HER2-Targeted ADCs in Advanced NSCLC: A Case-Based Approach to Targeted Treatment for Metastatic Disease

Transcript

Chapter 1: Dr. Gainor- Progressive HER2-Altered NSCLC After Standard Frontline Therapies

Chapter 2: Beyond the Blood–Brain Barrier: Intracranial Activity of HER2-Targeted ADC Therapy in HER2-Altered NSCLC with Brain Metastases

Dr. Sands:
Hi, my name is Jacob Sands, Thoracic Medical Oncologist at Dana-Farber Cancer Institute, and I'm excited to join you today to talk about Beyond the Blood Brain Barrier. We're going to talk about intracranial activity of HER2-targeted antibody drug conjugate, namely trastuzumab/deruxtecan, which is an FDA approved therapy for HER2-mutant positive non-small cell lung cancer. In the setting of brain metastases, this becomes a more nuanced topic.

Let's start with a case, and then we'll go a bit more into the data. Sixty-two-year-old-woman with metastatic non-small cell lung cancer So, in this case patient came in with a cough, worsening shortness of breath and cough. Workup showed multiple lung nodules, mediastinal adenopathy, liver metastases and a right adrenal metastasis. Now, biopsy demonstrated the non-small cell lung cancer. Her oncologist wanted to start treatment due to worsening symptoms. That being said, genomic testing wasn't back yet at that time, and so our oncologist started carboplatin and pemetrexed without immunotherapy. In this case the patient did not have a smoking history, so further increasing the, likelihood of an actionable genomic alteration wasn't yet known at the time, and so started carboplatin and pemetrexed. I'll make the point, I think that's a really important thing to consider in someone, particularly where you suspect, some kind of actionable genomic alteration. To start with, carboplatin/pemetrexed alone while saving the immunotherapy. And that's really important, especially in the setting of an eGFR mutation being discovered. And those with sensitizing eGFR mutations where you'd consider then starting osimertinib, if they've been on, immunotherapy, there's a higher risk of developing a pneumonitis in the setting of starting osimertinib with the prior immunotherapy.

So, in this case, started carboplatin and pemetrexed, while awaiting the genomic testing. Now, the genomic testing came back showing a HER2 mutation. This is after having already started the chemotherapy. in this case, the patient had, a wonderful response to carboplatin and pemetrexed and was tolerating that well and continued on therapy. After about 8 more months on maintenance pemetrexed, scans showed progression, and at that time, an MRI was done for restaging, and this showed multiple brain metastases, up to 6mm. So, multiple small brain mets. they’re not symptomatic, and there was not any significant edema around them. So, asymptomatic multiple brain metastases.

What to do in those cases? Let's go into the data a little bit around this. So, first of all, brain metastases represent a challenging scenario, in many cases, for solid tumor management. Some targeted therapies are very effective. things like osimertinib, things like alectinib. More recently erlotinib, that we've seen for eGFR and ALK, mutations. But when we're talking about cytotoxics, there's often some limitations to that. Now with DESTINY-Lung01 and 02, these were the trials looking at trastuzumab/deruxtecan for HER2-positive non-small cell lung cancer. These trials did allow enrollment of asymptomatic untreated brain mets, and that's something to really look at. Many trials do not allow asymptomatic and untreated brain mets. Many require prior treatment of brain mets, so, when looking at a trial, this is something really important, evaluate, whether or not were allowed enrollment.

Now, first of all, what did the data show? DESTINY-Lung02 is what led to FDA approval, and this was a trial looking at two different dose levels, the 5.4 milligram per kilogram every 3 weeks, or 6.4 milligram per kilogram every 3 weeks, and you see the waterfall plots here. Now, both really show the kind of waterfall plots we hope to see in that the vast majority of patients did have regression of tumor and met at least a partial response. They look fairly similar between the two, and so, representing the fact that we see, still sufficient outcomes in the 5.4 milligram per kilogram dose level. At the same time, on the bottom left there, you see adjudicated ILD. Now interstitial lung disease is an important consideration in any of these antibody drug conjugates with a deruxtecan payload. We see interstitial lung disease show up across the various trials. In this case, at the lower dose level of 5.4 milligram per kilogram dose level, we see less, adjudicated ILD, drug-related ILD. And so, this led to the approval and the use of the 5.4 milligram per kilogram dose particularly in non-small cell lung cancer. This is something worth highlighting and underlining, because it is a different dose than what we see in breast cancer. At the same time, I'll point out that these are for HER2-mutant non-small cell lung cancer, which is also a difference from breast cancer. Now HER2, we've had as a part of a biomarker for work-up the treatment of breast cancer for many years, and that's HER2 expression. In this case, it's HER2 mutation. So, for non-small cell lung cancer, HER2 mutant, the dose is 5.4 milligrams per kilogram.

Now, for brain metastases, there were 33 patients, in the DESTINY-Lung01 study, 33 patients with brain metastases at baseline were included. Fourteen of them had prior treatment with radiation, 19 of them presumably had not had treatment. Of those 19, there were a reported 10 that achieved a partial response. So, an indication of CNS efficacy. Among all of those 33 patients, so those are patients previously treated as well as some untreated or progressing brain mets, amongst those 33, the median progression-free survival was 7 months and median overall survival being 13.8 months. And the overall numbers, are similar to that, a little bit more. The overall numbers median progression-free survival was 8.2, relative to that 7.1 with the prior brain mets, and 17.8 months of median overall survival relative to the 13.8 months, median overall survival in those with brain mets. So, still seeing efficacy, some durability to that, numbers don't look quite numerically what we see in the overall population, but when we see brain metastases, that generally is a worse prognosis, and so this is holding up.

Now, when we look at pooled analysis from DESTINY-Breast01, 02, and 03, so this was taking three different studies and pulling all together, looking particularly at those with brain mets. You see here from the chart, on the left side there is, the trastuzumab/deruxtecan group in blue, and right is the comparator pool. And, scrolling all the way down, you see the prior treatment, about 30% of patients in both of the groups had not had prior treatment of their brain mets. now, also point out, though, that they define the untreated active events are new or progressive brain mets that have not been subjected to any CNS directed therapy since documented progression. So, some of those may have had prior treatment, but then progression, which is in systemic disease. We utilize that as a way of, we have to have seen some progression before you can call something active and measurable.

So, this is an important thing to look at, especially when looking at, these reported data around efficacy within the brain. Have they been treated? What was the prior treatment? sometimes you have to dig the manuscript to find that. So about 30% of patients in both groups, OK. Now, that being said, we're going to see the data that reports out on those with some prior treatment and without. So, here is the best intracranial response that we see across the two groups. And I really like the way that they separated these out, where on the left side you see the treated stable brain mets, and on the right side, within the blue and in both groups, the untreated and active brain mets. And the fact that we have the comparator pool there also gives us another way of evaluating this. Now, in both the treated and stable brain mets, as well as the untreated active brain mets, we do see numerically better responses. More complete responses, more partial responses, both of those groups. But I tend to focus more so on the untreated active. So, this is the ones where we know that there is disease there and it's growing. across that group, there were 7 patients, so not a huge number, but 7 with a complete response 13 with a partial response. But still, that's 45.5% of patients having a complete or partial response.

Now, further to this , you see the treated stable brain mets and the untreated active brain mets, curves, and so this is progression-free survival curves. And so, for the treated stable brain mass, these look quite a bit more similar. There's not as nearly as much separation, but there is still separation of the curves in advantage of trastuzumab/deruxtecan. And the untreated active brain mets is where we really see a very clear separation, and more stability than in that group that has, gotten trastuzumab/deruxtecan. So, we see a signal here. Even though they're low numbers, we do see a signal for some intracranial efficacy, as well as from a progression-free survival, an indication that there is some protection or some treatment preventing progression within the brain that group, as well.

We do have sufficient numbers here to say that there appears to be some intracranial activity. Now, that being said, to go back to our case, 62-year-old woman, metastatic non-small cell lung cancer, HER2 mutation with multiple new brain mets. Now remember, there were multiple less than 6mm brain mets, so asymptomatic, untreated in this case. Now, I think there are options. she could be started on trastuzumab/deruxtecan and monitor the, brain closely. it is something where there may be some durability to that. I don't think you necessarily have to rush to treating an asymptomatic, brain mets. but something that's symptomatic or a bit larger, particularly large to the point where you'd consider, neurosurgical resection. but even some where you're seeing some edema or some kind of symptoms, then getting radiation to that is probably an important consideration. Whether that's prior to starting trastuzumab/deruxtecan or later, and then potentially between cycles, I think is a clinical determination depending on the patient. And how much you need to treat any other disease is present beyond the brain.

So, there is, certainly more data to come, I'm sure, as this is now an FDA-approved widely-used drug, in the setting of HER2-positive non-small cell lung cancer. More data to come, from some of the toxicities that we're seeing, as well as then, brain efficacy in particular. But this is something that I think we can utilize in those with active brain mets that are asymptomatic, and a starting drug and monitoring closely. but in something that's bigger, I think starting treatment is important first.

I thank you for your attention.