Trastuzumab Deruxtecan in HER2+ Breast Cancer

Mark Pegram, MD: Let’s move on to talk about some of these newer agents that have just recently been approved. I’ll lead off to talk a little about trastuzumab deruxtecan, also known as DS-8201a. This is a new antibody-drug conjugate, so it’s in the same family, the same drug class, as T-DM1 [trastuzumab emtansine], but it has some differences as compared with T-DM1 [trastuzumab emtansine]. It does have a trastuzumab biosimilar as its backbone, so the amino acid sequence is identical to trastuzumab and T-DM1 [trastuzumab emtansine]. It is humanized. It’s an IgG1 backbone antibody. The linker is different. Rather than the stable linker, this is a cleavable peptide-based linker. And the payload is unique. Rather than microtubule-interacting agent like derivative of maytansine 1, this payload is a TOP1 inhibitor, topoisomerase 1.

Moreover, the drug-to-antibody ratio is different from T-DM1 [trastuzumab emtansine]. In the case of T-DM [trastuzumab emtansine], it’s about 3 DM1 molecules per trastuzumab backbone. But in the case of trastuzumab deruxtecan, it’s about 8, so it has more of the TOP1 payload per antibody molecule as compared with T-DM1 [trastuzumab emtansine]. Finally the other interesting attribute about the TOP1 inhibitor payload of trastuzumab deruxtecan is that in contrast to T-DM1 [trastuzumab emtansine], where DM1 is insoluble and is incapable of killing any neighboring cells even after it’s released from dead or dying cells, it has no bystander effect. Whereas, the trastuzumab deruxtecan payload, TOP1 inhibitor, has a potent bystander effect and can kill adjacent tumor cells, even if they’re HER2 [human epidermal growth factor receptor 2]–negative, at least in the laboratory for instance. It’s a really interesting molecule.

As you know, the results from the first nonrandomized phase 2 yet pivotal FDA registrational trial have recently been published this year by Shanu Modi and colleagues in the New England Journal of Medicine. This is called the DESTINY-Breast01 trial, with 184 patients who had had a median of 6 previous treatments, received trastuzumab deruxtecan at the FDA-approved dosing schedule of 5.4 mg/kg every 3 weeks intravenously. In the intent-to-treat analysis, a response to therapy was reported in 112 of those patients. That’s about a 61% response rate from a single agent in heavily pretreated HER2-positive metastatic breast cancer.

Julie R. Gralow, MD: That was the most impressive waterfall plot I’ve ever seen in breast cancer anyway when that was presented on that phase 2 trial.

Mark Pegram, MD: Absolutely right. This is the most active single-agent HER2-targeted therapy developed. It’s the most incredible waterfall plot I’ve seen. I call it the waterfall plot that looks like Victoria Falls. The median response duration was about 15 months. I mean, that’s really also unparalleled in a heavily pretreated population like this. Remember, all these patients had prior T-DM1 [trastuzumab emtansine] and two-thirds had prior pertuzumab, 92% had visceral disease, 29% had bone metastasis, and 13% had brain metastasis. The sum of diameters of the target lesions was greater than or equal to 5 cm in half the patients. Yet we see these extraordinary results. I’d like to comment for a moment about those patients. There were 24 patients who had brain metastasis at baseline in this study. In that group, the overall response rate was similar to the intent-to-treat population; that is, 58.3% compared with about 61% for the population as a whole. Moreover, the duration of response was similar at about 17 months and the median PFS [progression-free survival] was also similar to the intent-to-treat in this case at 18.1 months.

Julie R. Gralow, MD: We saw at ESMO [European Society for Medical Oncology] Breast [Cancer Congress] 2020 the data that you’re just describing with a CT [computed tomography] scan of 1 patient who had a dramatic response in the brain from trastuzumab deruxtecan. Do you think this antibody-drug conjugate is truly crossing the blood-brain barrier? These are disrupted blood-brain barriers in these patients. Or do you think this is because of the chemotherapy agent, what you’re calling the bystander effect, some of it getting back out into the blood and then getting into the brain? Or do you think it’s a combination of both?

Mark Pegram, MD: We know, Julie, that the backbone antibody, trastuzumab, if you label that with a PET [positron emission tomography] label—like zirconium 89, for example—you can get very nice imaging of HER2-positive brain metastasis in human subjects. And so we know that the antibody is able to get through these fenestrations of the disrupted endothelial barrier in the tumor microenvironment in a brain metastasis. Moreover, we have data from a phase 2 trial done in Italy in over 50 patients with HER2-positive brain metastasis looking at T-DM1 [trastuzumab emtansine]. Ironically in that trial, the intracranial response rate, which was about 30%, was similar to the extracranial response rate, which was about 35% in that small phase 2 study. It’s evidence that these antibody-drug conjugates like T-DM1 [trastuzumab emtansine] can and do cross the blood-brain barrier and can even be associated with responses. I will bet that this agent, trastuzumab deruxtecan, will similarly be able to gain access to HER2-positive brain metastasis and effect responses. But until we get larger numbers, we don’t have as much information as we’d like to have for this agent.

Julie R. Gralow, MD: This drug is not without its toxicities. We know that we have a black box warning about interstitial lung disease and pneumonitis. We’ve had a lot of conversation about this. It’s rare. There are a handful of cases. We need to be really vigilant. What was very interesting was that because it was during the COVID-19 [coronavirus disease 2019] era that this drug was approved, there was some concern about if we would be able to distinguish if we were starting this drug in our patients between a COVID-related pneumonia and a toxicity from trastuzumab deruxtecan. I have yet to see a case of it at our site. It does get a black box warning, though. It seems to happen in less than 1% of patients, but we do need to be really alert because we’ve got to stop the drug quickly if it happens.

Regarding other common toxicities, we’ve talked about how, as opposed to T-DM1 [trastuzumab emtansine], it does cause some alopecia. We’ve got to warn our patients about that. The typical chemotherapy adverse effects, such as nausea, fatigue, neutropenia, all exist. Some diarrhea was also seen in these trials. I’ve talked with my patients about the adverse effects. Many of my patients who have been dealing with the HER2 metastatic disease for years and years and years, they’ve had all the other drugs until these few recent approvals. We go over the adverse effects, and they say, “Well, they’re not any worse, for the most part, than anything else you’ve been giving me for the past 8 years.” If we put that in perspective with the balance of an extremely effective agent with tremendous response in very heavily pretreated patients, for the majority of our patients, the benefits will strongly outweigh the risks.

Mark Pegram, MD: Agreed.

Transcript edited for clarity.