Antibody-Drug Conjugates in TNBC: ASCENT and DESTINY-Breast04


An overview of antibody-drug conjugates in the recurrent triple-negative breast cancer treatment landscape, and the ASCENT and DESTINY-Breast04 trials.


Hope S. Rugo, MD, FASCO: The duration of disease control and even the response rate is short and not great in this setting. Sometimes we get some mileage out of our first-line chemotherapy, but we’re looking ahead to what we’re doing after that. We have 2 antibody-drug conjugates [ADCs], which have had variable data and led to approval in overall triple-negative disease or in a subset. Sacituzumab govitecan is approved overall in the second-line or greater setting, and trastuzumab deruxtecan is approved based on an exploratory subset from the DESTINY-Breast04 trial in the HER2 [human epidermal growth factor receptor 2]–low, triple-negative population. I’m interested in your thoughts on the ASCENT trial. There’s also the trial you mentioned with the I/O [immuno-oncology], and there are 2 phase 3 randomized trials in the first-line setting, either with a checkpoint inhibitor or not. But where we can use the drug now is what we want to understand for this patient.

Paolo Tarantino, MD: We saw the results of the ASCENT phase 3 trial, comparing sacituzumab govitecan vs chemotherapy of physician choice for patients with triple-negative breast cancer who progressed to 2 lines of chemotherapy. It was promising to see that you could obtain not only a progression-free survival [PFS] advantage that was meaningful—about 5.6 months of PFS with sacituzumab and less than 2 months with traditional chemotherapy—but also a meaningful overall survival advantage, almost doubled from 6 to 12 months, with sacituzumab.

This suggests that with ADCs we may be able to achieve meaningful responses and activity even though these patients progressed to more than 1 chemotherapy. This concept was confirmed also by DESTINY-Breast04. Although the numbers are very small—58 patients in DESTINY-Breast04 had a triple-negative breast cancer—T-DXd [trastuzumab deruxtecan] prolonged both PFS and overall survival compared with physician choice of chemotherapy.

In general, these conjugates are able to deliver chemotherapy in a more effective and active way. I’m also curious about what we’re going to see when we bring these in the first-line setting, with or without immunotherapy. Apart from sacituzumab and T-DXd [trastuzumab deruxtecan], we’ve seen datopotamab deruxtecan, an agent that’s very active. We haven’t seen all its potential. Do you think there might be a role for datopotamab in the future in treating triple-negative breast cancer?

Hope S. Rugo, MD, FASCO: To go back over some of these other data, we have a large phase 3 randomized trial with ASCENT, with sacituzumab in the second- or greater-line setting and improvement in progression-free and overall survival. We understand the toxicity, which is neutropenia primarily and diarrhea next, and about 50% of patients in ASCENT needed growth factors. Although we can treat patients a little earlier, we see less neutropenia. It’s easier to control. A lot of us have been using the long-acting pedfilgrastim after day 8, which means you have fewer issues with neutropenia overall.

The DESTINY-Breast04 trial, which is so practice-changing and has remarkable data, had only 58 patients. It’s important to keep in mind that it was a 2:1 randomization, so there were just 18 patients. A small number of patients were in the control arm. That comparison is exploratory, and that has to be taken into account when you’re thinking about which sequence you’re going to use with the agents. Trastuzumab deruxtecan has generally controllable nausea, although it can be delayed. Of course, there’s a risk of interstitial lung disease in 12% to 13% of patients, most of which can be controlled by holding or discontinuing drug if the patient is symptomatic. Both are really good options. I tend to use sacituzumab first because of the level 1 evidence, but sequencing these agents is the big question for us moving forward.

We also have this exciting new TROP2 ADC. It has the same toxin as trastuzumab but another TROP2 antibody, datopotamab deruxtecan. I’m interested in that drug also because it has a lower drug-to-antibody ratio than sacituzumab, trastuzumab, or T-DXd [trastuzumab deruxtecan]. It’s 4:1. But it seems to be very potent, and it has a different toxicity profile. We’ve seen data with dato-DXd [datopotamab deruxtecan], as it’s colloquially known, in heavily pretreated patients with a median of 3 lines of chemotherapy. Responses were similar to what we saw in the phase 1b/2 sacituzumab I/O trial. There’s a first-line study that has a high response rate that’s quite durable. It’s in the first-line setting in combination with checkpoint inhibitor durvalumab—the BEGONIA trial. We have data sets showing that datopotamab may be very effective in this setting as well. A first-line trial, TROPION-Breast02, is studying datopotamab compared with treatment of physician choice in a first-line setting. That trial is accruing, so it will be interesting to see.

One other point is that people say, “You’ve got a topoisomerase 1 inhibitor, so you can’t use the drugs in sequence.” But you can use taxanes in sequence. Drugs that target the microtubule, like eribulin, are all effective. What if the antibody is the same? It’s both TROP2, but we see sequential efficacy. What’s interesting when you look at these drugs is that the toxicity profiles are so different. For datopotamab, the primary toxicity that we’ve seen other than nausea has been stomatitis—and high rates, over 70%. It’s an intriguing reason. We have no idea why. It must have something to do with the target and delivery, but using a steroid mouthwash seems to markedly reduce the incidence and severity of stomatitis. We’ve been doing that in our neoadjuvant I-SPY2 trial with great success in patients who are receiving 4 doses every 3 weeks of dato-DXd [datopotamab deruxtecan].

Transcript edited for clarity.

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