Opinion

Video

Antibody-Drug Conjugates in Lung Cancer

A medical oncologist reviews the antibody-drug conjugate landscape in lung cancer.

Sponsored in part by Daiichi Sankyo. Content independently developed by OncLive®.

Transcript:

Benjamin P. Levy, MD: We can move on to lung [cancer]. The lung story is much cleaner, or more simple, than the breast [cancer] story. Interestingly, the first ADC [antibody-drug conjugate] that was tested in lung [cancer] was T-DM1 [ado-trastuzumab emtansine (Kadcyla)], in a small basket study out of Memorial Sloan-Kettering led by Bob Lee, [MD], looking at HER2-amplified tumors, HER2 exon 20 insertions and HER2 overexpressed. And we'll talk about the difference in biomarkers. The cohort that was presented at ASCO [the American Society of Clinical Oncology’s annual meeting] was looking specifically at HER2 exon 20 insertion mutations; mutations, mutations, mutations. Rasheda and I talk about this all the time, we hear about IHC [immunohistochemical] and overexpression and amplification and other tumor types, and we've got to table that for the moment in lung, it doesn't make a lot of sense and, as Ben was saying, how do these drugs really work?

In lung cancer, the story has been pretty simple. After T-DM1, we had DESTINY-Lung01 [NCT03505710], which was the first study looking at trastuzumab deruxtecan [T-DXd] in lung cancer. And this is to Ben Musher’s question. There were 2 cohorts. There was an advanced non–small cell lung cancer, that's a given, that's refractory to standard treatment. Cohort 1 was a HER2 overexpressed, cohort – IC 2 or 3 receiving single-agent T-DXd and cohort 2, which was only HER2 mutated exon 20. If you had asked me before this study started what cohort is going to win, I would have of course said the overexpressers because overexpression should predict response to these drugs based on what we know about them. But when we looked at the data cohort 1, the overexpressed patients had a response rate of 23%. Cohort 2, the mutated patients, had a response rate of 60%.

So what's the deal? What's going on? How is this possible? If we're sitting here talking about how these drugs engage a target and that target is a protein expressed in the cell. If you have a lot of target, you're going to get a lot of engagement. These results would suggest that something else is at play. So my postulate, which I won't make 45 minutes, I'll make it 2, is that some very nice data came out of Memorial to try to explain this and what the going theory in lung cancer is, is that for reasons that we don't understand, protein expression has nothing to do with the efficacy of these drugs. It's about mutant proteins. The reason that is, is that mutant proteins, we believe, and this is based on some preclinical data, are better able to traffic drugs, they're better able to internalize. So this is why we're now seeing these drugs work really well and EGFR [epidermal growth factor receptor] mutant as well as ALK [anaplastic lymphoma kinase] mutant independent of what the overexpression is, because the thought is, potentially the mutant protein, the transmembrane protein, is better able to bind to that ADC and traffic it in vs just overexpression. Some elegant work by Bob Lee [MD] shows this in preclinical data, photo dye labeling ADCs, and showing in cell lines that they light up only in the HER2 mutant cell lines, not the HER2 overexpressed cell lines.

We're very early on, but this is what we've been struggling with. I don't want to get too involved in this, but this is one of the areas of interest and research. How is this possible? DESTINY-Lung01 led to DESTINY-Lung02 [NCT04644237], which was comparing 2doses of T-DXd and HER2 mutant lung cancer. So we learned from DESTINY-Lung01 that HER2 overexpression is not going to cut it. So we just looked at HER2 mutated, HER 2 exon 20 insertion mutations and compared 2 doses – 5.4 mg/kg vs 6.4 mg/kg. The reason that there were 2 doses was because the 6.4 mg/kg per dose from DESTINY-Lung01 had a high rate of ILD [interstitial lung disease]. It was on the order of 23% or 24%. What we found from DESTINY-Lung02 was that the T-DXd dose of 5.4 mg/kg objective response rate was 53%. The ILD rate was less than, I believe, 6% of any grade ILD. Basically, it solidified the drug in HER2 mutated.

The problem is that HER2 mutations in lung cancer are only 2%. So we're really restricted in how we use this drug. And HER2 overexpression doesn't seem to make a difference now. I know we don't have time to go through this, but there was a paper published yesterday with HER3 ADC, patritumab deruxtecan, and once again HER3 expression makes no difference but the drug is very active in EGFR [epidermal growth factor receptor] mutant lung cancer. So I’m starting to think that maybe it has something to do with a mutant protein better able to traffic the ADC vs just overexpression.

Benjamin L. Musher, MD: For those with HER2 mutation, are there predictors for who may have that mutation, are there specific histology or have there been?

Benjamin P. Levy, MD: Yeah, I’m sure you guys have all seen the beautiful pie graph of lung cancer with the different slices. So for HER2 exon 20, it's generally never smokers although we do see smokers and that's really, as you know, [squamous cell] carcinoma. So we now have 10-targeted therapies for lung cancer. The nice thing is that all of these targets are mutually exclusive. So if you have a HER2, you don't have an EGFR. If you have an EGFR, you don't have an ALK. If you have an ALD, you don't have a KRAS G12C. There are nice mutually exclusive slices of the pie that make this a lot of fun to do because treatment is entirely predicated on what the genomic alterations are. We can't even start until we know those types of things. You can default to chemotherapy, but I think that’s why it’s so important to mention liquid is our savior because tissue exhaustion has been mentioned and is real. Immunostaining exhaustion is real, even at Hopkins, and we can't reflexively do the testing. It has to be ordered. Liquid is such a resource for us when we can find an alteration. So, unfortunately, HER2 exon 20 is, again, only 2% of all lung cancer we find.

The other thing is we can't use it first line we can only use it after platinum treatment. There are multiple studies now trying to place it. But I think this drug and anything that has a response rate above 60%, which is most of our targeted therapies, should be considered to be targeted therapy. So I think it's extremely well tolerated and we have several patients on it. We try to give it first because, again, it fits into the algorithm of our targeted therapy sort of approach. For every genetic alteration, if you can identify it, give it target therapy upfront minus KRAS G12C, and EGFR exon 20. But that's going to change. EGFR exon 20 is going to change in the next 6 to 12 months. It's really, really exciting.

Transcript is AI-generated and edited for clarity and readability.

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