Trastuzumab Deruxtecan in HER2+ mCRC


Centering discussion on clinical trials and experience with trastuzumab deruxtecan, expert oncologists identify its value in the HER2+ treatment landscape.


Kristen K. Ciombor, MD: Dr Hecht, tell us a little about the data behind trastuzumab deruxtecan. That’s been something that we’ve seen in other tumor types, and the data in colon cancer look interesting.

Joel R. Hecht, MD: In a way, we’re lucky that we follow in the footsteps of our breast [cancer] colleagues. To a certain extent, we even follow in the footsteps of our upper–GI [gastrointestional] colleagues as well. Colon [cancer] is the third step down. Despite that, it’s not that uncommon. But we have all these drugs, none of which were developed for colorectal cancer, that we have the ability to [use]. We already know how to dose them to a certain extent. We know about the PKs [pharmacokinetics], and we know a lot about their adverse effects. We know about the safety. We have older trials with older drugs, like trastuzumab and pertuzumab and combinations with lapatinib. Those have become older and not done as much.

T-DXd, or trastuzumab deruxtecan, is an antibody-drug conjugate [ADC] with very interesting data in breast cancer, where it’s been integrated and seems to be significantly more active in some of the older ADCs. It does have toxicities, which we’ll talk about in a minute. But we’re lucky because we have a number of agents now. We have better small molecules, combinations of antibodies, and antibody-drug conjugates. This is the third part of a development, both initially in breast and then in gastric.

In the DESTINY-CRC01 trial, there were several groups. It’s not a huge study, but it’s only 3% to 5%, so it takes awhile to get these patients together. They showed us that the activity was significantly higher than we’ve seen with other small trials with other ADCs. In patients who were 3+ positive—remember, we do FISH [fluorescence in situ hybridization] as well as IHC [immunohistochemistry], and it makes sense because that’s your target—you’re not having as much of a signal transduction effect. You’re just trying to target the chemotherapy. There was a high response rate, over 40%.

They also looked at some other interesting cohorts, but it depends on whether you [think the] glass is half full or half empty. In breast cancer, this whole idea of low HER2 [human epidermal growth factor receptor 2] is exciting. I’m not a breast oncologist, but there may be a little data, particularly in the stable disease, in 2+ and FISH negative. The other thing that I was just discussing with Dr Hubbard before that was interesting is that in that cohort of patients, a number of them had already been treated with anti-HER2 therapies. One thing that we know from upper GI is that it’s been very difficult to treat —other than with this ADC—because often people will lose the HER2 positivity.

There may also be some biological differences. My pathology colleagues tell me that while gastric cancer is much more heterogeneous when they’re HER2 positive, the colon—because you were talking about staining—may be more homogeneous. This brings up questions. Dr Hubbard brought up that we have an embarrassment of riches, like in ctDNA [circulating tumor DNA]. We have several active drugs. None of them is curative, so I don’t want to get carried away. But when you have several active drugs, you start talking about sequencing. We do trials for a living, and that leads to a whole other set of trials to do. These are active drugs.

The other thing that’s important with all these drugs is that this is chemotherapy as well. We have toxicity with standard cytotoxic drugs, and we have toxicity with this. With interstitial lung disease being the fear, patients had a relatively high rate of significant interstitial lung disease. The 1 thing I’ll say, as this diffuses into the community, is that our community physicians may be more aware of how to use this drug because they’re using it in breast cancer, as opposed to the GI oncologist. The point is that it’s important to stay on top of that from a toxicity standpoint. But these results are really good. We had modest activity with anti-HER2 therapy for a long time, and then suddenly we have several trials with response rates of 30% to 40% or higher.

Transcript edited for clarity.

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