see here, overall survival in all of the cohorts looks very favorable.

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

Thinking about managing side effects of T-DXd. The most common side effects that are seen include fatigue seen in 45% to 53%, neutropenia in 35% to 43%, nausea vomiting, and then important additional ones include alopecia, anemia, diarrhea, constipation.

ILD/pneumonitis is definitely a side effect, especially in lung cancer, that we worry about. We saw rates at 13% of any grade, although the rates of grade 3 or higher are lower. I think it is important to note that based on the development of T-DXd, the dose of 5.4 mg/kg was the 1 chosen for approval based on the activity and lower rates of toxicity. 5.4 mg/kg is the dose to be used.

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DESTINY-Lung02: Safety Summary With T-DXd

Here is the safety summary with T-DXd and DESTINY-Lung02. Again, as we were talking about the most common side effects are shown at the bottom of any grade with nausea, neutropenia, fatigue, decreased appetite, and anemia. A lot of these are related to the payload or the cytotoxic payload with grade 3 or higher adverse events of lower grade or lower rates. 18% grades of neutropenia but low rates of febrile neutropenia.

Grade 3 or higher adverse events were lower in the 5.4 compared to the 6.4 as shown at the top, 38.6% and 58%, respectively. Then rates associated with discontinuation for the 5.4%, 13.9%, and 20%. Then dose reduction 16% and 32%.

Rates associated with death, 1% and 2%. So 1 death on each cohort and both deaths were associated with drug-related treatment-emergent adverse events due to adjudicated drug-related ILD.

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DESTINY-Lung02: Adjudicated T-DXd-Related ILD

In terms of any grade ILD, we are seeing here 12.9% in the 5.4, and then 28% in the 6.4. When you think about the grade 3 or higher adverse events, we are seeing lower rates here. Grade 3 events, 1% in the 5.4, 0% and the 6.4, and then grade 4, 0%. As noted, 2 deaths occurred, 1 in each cohort.

Of note, 84% of the patients received steroids in the 5.4. 71% in the 6.4 mg/kg. There was no recurrence of ILD or pneumonitis observed in 2 patients with grade 1 events who were then retreated with T-DXd.

[00:22:44]

Management of ILD Associated With T-DXd

It is important that we look for any signs of ILD associated with T-DXd during treatment. The most important thing is to monitor for symptoms that could be associated with ILD, such as shortness of breath, dry cough, chest discomfort, and fatigue, and certainly having a low threshold to investigate these symptoms with high resolution CT scans to look for any evidence of suspected ILD or pneumonitis. As needed, to also consult pulmonology and make sure that we rule out infection.

For patients with grade 1 ILD, which means that this is a patient who is asymptomatic and who we find findings on imaging of ILD, the recommendation is to hold T-DXd until resolution to grade 0. If the AE resolves within 28 days or less, you can resume at the same dose of T-DXd. If it takes greater to resolve of 28 days, you can resume with a reduced dose of T-DXd and consider corticosteroid treatment, according to clinical judgment.

For patients now with grade 2, which is limiting instrumental ADL, or grade 3 that have severe symptoms or requiring oxygen, you should discontinue T-DXd and initiate corticosteroid treatment. For all grades, providing best supportive care with oxygen supplementation for hypoxia, supportive treatment if prolonged corticosteroid is used, and importantly, multidisciplinary evaluation, having pulmonology on board as clinically appropriate.

[00:24:23]

Management of Hematologic AEs Associated With T-DXd

Other important side effects to manage include neutropenia and thrombocytopenia. Again, I think this is pretty consistent with what we do for other agents that have myelotoxicity for grade 3 or 4 or febrile neutropenia, certainly holding T-DXd until resolution. Then for grade 4, you have to dose reduce when you resume it, as well as for febrile neutropenia.

[00:24:49]

Management of LVEF Associated With T-DXd

Left ventricular dysfunction has been seen with T-DXd. In terms of rates of left ventricular ejection fraction decrease in the trials with non-small-cell lung cancer is less than 5% and grade 3 or higher, LVEF decrease is actually quite rare at 0.6%. However, monitoring is recommended. If the LVEF is greater than 45% and there is an absolute decrease from baseline by 10% to 20%, you should continue T-DXd. If the absolute decrease from baseline is less than 10%, you can continue and repeat it within 3 weeks.

For patients who have an EF of 40% to 45% and an absolute decrease from baseline is 10% to 20%, recommendation is to hold, repeat the LVEF assessment within 3 weeks. If it recovers to within 10% from baseline, you can resume at the same dose. If it does not recover within 10%, permanently discontinue. Again, if it is less than 40% with an absolute decrease from baseline of greater than 20% decrease, you are supposed to hold the T-DXd, repeat assessment within 3 weeks; and if the LVEF results are confirmed, permanently discontinue T-DXd.

Then certainly if patients are symptomatic and develop heart failure, permanently discontinue T-DXd. Thankfully, the rates of severe events are actually quite rare, but I think the main recommendation here is for patients on T-DXd. It is important to do a baseline LVEF ejection fraction, and to monitor during treatment and to follow the prescribing information management recommendations.

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Key Learning Points

The NCCN guidelines recommend complete genotyping for HER2 in all patients with non-small-cell lung cancer. I think, both liquid biopsy and tissue NGS are options that we have in clinical practice. For patients with HER2 alterations, we have 2 targets: HER2 mutation with approval of T-DXd for HER2 mutations, and then HER2 3+ overexpression identified on immunohistochemistry.

Really important when you are getting your tissue NGS, because you cannot identify overexpression on liquid biopsy, you have to request immunohistochemistry for HER2 overexpression.

In addition, just to summarize, T-DXd has robust and durable anti-cancer activity in patients previously treated with HER2-mutant metastatic non-small-cell lung cancer based on the results of DESTINY-Lung02 with response rates of 50%. Using T-DXd at the select dose of 5.4 mg/kg and ILD/pneumonitis remains an important identified risk. Really important to identify this early and manage so that patients are not at risk for high grade ILD and pneumonitis.

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EGFR

Let us move on to EGFR.

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Treatment Sequencing in EGFRm Lung Cancer

A lot of excitement with new approvals for patients with EGFR-mutated non-small-cell lung cancer. Here focusing mainly on exon 19 deletion and L858R. In terms of risk stratification and whether or not to intensify treatment or use combinations upfront, we are looking for certain patient characteristics and potential biomarkers. For example, patients with comorbidities, patients who have low burden of disease or slow growing cancers, no comorbidities or have brain mets. This may help you decide what therapeutic option you might employ in the front line.

Then high-risk factors, definitely high burden of disease, symptomatic brain mets, ctDNA positive at baseline, not clearing the ctDNA, and then L858R and presence of p53 or RB1 loss can be high risk factors for patients at initial diagnosis.

As you can see by the red line, we have increasing toxicity as we combine treatment strategies for patients. In frontline, depending on what we use in frontline, that will certainly change the decision of second and third-line options.

With osimertinib monotherapy in the front-line based on the FLAURA data, the median PFS is 18.9 months. When you combine osimertinib with chemotherapy with carboplatin/pemetrexed based on the FLAURA2 data, the median PFS is 25.5 months. We just saw the press release that showed that the FLAURA2 regimen led to an improved overall survival.

Then amivantamab plus Lazertinib, we will talk about these 2 as well. Amivantamab is an EGFR-MET bispecific and lazertinib is an EGFR TKI. Based on the MARIPOSA data, a median PFS of 23.7 months and also demonstrating improved overall survival. Depending which choice you make in the front line, that will certainly change your options for second or third line. We do have the option now also of using ADCs either in second or third line depending on what we use in front line with approval of datopotamab deruxtecan in patients previously treated.

[00:30:07]

ADCs Targeting HER3

Let us talk about ADCs targeting HER3. Here is patritumab deruxtecan. This is an anti-HER3 antibody drug conjugate. We also have other ADCs that are targeting EGFR and HER3 such as BL-01D1. Then on the left, you are seeing multiple anti-HER3 antibodies that are also in development targeting HER3.

[00:30:34]

Patritumab Deruxtecan (HER3-DXd): Novel HER3-Targeted ADC

Patritumab deruxtecan specifically is a HER3-DXd. Again, here we have a human IgG1 anti-HER3 monoclonal antibody with a tetrapeptide-based linker and a tumor selectable cleavable linker, and a DXd payload with a topo 1 inhibitor.

HER3-DXd was demonstrated to have encouraging anti-tumor activity and manageable adverse events and previously treated advanced EGFR mutant non-small-cell lung cancer across multiple EGFR TKI mechanisms of resistance in the HERTHENA-Lung01 phase II trial.

[00:31:10]

HERTHENA-Lung01: Phase II Study of Patritumab Deruxtecan in EGFRm NSCLC

Here is the HERTHENA-Lung01 phase II trial of patritumab deruxtecan EGFR-mutated non-small-cell lung cancer. This was an international, open-label, randomized phase II trial that included patients with EGFR-mutated non-small-cell lung cancer with progression on most recent systemic therapy prior to treatment with an EGFR, TKI, as well as platinum-based chemotherapy. There was an amendment that actually changed the requirement to having had prior osimertinib.

In this study, patients received HER3-DXd at 5.6 mg/kg IV every 3 weeks, and the primary endpoint was overall response rate.

[00:31:51]

HERTHENA-Lung01: Antitumor Activity Across EGFR To Resistance Mechanisms

What it showed was that patritumab deruxtecan in this patient population showed a response rate of about 30%, and this activity was seen across different types of resistance mechanisms observed in the study.

[00:32:07]

HERTHENA-Lung02: Ongoing Phase III Study of Patritumab Deruxtecan in EGFRm NSCLC

This led to then the randomized phase III study, the HERTHENA-Lung02, which was international, open-label, randomized phase III study that included patients with nonsquamous non-small-cell lung cancer with EGFR activating mutations in exon 19 deletion, or L858R, with 1 to 2 prior lines of EGFR TKI treatment, including progression after third generation EGFR TKI.

In this study, patients were randomized 1:1 to patritumab deruxtecan at 5.6 mg/kg IV every 3 weeks, or platinum-based chemotherapy with the primary endpoint of progression-free survival.

This study was presented at ASCO 2025, and it did meet the primary endpoint of progression-free survival, but not overall survival. The biologic license application was withdrawn by Merck, and actually patritumab deruxtecan is not commercially available and was not FDA approved.

[00:33:02]

TROP-2 as Therapeutic Target

Another important target is TROP-2. TROP-2 is a transmembrane glycoprotein overexpressed in solid tumors, including non-small-cell lung cancer, and has been associated with the worst outcomes. TROP-2 is an epithelial adhesion molecule and regulates stem cell marker associated with cellular regeneration.

[00:33:22]

TROP-2 Overexpression in NSCLC and Other Cancers

As stated, TROP-2 is overexpressed in non-small-cell lung and other cancers. It is seen in 64% of adenocarcinomas and 75% of squamous cell carcinomas.

[00:33:34]

Datopotamab Deruxtecan (DS-1062; Dato-DXd): TROP-2-Directed ADC

Datopotamab deruxtecan is a TROP2-directed ADC. It has a humanized anti TROP2 IgG1 monoclonal antibody attached to a topo 1 inhibitor payload.

[00:33:49]

TROPION-Lung01: Dato-DXd vs Docetaxel in Previously Treated Advanced NSCLC With or Without AGAs

Dato-DXd was investigated in the TROPION-Lung01 trial. This was a randomized phase III trial comparing datopotamab deruxtecan vs docetaxel in patients with previously treated advanced non-small-cell lung cancer with no prior docetaxel. As you can see here, patients received dato-DXd at 6 mg/kg IV every 3 weeks compared to docetaxel at the standard dose.

In this study, about 80% of the patients had nonsquamous histology, and there was a subset of patients here that had EGFR mutations. 13% in the dato-DXd arm and then 23% in the patients in the docetaxel arm. Co-primary endpoints were progression-free survival and overall survival.

[00:34:35]

TROPION-Lung01: PFS in ITT Population

TROPION-Lung01 met the primary endpoint of progression-free survival with a modest improvement in the median progression-free survival from 3.7 months in docetaxel arm vs 4.4 months in the dato-DXd arm with a hazard ratio of 0.75. The overall response rate was also improved in dato-DXd vs docetaxel, and there was also a slight improvement in the duration of response with dato-DXd.

[00:35:00]

TROPION-Lung01: PFS by Histology

When we looked at the benefit across histologies, the hazard ratio for the nonsquamous population was 0.63. The majority of the benefit was here being derived by the nonsquamous population. Importantly, the hazard ratio for the PFS for the nonsquamous without actual genomic alteration was 0.71.

[00:35:24]

TROPION-Lung01: OS in ITT Population

There was no statistical significance in terms of the overall survival in the intent-to-treat population. The hazard ratio is 0.94.

[00:35:33]

TROPION-Lung01: Safety   

In terms of the safety, overall, what was seen here is all grades dato-DXd was 87.5% and docetaxel 86.9%. There were lower rates of grade 3 or higher adverse events in the dato-DXd of 25.6% vs 42% with docetaxel.

The number of dose reductions and dose delays are shown here. 20% with dato-DXd, 29% with docetaxel, and associated with dose delays 17% and 12%, respectively.

Lower rates associated with discontinuation under dato-DXd of 8.1% and 12.1%. In terms of the most common side effects associated with dato-DXd shown on the right of any grade, as you can see here, stomatitis 47.5%, nausea, diarrhea, fatigue, decreased appetite, alopecia, and also anemia is also shown at the top.

8.8% any grade of ILD or pneumonitis, the rates of grade 3 are higher ILD or pneumonitis are low at 3.7%. The investigator-assessed causes of death: dato-DXd, there were 2 patients with ILD or pneumonitis, 1 patient with sepsis; and with docetaxel, 1 patient with ILD/pneumonitis, and 1 patient with septic shock.

[00:36:55]

TROPION-Lung01: AEs of Special Interest

AEs of special interest related to datopotamab deruxtecan include:

• Stomatitis;
• Ocular events; and
• ILD.

As stated, the majority of the events are any grade. The grade 3 or higher stomatitis or oral mucositis was 6%. Ocular events grade 3 or higher, 2%; and then ILD grade 3 or higher 3.7% with 2 grade 5 events seen on the study.

The discontinuation rates due to dato-DXd associated stomatitis or oral mucositis were low at 0.7% and the grade 5 ILDs, the 4 primary causes of death were ruled by PD by the investigator.

We also monitor for injection infusion-related reactions, which were 8% in each arm, and the most common ocular events are dry eyes and increased lacrimation.

[00:37:48]

Phase II TROPION-Lung05: Dato-DXd in Previously Treated Advanced NSCLC With AGAs

The phase II TROPION-Lung05 investigated dato-DXd and previously treated advanced non-small-cell lung cancer with AGAs or actionable genomic alterations. What you are seeing here is the breakdown by the most common AGAs or actionable genomic alterations. The confirmed response rate of dato-DXd in patients with EGFR mutations with 43% and with ALK 23.5%.

Importantly, what you are seeing here is that the median PFS in all patients was 5.8 and 4.3 months, with a median duration of response of 7 months. Some patients achieve durable responses with the use of dato-DXd.

Among 68 patients with EGFR sensitizing, or T790M mutations, the response rate was 49% among those with prior osimertinib treatment.

[00:38:36]

TROPION-Lung05: Intracranial Efficacy of Dato-DXd in Previously Treated Advanced NSCLC With AGAs

We also saw the report of intracranial efficacy of dato-DXd in previously treated advanced non-small-cell lung cancer with actionable genomic alterations. This was a post-hoc analysis of the intracranial efficacy of data-DXd from TROPION-Lung05 and it included patients with brain mets that were either untreated and asymptomatic or treated in symptomatic. All patients had baseline brain imaging at baseline, and further imaging was done as clinically indicated.

What is shown here is that responses were seen in the CNS in these patients and the median PFS by baseline brain met status for patients with baseline brain mets was 5.4. Then without baseline brain metastases was 5.6, suggesting that patients benefited regardless or not whether they had brain mets at baseline.

[00:39:26]

Pooled Analysis of TROPION-Lung01 and TROPION-Lung05

This is a pooled analysis of the TROPION-Lung01 and the TROPION-Lung05 data focusing here on the EGFR-mutated population of patients. We have an N of 117 patients total with 96 receiving prior osimertinib and response rate of 42.7% and 44%, respectively. The median duration of response of approximately 7 months, and then a median PFS of 5.8 months.

The median overall survival of 15.6 months and is shown here on the right just to highlight that landmark analysis of PFS and OS. This data actually led to the approval of datopotamab deruxtecan in patients with EGFR-mutated non-small-cell lung cancer previously treated.

[00:40:11]

Sacituzumab Tirumotecan

Another agent in development is sacituzumab tirumotecan. This is another TROP-2 ADC which also is a topo 1 inhibitor cytotoxic payload.

[00:40:26]

OptiTROP-Lung03: Sac-TMT vs Docetaxel in EGFRm NSCLC

This is the OptiTROP-Lung03, sac-TMT vs docetaxel and EGFR mutated non-small-cell lung cancer. This was a randomized phase II trial of sac-TMT at 5 mg/kg IV every 2 weeks vs docetaxel with the primary endpoint of overall response rate.

[00:40:44]

OptiTROP-Lung03: Responses

What it showed was the response rates of 45% with sac-TMT that you are seeing on the right and 15.6% with docetaxel. It also showed improved disease control rates of 82.4% vs 60%, respectively. Then the duration of response of 7 months vs 5.1 months.

[00:41:07]

OptiTROP-Lung03: PFS and OS

In terms of the median progression-free survival in the sac-TMT arm, 6.9 months vs docetaxel 2.8 months. Sac-TMT was associated with significant improvement in progression-free survival, and it was also associated with significant improvement in overall survival. The median overall survival was not reached in both arms. Hazard ratio was 0.49, so 51% reduced risk of death vs docetaxel at this interim analysis.

[00:41:36]

OptiTROP-Lung03: Safety

Here is the safety of OptiTROP-Lung03. All grade events were 97% in both arms with lower rates of grade 3 or higher adverse events with sac-TMT. Then here leading to dose reduction, 31.9% and 43.5%, respectively. And leading to dose discontinuation, as you can see here with sac-TMT 0% vs 2.2%.

Again, the most common adverse events that are shown include myelosuppression, stomatitis, alopecia, asthenia, weight decreased. There were zero rates of febrile neutropenia. There is 1% grade 3 or higher pneumonia noted here.

[00:42:22]

c-MET

This actually led to approval of sac-TMT in Asia, in China.

[00:42:28]

Temab-A: A Novel Anti-c-Met Antibody-Drug Conjugate

Our next agent is temab-A, which is a novel anti-c-Met antibody drug conjugate. c-Met protein expression promotes tumor progression and metastasis. In a phase I study of temab-A in patients with advanced solid tumors who had progression on standard treatment is currently ongoing. In this study, the dose expansion has shown that this agent has a manageable safety profile and efficacy in patients with nonsquamous EGFR wild-type. Responses are seen across a wide range of c-Met expression. Again another ADC here. Now the target is c-Met with a topo 1 payload.

[00:43:04]

Phase I Trial of Temab-A: Safety (EGFRm NSCLC Cohort)

This is the phase I trial investigating here 2 doses of temab-A, ABBV-400 at 2.4 or 3 mg/kg.

The most common treatment-emergent adverse events were GI and hematologic in nature and treatment-emergent adverse events included ILD or pneumonitis, alopecia, and stomatitis. There were 12% or 5 patients that experienced fatal to treatment-emergent adverse events, and 1 death due to pneumonitis.

58% of the patients who reported anemia did not require transfusions, and 47% of the patients who had neutropenia did not require growth factors. Again, speaking to the grade 3 or higher adverse events, the rates of the hematologic events grade or higher you are seeing here, 51%, but the non-hematologic, the grade 3 or higher adverse events are low rate in nature.

[00:44:00]

Phase I Trial of Temab-A: Postbaseline Data

This is post-baseline data to show that in this patient population in this study the responses were observed across all levels of MET expression and were also observed regardless of the presence of EGFR, L858R, exon 19 or TKI resistance mutations including T790M or C797X.

[00:44:23]

LUMINOSITY: Telisotuzumab Vedotin For Advanced NSCLC With High c-MET Expression

Another study to highlight another met ADC is luminosity investigating telisotuzumab which is a met ADC in patients with advanced non-small-cell lung cancer with high c-Met expression. In this study, this was a multicenter, open label, multicohort study, as you can see here investigating the use of telisotuzumab vedotin in the squamous cell population, the nonsquamous EGFR mutant population, as well as the nonsquamous EGFR wild-type.

To just highlight this study, we saw efficacy in patients with c-high Met expression in the nonsquamous EGFR wild-type population, which has led to the FDA approval of telisotuzumab vedotin for these patients.

[00:45:06]

LUMINOSITY: PFS of EGFR WT NSCLC With Various Levels of c-Met Protein Expression

Here is the PFS of the EGFR wild-type non-small-cell lung cancer with various levels of c-Met expression. As you can see here, the probability of overall survival here for the nonsquamous EGFR wild-type non-small-cell lung cancer with high c-Met expression, the median here is 14.6 months, for the patients with intermediate 14.2 months, and for the wild-type, the total population 14.5 months.

[00:45:37]

Other Select Investigational ADCs for NSCLC

Other agents that are currently in development and are being investigated are SHR-A2009, which targets HER3. The response rates to date have been about 30%, and then the other agent I will call it iza EGFR/HER3 ADC. That is also being investigated not only in patients with EGFR-mutant disease, with a response rate of 67.5%, but also in the wild-type population with response rate of 40.3%.

[00:46:08]

ADC TRAE Management

Let us talk about ADCs and management.

[00:46:11]

TROPION-PanTumor01 Substudy: Prophylactic Mouthwash for Mucositis/Stomatitis

I think really important as we think about these adverse events of special interest. TROPION-PanTumor01, there was a sub-study investigating how to manage the mucositis or stomatitis. This was a sub-study of the phase I dose expansion that included patients that were enrolling on ongoing and new cohorts on the dose expansion. 76 patients were included, and they were randomized to receive prophylactic steroid mouthwash or prophylactic non-steroidal mouthwash.

After 8 weeks, to evaluate for the incidence and severity of mucositis or stomatitis in the mouthwash can be extended for an additional 8 weeks at the discretion of the investigator.

[00:46:51]

Management of Stomatitis / Mucositis Associated With Datopotamab Deruxtecan

Again, when patients are on ADC specific here, thinking about datopotamab deruxtecan or TROP2 ADC to watch out for any early signs of mucositis. The lips and mucosa can appear redder than usual. There can be visible sores on the oral mucosa, mouth pain, which can affect chewing and swallowing, and certainly changes in the ability to taste.

For patients who have grade 1 mucositis or stomatitis, that means they are asymptomatic or have mild symptoms. The recommendation is to maintain the dose and optimize the prophylactic and supportive medication.

For patients that have grade 2 mucositis or stomatitis, which is moderate pain or ulceration, should delay the dose until resolution to grade 1 or less, resume at the same dose, and if recurrent, reduce dose level upon restart and certainly continue to optimize prophylactic and supportive medication. For patients with grade 3, which means severe pain, ulceration and interfering with oral intake, delay the dose until resolve to grade 1 or less and resume at a reduced dose. Then grade 4, oral intake not possible, life-threatening consequences, permanently discontinue drug.

In all levels, make sure that you optimize to provide pain relief. Viscous lidocaine rinses can also be used to help with that.

[00:48:10]

Supportive Care and Management of Stomatitis/Mucositis

Other important things to educate our patients about are to avoid spicy or highly acidic foods and beverages. Consider a soft or liquid diet. Use artificial saliva, topical anesthetics such as viscous lidocaine, mouth rinses with salt and baking soda, compound rinses, and then oral liquid dexamethasone mouth rinses.

[00:48:33]

Management of Ocular Surface Toxicities Associated With Datopotamab Deruxtecan

For management of ocular toxicities associated with datopotamab deruxtecan, really important to have an assessment at baseline of the visual health or eye health. Make sure to ask patients about dry eyes, eye redness, stinging, burning or scratchy sensation, sensation of having something in the eye, sensitivity to light or blurred vision, and also to look out for keratitis, which could be eye pain, excess tears, or discharge from the eyes, difficulty opening the eyelid to pain or irritation and decreased vision.

For patients who have grade 1 or asymptomatic, maintain the dose and consider ophthalmology assessment and follow up. For grade 2, meaning they are symptomatic with moderate decrease in visual acuity, obtain ophthalmology assessment, delay the dose until resolved to grade 1 or less, and maintain the dose.

For grade 3 or higher, certainly obtain ophthalmology assessment. You have to delay until resolve to grade 1 or less. For grade 3, you can then reduce by 1 dose level, but if grade 4, you have to discontinue the drug. Also make sure you ask your patients about use of contact lenses and avoid contact lenses if they are having ocular surface toxicities.

[00:49:46]

Management of Interstitial Lung Disease Associated With Datopotamab Deruxtecan

Now management of ILD associated with datopotamab deruxtecan. This also I think can be used for as we talked about trastuzumab deruxtecan as well, monitoring for shortness of breath, dry cough, chest discomfort and fatigue. Certainly, as we are doing follow-up scans monitoring for any changes in the CT scans.

For patients who are asymptomatic, and this is radiographic findings only, you can actually monitor symptoms and closely follow-up and consider oral prednisone and hold treatment until fully resolved, and consider dose reduction based on onset date.

For patients with symptomatic, you have to start oral prednisone or consider IV if no improvement after 5 days. For patients with grade 3, those patients need to be hospitalized, permanently discontinue dato-DXd, and they have to be started on high dose steroids, followed by a slow taper.

For all grades, I think it is really important to, number 1, make sure you consult a pulmonary, if needed to rule out infections. Sometimes it can be confusing. Oxygen supplementation for hypoxia that you are using supportive treatment for prolonged corticosteroid use.

[00:50:58]

Now let us go back to some of our questions.

[00:51:00]

Posttest 1

I know that was a lot of data. Exciting to see so much new data come about, including new approvals of ADCs for our patients with non-small-cell lung cancer. Let us go back to our posttest. Which investigational HER3-targeting ADC has shown durable anti-tumor response in a phase II trial that included patients with advanced EGFR-mutated non-small-cell lung cancer after previous treatment with an EGFR TKI and platinum-based chemotherapy?

A. Datopotamab deruxtecan; I hope you guys took notes. There were a lot of targets.

B. Patritumab deruxtecan;

C. Sacituzumab govitecan;

D. Sacituzumab tirumotecan;

E. Telisotuzumab vedotin;

Speaker: The poll is open. Five more seconds for incoming answers. All right. Thank you. We will close the poll. Share the results.

Dr Leal: The correct answer is patritumab deruxtecan. That is a HER3-ADC.

[00:52:20]

Posttest 1: Rationale 

Here is the rationale. In the HERTHENA-Lung01 trial, HER3-targeted ADC patritumab deruxtecan showed a response rate of 30% in patients with previously treated EGFR-mutated non-small-cell lung cancer who had prior TKI, as well as platinum chemotherapy. Although datopotamab deruxtecan did show response in patients with EGFR-mutated lung cancer, this is a TROP2 ADC.

[00:52:53]

Posttest 2

Let us go to our next question based on the guidelines. How would you manage grade 1 mucositis associated with datopotamab deruxtecan?

A. Consider dose reduction by one level if supportive medications are already optimized;

B. Delay dose until resolved to grade 1 or baseline;

C. Discontinue drug;

D. Maintain dose with best supportive care measures;

Speaker: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr Leal: 100%. Let us look at the rationale now.

[00:53:47]

Posttest 2: Rationale 

Great job. Option D is correct because with grade 1 mucositis, the recommendation is to maintain the dose with best supportive care measures. Make sure you are optimizing pain management and optimizing with mouthwash, and potentially the dexamethasone solution is needed. For grade 2 mucositis, that is when you should dose delay or dose reduction should be considered, especially persistent grade 2 mucositis. Great job guys on this one.

[00:54:16]

Posttest 3

Which of the following genomic alterations is actionable with an approved ADC and you would test for in your patients with metastatic non-small-cell lung cancer?

A. HER2-activating mutation;

B. TROP2-activating mutation;

C. HER3 overexpression;

D. TROP2 overexpression; and

E. HER3 mutation;

Speaker: Poll is open. Five more seconds. All right. Thank you. I will close the poll. Share the results.

Dr Leal: 67% said HER2-activating mutation. That is the correct one.

[00:55:19]

Posttest 3: Rationale 

HER3 overexpression is not a target. Only the HER2-activating mutations are associated with an FDA approved indication. You can identify HER2-activating mutations, both in liquid biopsy as well as in tissue NGS or next-generation sequencing. Trastuzumab deruxtecan is currently approved for second-line therapy for patients with the HER2 activating mutation and also patients that have HER2 3+ overexpression IHC. You have to make that special request when you submit the NGS to request IHC for HER2.

[00:55:57]

Patient Case: Patient With Advanced NSCLC

Let us go back to our case. Same patient with history of smoking with cough, weight loss, right upper quadrant pain. Diagnosed with advanced non-small-cell lung cancer adenocarcinoma with a HER2 exon 20 insertion mutation, PD-L1 of 60%, initially treated with frontline, platinum double immunotherapy, and then after an initial response lasting 6 months, now has progression in the liver. Maintains a good performance status, mildly elevated liver enzymes, and no other comorbidities.

[00:56:29]

Posttest 4

Which therapy would you recommend?

A. Afatinib;

B. Docetaxel and ramucirumab;

C. Immunotherapy and ramucirumab;

D. Sacituzumab govitecan;

E. Telisotuzumab vedotin;

F. Trastuzumab deruxtecan;

Speaker: Poll is open. Five more seconds for incoming answers. Thank you. We will close the poll and share the results.

Dr Leal: 75% said trastuzumab deruxtecan. That is the correct answer. Let us review that.

[00:57:27]

Posttest 4: Rationale 

Answer D is correct and that is based on the DESTINY-Lung01 and 02 trials and the FDA approval of trastuzumab deruxtecan for patients in second line after platinum chemotherapy therapy with a HER2 mutation. The response rates are higher. The PFS is higher. The overall survival is higher than what we would see with docetaxel ramucirumab. I would reserve docetaxel ramucirumab for third line, or if there was some significant contraindication to trastuzumab deruxtecan.

Telisotuzumab vedotin is approved by the FDA for patients with met expression, not HER2 mutation.

[00:58:08]

Poll

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

1. Yes;

2. No;

3. Uncertain;

Speaker: The poll is open. Please vote. Five more seconds. All right. Thank you. Close the poll and share the results.

Dr Leal: 71% said yes. Awesome.

[00:58:48]

Poll

Now please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education. You can scan the QR code or answer in the text in the box.

Speaker: Thank you. We will give you a couple of seconds to scan the QR code, and we will leave the poll up for a little longer so people can answer. All right, doctor, you can move ahead.

Dr Leal: I think we have a few minutes for questions.

[00:59:29]

Thank You For Attending Our Program!

Speaker: Yes. At this time, we are taking any questions that you may have for Dr Leal. Please enter those using the Q&A function, and while you have a chance to do so, I would like you to point out on the screen there are 2 QR codes, and there are also links in the chat panel. One will be to the downloadable slide deck from today's presentation, and the other will be to the program evaluation link that you will need to complete to claim your credit for attending today's program. You will need to log into or create a CCO account. Please claim your credit within 30 days as credit for today's program will expire after this time.

Dr Leal, there are a few questions. Are you able to see those? I will also be happy to read those out to you.

[01:00:11]

Q&A

Dr Leal: Let me end this slide show. Was there anything else you wanted to show?

Speaker: No, I do not think so. We will put those QR codes up again as well when we are finished as well.

Dr Leal: The first question is how do you manage access for patients eligible for tumor-agnostic ADCs like HER2, IHC 3+ without the classic histology?

For the patients with HER2 IHC 3+, this is actually a tumor-agnostic approval. Any tumor that has HER2 IHC 3+ that is a solid tumor is potentially eligible. Now for the patients that do not have the classic histology, it depends on what the other options are available for the patient.

I think I would still consider using it and have that discussion with the patient, even if they did not have a classic histology but had the biomarker.

How confident are you using ADCs in patients with active or treated brain metastasis? I am very confident. I think we have some indirect data for some of these ADCs of a signal of efficacy for patients with active or treated brain metastases. Certainly, I favor treating the brain metastasis in collaboration and consultation with the radiation oncologist, but I have seen responses in the brain. For patients that you are trying to avoid whole brain radiation, I would feel comfortable using an ADC like trastuzumab deruxtecan, with close monitoring and in collaboration and consultation with radiation oncology.

How do you identify and manage ILD early with trastuzumab deruxtecan or patritumab deruxtecan?

The ILD was mainly seen with trastuzumab deruxtecan and also datopotamab deruxtecan. I will say that in lung cancer we tend to have very low threshold to investigate symptoms. Again, that is the most important piece is symptoms, cough, shortness of breath, changes in the oxygen level are very important to investigate and make sure that this is not the early start of ILD and then frequent scans.

I think in the lung cancer field, we probably do more scans than perhaps somebody that is using it for breast cancer. I frequently do scans every 6 to 9 weeks in the beginning to make sure that patients are doing well, getting a response, and monitoring for ILD. I think it is using clinical judgment but close monitoring means symptoms. Then imaging, having a low threshold to investigate that with imaging.

I will say that sometimes it can be tricky especially with grade I pneumonitis. Somebody has already had radiation. I am going to keep a closer eye on how they are doing and what their symptoms are but also making sure that I investigate it fully and not just call it pneumonitis if a patient is benefiting. That is where you bring in multidisciplinary evaluation. Perhaps this patient may be a candidate for bronchoscopy to fully evaluate if there is an infection vs is this truly ILD?

Then if it is deemed to be ILD, then I think it is important to treat as soon as possible holding T-DXd, initiating steroids. Doing all the supportive care for patients for that prolonged steroid course. I think the biggest decision at that point is going to be, depending on what is happening with the patient, whether the patient is safe to rechallenge or not. I think with grade 1, I would feel very comfortable. With grade 3, certainly not. Grade 2, I think is the grey zone where you really have to have a lot of thought and consideration whether it is worth rechallenging with T-DXd in those cases. I think it is something that in real-time practice we just have to be super cautious.