Chapters Transcript Video HER2: ADC All right. So, um, I'm gonna be talking about, um, a more specific subset of non-small cell lung cancer, and, and the next two topics we'll, we'll be covering that, which is HER2 alteration in lung cancer. So I'll be talking briefly about, um, introduction to the, the HER2 altered non-small cell lung cancer. Since it's a relatively new. Uh, and they were in, in, in lung cancer space, beaten to death in breast cancer, and I'm going to be briefly talking about the ADC data, and then Doctor Sun will be talking more about the TKI data, which has been also very promising. Um, these are my disclosures. So, just, um, to get into the, uh, introduction, so HER2 belongs to the, the, the broad class of her family, which is human epidermal growth receptors. HER1 is EGFR, the whole first hour of our talk, uh, and then HER2 are, are these other cousins of HER1, uh, family. So these are usually, uh, molecules that, that, uh, drive, um, uh, differentiation, especially of epithelial cell states and, and also proliferation. Uh, and HER2 alterations, uh, at least what we know so far, there are sort of, um, three broad categories, but you could, you could say there may be two that are possibly actionable at this moment. So, the big one is the HER2 mutations. So these are mutations that especially happen in the intracellular. Intracellular domain, uh, the tyrosine kinase domain, and, and the majority of these are exon 20 insertion mutations, making the HER2 overactive and, and, and, um, not, not, uh, not, uh, based on the, on the, on the ligand. And then there is the HER2 overexpression, which, which we know so much from the breast cancer that, that happens, uh, with variable frequency in non-small cell lung cancer, maybe a little bit more prominent in EGFR driven. resistant subsets and so forth. And then there is HER2 amplification. Uh, the correlation of that with HER2 expression is, is not well known in lung cancer. So this is just again describing that these alterations, uh, do happen in different, different clinical contexts in non-small cell lung cancer. HER2 mutations are relatively rare, but they're about 2 to 4% of total non-small cell lung cancer patients. These are usually females, never smokers, adenocarcinomas, very similar to our HER1, which is EGFR altered non-small cell lung cancers. As I said, exon 20 insertions are the most common. Uh, and, and they could happen as, as primary or secondary mechanisms of resistance to EGFR mutant, non-small cell lung cancers. HER2 mutant non-small cell lung cancers have a specific predilection to have brain mets, de novo brain mets, uh, especially the YVMA insertion mutations. And then there is the, the broader category, which is HER2 protein overexpressed non-small cell lung cancers. This is not. Very well defined biomarker subset, but we know that about variably about 2 to 20%. So it's a big variation across different studies express overexpress HER2 either 2+ or more interestingly, 3+. These are dimerization dependent. So these are dependent on the actual HER2 protein to be, to be working. They're just more in number and that's why probably. Driving may be driving the disease, but at least they, they may be partially actionable with with the type of drugs that we have. These are associated with papillary histology. They are associated with poor prognosis and outcome. I'm not going to talk about HER2 amplification because it's, it's not very clear if we should be digging out at this moment HER2 amplified cancers. So the, the main, um, topic of my talk is trastuzumab dan, which is, I think those of you who have taken care of patients with lung cancer, but also with breast cancer are aware it's an ADC. It's a, it's, it's really changed the landscape of breast cancer. It's Essentially, it's a, it's an NDC targeting HER2, uh, with the payload, which is a drutuan derivative, and it has these interesting properties, which is, you know, a highly tumor selectively waable linker, uh, and has a bystander effect, uh, a very high potency and a, and a, and a novel payload. Um, so really, the data of, of, um, HER2 mutated non-small cell lung cancer and, and, and trastuzumabducan comes from Destiny Lung 01. So these were, uh, this is, um, uh, two cohort study where actually there were, there were more cohorts, which I'll talk later about, but essentially pertaining to patients with HER2 mutated, which were tested in cohort 2, which were undresectable, metastatic, uh, non-squamous, non-small cell lung cancer. Uh, who had, uh, you know, who had, uh, you know, no prior HER2 targeted therapy, but had some other type of therapy, usually chemo immunotherapy in the landscape. And we saw that, uh, in the single arm study, the overall response rates was pretty fascinating, 55%, with a very good median duration of response of 9.3 months, the median PFS of 8.2 months, and a median OS of 17.8 months. Um, the big problem with, uh, any ADC, but especially with the TDXT has been, um, toxicity. So these contain chemo-like toxicities, but also, uh, the big class effect toxicity of interstitial lung disease. And this was about, um, 10 to 15%, especially with the higher dose, which is the 6.4 mg per kilogram. And I'll talk about an attempt to lower the dose and, and trying to reduce the incidence to about 5%. But these are, these are serious, uh, and there, there were, there were two patient deaths that were reported in Destiny Lungo 1. Um, so, in order to address the issue with toxicity, Destiny Lango 2, was a sort of a dose optimization trial Project Optimus, where they compared, um, TDXT at a dose of 5.4 mg per kilogram with TDXT 6.4 mg per kilogram. And the idea was to find which is the best dose based on the overall response rate, but also combination of toxicity, pharmacodynamics, and so forth. So what they identified is that 5.4 mg per kilogram is similarly efficacious, uh, broadly to 6.4 mg per kilogram, but it does significantly reduce the, the rates of toxicities, especially, especially ILD-related toxicity and the grades of ILD-related toxicities, uh, from 14%, 14% from, from the initial 32% all grade toxicities with the 6.4 mg per kilogram. Um. We also have some data, and this was mentioned just in talk before, that there is some early data that the CNS activity of TDXT in HER2 mutant, non-small cell lung cancer. This was presented recently. Um, however, we'll see that probably TKIs may, may have a, may have more robust data in this, in this space. Um, so based on this, the FDA granted accelerated approval, uh, for, uh, TDXT for HER2 mutant non-small cell lung cancer back in August 11, 2022. Um, So again, this was a, this was a, um, this was an early study. It needs a, it needs a confirmatory trial for an, for a, for a more sort of stronger approval. So this is Destiny Lungo 4, which is, which is going on right now, which essentially uh enrolls patients with uh HER2 altered lung cancers, but this is in the frontline setting, uh, and you can see here it's comparing TDXT versus standard of care, which would be chemo immunotherapy for, for these patients. Um, next, quickly moving on to, uh, HER2 overexpressed non-small cell lung cancer. So some of the data comes from Destiny Lung 01. This is again, now we're talking about smaller data, so the cohort 1 and cohort 1A. Uh, of the Destiny Langer one, had accrued patients with high expression. This is protein expression. Again, previously treated patients, uh, with, with, uh, with high expression of HER2 disease. They initially had the cohorts with the cohort one with 6.4 mg per kilogram, but as soon as they realized that there were more ILDs happening, they, they have opened up a cohort 1A for these patients with, with the lower dose, the 5.4 mg per kilogram. Uh, and you can see here again from, you know, just from the comparison of the cohorts, these were not, you know, compared head to head, but just looking at it, you can see that the objective response rates are similar, but you can also see that the objective response rates are less than what you saw with the HER2 mutated non-small cell lung cancer. There's roughly around 30%. These were previously treated patients, second line, third line. And so these fall right where within, you know, maybe what we would expect with a stronger chemotherapy. But what you see in the bottom is that the ILD rates significantly dropped, you know, from 20% maybe to 5%. Um, again, still a big issue and, and something to continuously monitor these patients. What they also saw in a subset analysis that it's actually the HER2 IHC3+ patients that probably benefit the most, where the ORR reaches up to 50%, uh, close to what we see in, in the HER2 mutated. Space. And so based on this and other studies, there was actually a, a, a tumor agnostic approval that HER2-DXT got, uh, back in 2024, uh, based on three studies, but it, it included, uh, supporting data from the Destiny Lango one in, and HER2R express patients. So we often, uh, test HER2 IHC for relapse patients, uh, in multiple different disease settings to identify if this is a potential option for these patients. Again, this was, um, this was, you know, sort of, um, an initial study. So there is this Destiny Lungo 3 study, which is essentially looking at activity, uh, of TDXT and TDXT combinations in, in HER2 overexpressing non-small cell lung cancer. Uh, and, and it has two parts, essentially a part 1 and, and then a part 3 where part one. Uh, Essentially enrolling in, in previously treated patients, but part 3, the goal is to go for combination strategies with TDXT with other drugs, immunotherapy, chemo, um, other, other sort of digit inhibitors, and so forth in the upfront setting in the, in the HERER2 space and, and try to establish a new standard there. There's some initial data from Destiny Lungo 3. This is Previously treated patients, uh, in HER2 IHC3. Again, you will see the confirmed overall response is similar to Destiny Lungo one, which is about 56%, but really small numbers, you know, and of 1520 patients. Um, um, but it again supports the use of, uh, TDHT in second line, second line, or third line, second line setting, uh, uh, previously treated patients. Um, and then there's this new data. There's just not TDHT. There's another, uh, another HER2 targeting ADC, which is trastuzumab rizatican. Which has shown some really promising data with a confirmed overall response of 73%. So really trying to notch up that bar in about 94 patients. KVR. This is a Chinese study. Um, I don't think we have any data in the, in the US shores here, but a median PFS of 11.5%. You can see the ILD rates are pretty similar, around 8%, 1%, grade 3. So ILD remains a concern. So really the key key takeaway from my talk is HER2 alterations drive a minor subset of non-small cell lung cancer. HER2 mutant non-small cell and HER2 overexpressed non-small cells are distinct entities, as I would call them. TDHT remains an important option of previously treated patients with HER2 altered non-small cell lung cancer. TDHT associated ILD pneumonitis remains a key consideration, and I always reach out to my breast oncologists who treat. With these drugs often as to what they are doing, you know, are they getting echoes upfront? Obviously, they are, and how frequently they are getting chest CTs, which we, we usually don't have a problem in, in monitoring for non-small cell lung cancer. Uh, and then, you know, the next talk, we'll talk about TKISs have emerged as a great option for HER2 mutant non-small cell lung cancer. So I'll end there. Thank you. Created by Related Presenters Parth A. Desai, MBBS, MD Assistant Professor, Department of Hematology/Oncology,Fox Chase Cancer Center
