Trastuzumab Deruxtecan for HER2+ Non–Small Cell Lung Cancer



Benjamin Levy, MD: We’re going to move on to HER2 mutations. We’ve all been confused on what is potentially the right biomarker for HER2. HER2 mutations are roughly 2% to 3% of all non–small cell lung cancer. We’ve looked at alterations. We’ve looked at IHC [immunohistochemistry]. We’ve looked at amplification. The data that were just presented at ASCO [American Society of Clinical Oncology Annual Meeting] had 2 cohorts. It was evaluating a drug, trastuzumab deruxtecan, which is an antibody-drug conjugate [ADC]. These are a class of drugs that are more familiar to our breast cancer colleagues that we’re just learning about in the lung cancer space. But this is an antibody-drug conjugate.

It is a humanized HER2 IgG1 monoclonal antibody. It has the same amino acid sequence as trastuzumab, and then it has a topoisomerase 1 inhibitor payload. This trial was looking at this drug as a single agent in about 42 patients that had HER2-mutated lung cancer. The median line of therapy was 2 for these patients. These were patients that were highly pretreated. We saw in these 42 patients quite a high response rate. The response rate was north of 60%. Twenty-six patients responded out of 42. Some of these responses were very durable.

We looked at the waterfall plot. Again, we saw quite compelling outcomes for these patients, with most patients achieving stable disease. The disease-control rate in this trial was 90%, and the PFS [progression-free survival] was 14 months. That’s after a median 2 lines of therapy for most of these patients.

Importantly, the drug does have toxicities, and the lung cancer community is starting to understand a bit more about ADCs. But there were patients that had to come off the drug. In fact, about 23% of patients had to discontinue the drug because of a treatment-emergent adverse event.

There’s obviously a pneumonitis signal here as well that we’ll need to look at. Roughly 12% of patients had pneumonitis. All these were grade 1 or 2. If you put this drug in the context of other efforts for HER2-mutated lung cancer, by cross-trial comparison, there’s no doubt this drug seems to be the most favorable in terms of outcomes, as it relates to both response rate and PFS.

Some of the other strategies we’ve looked at include poziotinib, as Lyuda mentioned. That’s been looked at for HER2 exon 20 mutations. Neratinib has been looked at. Ado-trastuzumab has been looked at as well. But this seems to be 1 of the better drugs we’ve seen. We’ll see this drug in our clinical space sooner rather than later.

Lyuda, I’ll start with you. What are your impressions on this presentation? Do you have experience with the drug? Where do you think this drug will land, and when?

Lyudmila Bazhenova, MD: That presentation gets my “best abstract of ASCO” award. I’m impressed with that abstract much more than I’m impressed with the ADAURA trial.

I have personal experience with the drug. My personal experience is exactly how it was presented at ASCO. It does work and definitely has responses. But pneumonitis is a real risk. I don’t think everyone understands yet which patients develop pneumonitis. If you look at the data that they presented, they show that maybe Asian patients have a higher incidence of pneumonitis. Maybe, since the majority of our population is not Asian, the pneumonitis risk in the United States will be a bit lower. This has the highest possible response rate in that mutation.

The only thing I wanted to point out is I’ve been using multiple NGS [next-generation sequencing] companies to do my molecular testing. From some NGS companies, the report comes in saying ERBB2. I have gotten some questions from the community physician who worked in my area asking what ERBB2 is. ERBB2 is HER2. When you see that mutation, see if you can access that compound and send your patient to a clinical trial.

Benjamin Levy, MD: Rebecca, what are your thoughts on this drug and your impressions of the data?

Rebecca Heist, MD: I agree. This was a very impressive abstract and I’m very excited to see this. It’s interesting that some of the best data in HER2 mutations are with ADCs. I agree. ADCs are here to stay as a general paradigm and treatment strategy.

You mentioned ado-trastuzumab emtansine. In a report that Bob Li published a year or so ago, it had a response rate of 44%, and that also is an ADC. It’s interesting that in this mutation, the ADCs seem to have some of the best reported response rates. We’ve been so focused on small-molecule inhibitors, and we have to expand our wheelhouse, which is great.

Benjamin Levy, MD: Yes, it’s great, exciting, and also confusing. It’s interesting; your point is well taken. Why do the ADCs have such traction in this mutation? TKIs haven’t done a lot in this space. Josh, what’s your take? Do you have experience with the drug? Off of a trial, how do you generally treat patients who have HER2 mutations?

Joshua Bauml, MD: One of the most interesting aspects of that paper by Bob Li was that they rather elegantly went through every possible reason why ado-trastuzumab emtansine might work. They looked at IHC. They looked at mutation. They looked at mass spectroscopy. They looked at everything. The only thing that was associated with response to ado-trastuzumab emtansine was mutation status, which makes no sense biologically to me. But I’ll go with it, right?

I thought this drug was really exciting, and it is FDA approved in breast cancer. I might, if I were reaching for an ADC in this setting, reach for this off-label instead of ado-trastuzumab emtansine. In the past, I had started with chemotherapy or chemoimmunotherapy at the time of progression as a second line. I had been using ado-trastuzumab emtansine. But now I feel I would much more likely try to get the trastuzumab deruxtecan. It’s not only the response rate. That’s relatively comparable. It’s the duration of those responses that was most impressive to me.

Benjamin Levy, MD: Yes, that’s where the separation comes with this drug versus others. To see that PFS as long as it was and its durability, we’ll all learn how to better manage these patients and the toxicity. I’ll be honest. I have not used an ADC for my patients, not even ado-trastuzumab. I am excited to start this very soon.

We have a trial looking at this drug in a different setting, so it will be interesting to see how I feel after I’ve gained some experience. But it is very exciting. I would agree with Lyuda. This gets my gold star smiley face for an ASCO presentation. This was 1 that really separated itself from the others.

Transcript Edited for Clarity

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