Perspectives on Systemic Therapy for Breast Cancer - Episode 10

Trastuzumab Deruxtecan for HER2+ Breast Cancer


Adam M. Brufsky, MD, PhD, FACP: Komal, do you want to talk about some of these novel ADCs, these novel antibody drug conjugates, for HER2?

Komal Jhaveri, MD, FACP: I think this has been a very exciting time for antibody drug conjugates, for sure. And surely, we all have experience and a lot of clinical data, including overall survival, with our first prototype antibody drug conjugate in the HER2-positive subtype, which is either trastuzumab emtansine or T-DM1. But we’re now looking at other next-generation, antibody-drug conjugates, and one among them that certainly caught my attention was the Daiichi compound, DS-8201a or trastuzumab deruxtecan as they call it.

Adam M. Brufsky, MD, PhD, FACP: We’ll never pronounce that. I just remember TrasD. Not T-DM1, TrasD.

Komal Jhaveri, MD, FACP: I’m totally working on that one.

Lee Schwartzberg, MD, FACP: Very impressive.

Adam M. Brufsky, MD, PhD, FACP: I just coined it, TrasD.

Komal Jhaveri, MD, FACP: We have the “ibs” and the “mAbs” to worry about, and now we also have the “tecans” to worry about. Unlike what we have in an antibody-drug conjugate, in T-DM1 our payload, our drug conjugate, is a maytansine derivative. This one is a TOPO1 [topoisomerase] inhibitor derivative. It’s the trastuzumab antibody with a protease-cleaved linker to this payload, which is a TOPO1 inhibitor. But what was very impressive was that there were 2 cohorts that were presented. One was a HER2-positive cohort that was pretreated and heavily pretreated, including patients with pertuzumab and T-DM1, and then there was a HER2 low-expressing cohort. In both of these, there was activity seen, 61% overall response rates in the HER2-positive cohort and about 30% in the HER2 low expressers. This includes ER-positive, HER2-negative, and triple-negative patients. So, I thought it was nice to see those data.

Adam M. Brufsky, MD, PhD, FACP: It was always thought that TOPO inhibitors had some response in breast. They’ve always been sneaking around.

Hope S. Rugo, MD: Oh, they do, they do.

Lee Schwartzberg, MD, FACP: They do, yes.

Adam M. Brufsky, MD, PhD, FACP: It has always been in the abstracts at meetings for years.

Komal Jhaveri, MD, FACP: And we use that. I have used that. I agree. I think we agree and we use that, but what was novel here is that in T-DM1, the drug to antibody ratio is about 3.5 to 1; this is 8 is to 1.

Adam M. Brufsky, MD, PhD, FACP: Right, so it’s a better delivery.

Komal Jhaveri, MD, FACP: Correct. And so, there was not increased toxicity. Duration of response was really, really impressive with some patients, as long as 1-and-a-half years into the study. This drug actually has breakthrough designation with the FDA, so I think it’s an impressive compound and great data.

Hope S. Rugo, MD: And a randomized trial.

Adam M. Brufsky, MD, PhD, FACP: There’s a randomized against physician's choice.

Komal Jhaveri, MD, FACP: Right, I think it’s called DESTINY.

Adam M. Brufsky, MD, PhD, FACP: Is it called DESTINY?

Komal Jhaveri, MD, FACP: I think so.

Francisco Esteva, MD, PhD: T-DM1 did not seem to work in low-HER2 expressers.

Hope S. Rugo, MD: Right.

Adam M. Brufsky, MD, PhD, FACP: Probably because of the payload. I think that’s a really good point that Komal has brought up. It’s a payload issue if you’re only using 3:1 as opposed to 8:1, that’s a very good point. Personally, I think TOPO inhibitors are probably better than emtansine as chemotherapy in general.

Komal Jhaveri, MD, FACP: Right.

Lee Schwartzberg, MD, FACP: And it’s probably still reaching the target because we have low levels of HER2 on breast cancer cells.

Komal Jhaveri, MD, FACP: Right.

Adam M. Brufsky, MD, PhD, FACP: Correct.

Komal Jhaveri, MD, FACP: Absolutely. I think these are all T-DM1—resistant patients.

Adam M. Brufsky, MD, PhD, FACP: Which is even more fascinating, and I can’t wait to see that randomized trial. We’re going to participate. I don’t know if you guys are. It’s a great trial.

Hope S. Rugo, MD: We are, too.

Transcript Edited for Clarity