'It's an ADC World': New Breast Cancer Data From ASCO 2022

Kathy D. Miller, MD; Harold J. Burstein, MD, PhD


July 05, 2022

This transcript has been edited for clarity.

Kathy D. Miller, MD: Welcome to Medscape Oncology Insights. I'm Kathy Miller, professor of oncology at Indiana University. Joining me today is Dr Harold Burstein, professor of medicine at the Harvard Medical School and a breast oncologist at the Dana-Farber Cancer Institute.

Harold J. Burstein, MD, PhD: Great to be back.

Miller: I asked you to join me today to talk about what's new and exciting in the world of breast cancer at ASCO this year. Let's just cut to the chase and talk about the antibody-drug conjugates (ADCs).

Burstein: I was walking over here, and I ran into some lung cancer colleagues. They asked, how does breast cancer always has such exciting things? I assured them it wasn't just me.

Regarding the data this year, the big story is the DESTINY-Breast04 trial. This is the trastuzumab deruxtecan ADC, which has been approved already in human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer. The DESTINY-Breast04 trial was a study of HER2-low tumors, so estrogen receptor (ER) positive or negative and then HER2 1+ or 2+. This is actually a big group of breast cancers — about 50% of all breast cancers.

Miller: It's a group that folks have tried to study before with a couple of other agents. It's difficult to identify them, even though it's a large group, because in many databases they just get written off as HER2-negative.

Burstein: Well, they probably are HER2-negative in the sense that I don't think there's a biological subset here, but there is a spectrum of tumors that have a whiff of ER expression or lack thereof, but also have some degree of HER2 overexpression on the surface. It's important to note these are not tumors that are truly FISH-amplified or truly HER2-positive, as we have conventionally understood that.

Miller: And not the tumors that are HER2 immunohistochemistry (IHC) zero.

Burstein: So far, not yet. The interesting thing here is — and we'll talk about the data — it's beginning to look like it doesn't matter how much HER2 there really is on these cells. This drug has activity.

Miller: This is really using HER2 as a flag, not as something to stop the signaling.

Burstein: I think that's probably correct. Or perhaps glue to sort of bring it into the area, if you will. That's the advantage of the antibody-drug part of it. It brings the chemotherapy into the tumor milieu. At least that's the sort of hand-waving cartoon argument. It's a very potent chemotherapy molecule that's linked to the antibody as well.

Miller: It was a randomized phase 3 trial, a plenary presentation, with simultaneous publication in The New England Journal of Medicine. This must work.

Burstein: It's a very clean and compelling study. In this trial, patients who'd had previous chemotherapy for advanced breast cancer were randomized 2:1 to either trastuzumab deruxtecan or a dealer's choice of different chemotherapies, such as eribulin, taxane, gemcitabine, and drugs like that. Most actually got eribulin in the control arm, presumably because almost everybody had received a taxane.

The primary endpoints were progression-free and overall survival. There was a dramatic benefit for both progression-free and overall survival in both the ER-positive/HER2-low and in the ER-negative/HER2-low subsets.

Also dramatically different were the response rates: 50% response rates in refractory disease, essentially triple-negative, and in ER-positive/HER2-low vs 16% with our control chemotherapies. One of the really sobering things here is just how little activity there is in refractory breast cancer for standard chemotherapy.

Miller: Now, that begs a question: This trial required patients to have had previous chemotherapy for advanced disease. Are you going to stick to that come next week when you're back in clinic?

Burstein: I think so. Remember, for most women who have metastatic breast cancer, you're going to get multiple lines of therapy. It's not a question of yes or no on this drug. It's going to be a question of, where do you sequence it? This study looked at more refractory disease, demonstrating clear benefit and clear activity.

There are some side effects. There is still a 10%-12% risk for interstitial lung disease (ILD). There was a very small but measurable risk for lethal ILD, so that's something people have to be very aware of. I'm sure that the company will be developing studies to move it earlier in the course of the treatment sequence, just as they have in HER2-positive breast cancer, where it began in more refractory [disease and it] now looks like a very compelling second-line [treatment], and they're taking on first-line treatment as well.

Miller: This is not the only ADC that we need to talk about in terms of expanding patients.

Burstein: It's an ADC world, and we are just living in it. The other drug that has gotten a lot of attention of late is sacituzumab govitecan, which, of course, is also already on the market and approved for refractory triple-negative breast cancer based on the ASCENT trial.

What we saw at ASCO this year was the so-called TROPiCS-02 study, shifting from triple-negative breast cancer to ER-positive/HER2-negative breast cancer, as conventionally defined, and again, comparing against standard chemotherapy drugs.

Miller: Also effective, but the results were more modest.

Burstein: I would say for sure. Here, there was improvement in progression-free survival. It went from around 4 months to 5.5 months, so not a huge gap. Clearly, it's an active drug, but at the moment, it doesn't look like a game changer in the same way that the trastuzumab deruxtecan does.

You're a journal editor, so you'll yell at me for doing this, but if you sort of eyeball these things side to side, trastuzumab deruxtecan looks like a far more active drug. In fact, it's probably the most active drug we have now in triple-negative breast cancer, as well as other subtypes.

Miller: If we focus on the hazard ratios, there was much greater improvement with trastuzumab deruxtecan.

Burstein: The hazard ratios are probably a little better there as well, though there's so much issue about patient selection and tumor selection there that it's hard to read that. You can overstate that pretty easily.

Miller: Now, it's hard to talk about updates in breast cancer without thinking about our largest patient population: those who have ER-positive disease. We have news here to inform practice of both our older patients and our younger patients.

Burstein: Yes. Now we're shifting to early-stage breast cancer. It's important, I think, when we look at early-stage disease these days to really imagine how we're sort of titrating in or titrating out treatment based on things like tumor risk — we're all familiar with using genomic assays for that — and also patient health and biology.

There are two very nice studies that I think will continue to inform practice. One was the so-called ASTRRA study, which was a long-term follow-up of another study of ovarian suppression, a high-risk group of patients who got chemotherapy but remain premenopausal. Now, with close to 10 years of follow-up, there is a 5% absolute difference favoring ovarian suppression in terms of preventing recurrence of breast cancer, underscoring the point that ovarian suppression remains an active treatment approach. It clearly brings more side effects for younger women.

This may be something interesting to talk about, but if you look at the data from RxPONDER and TAILORx where there's been that signal of activity in younger women, I really believe most of that is because of the ovarian suppression effects of chemotherapy and these data support that idea, I think.

Miller: My bias is with you in the RxPONDER data. The good news is that we will, at some point, have data to see if that bias is true because there will be a large, national study randomizing those patients.

Burstein: I think so. I think is going to be a really hard study to accrue to it. It takes 5-10 years to see these late endocrine effects manifest. Sign up now for ASCO 2032, and we'll be talking about whatever that is.

The other study was a study called ASTER 70s, which is a European trial, also ER-positive tumors, this time with high genomic grade readouts, but they were patients aged 70 years or older. They randomized such patients to endocrine therapy alone, with or without chemotherapy. Interestingly, there was no real benefit for chemotherapy there.

This adds to an existing literature that older patients get relatively little benefit from chemotherapy. In this case, even if you select for these higher-risk, higher-grade, higher-genomic indices scores, there's really very negligible benefit.

Miller: In your next clinic, when you see a reasonably healthy but perhaps not out-on-the-tennis-court healthy 75-year-old, are you still going to send a genomic assay?

Burstein: You have to really imagine in your mind you're going to give chemotherapy. We just did an internal quality analysis at our program, and the breakpoint was at 72 years. Up to age 72, people were ordering many recurrence scores and trying to see if they might think about chemo. Beyond that, almost never. I'm not sure that that's exactly the right number, but it's pretty uncommon to give women in their mid- to late 70s adjuvant chemotherapy for ER-positive breast cancer.

Miller: When we think about ER-positive breast cancer in the early-stage setting, we also have to think about bone health. It's really important to monitor patient's bone health. There has been discussion for decades about whether skeletal protective therapy might reduce recurrences or might improve survival. The results have been decidedly mixed, but we did see long-term results of the ABCSG-18 denosumab study today.

Burstein: That's right. Many of us have gotten into the habit of giving zoledronic acid or other bisphosphonates, and a meta-analysis supports the idea that those both preserve bone health in postmenopausal women and can also help prevent recurrence in the bone for patients who have higher-risk, ER-positive tumors, in particular. It's been a little less clear for the RANK ligand inhibitor denosumab whether that would be the case.

There have been two big studies of this. The D-CARE study, reported a year and a half ago, showed no benefit in terms of using denosumab to prevent recurrence of breast cancer.

At this meeting, we saw an update with long-term follow-up from the ABCSG-18 trial from Michael Gnant. In that trial, denosumab actually did lower the rate of fractures, but also seems to be associated with an overall survival benefit. The data are a little quirky in the sense that it's not so clear what's driving that survival. Is it osteoporosis or bone health? Is it truly breast cancer recurrence, of which there's a little bit of benefit?

It's also very hard to reconcile those two trials of denosumab, though they're very different patient populations. D-CARE included a high-risk population with chemotherapy and hormone receptor–negative tumors. The ABCSG-18 trial included mostly stage I and II, ER-positive tumors, with less chemotherapy. Perhaps there will be some brilliant biostatistician who will reconcile this. For the moment, if you're going to give bone-modifying therapy, I think zoledronic acid remains the agent of choice.

Miller: The discussions will continue.

Burstein: The discussions will continue.

Miller: The last thing I want to ask you about is an NRG study, another study that took a long time to get done but gave really important results for the management of patients with oligometastatic disease.

Burstein: This is a very nice study, and credit to the cooperative groups because it's hard to do these studies; they take a long time, there is no pharma support for them, but it's a very compelling clinical question. The question is, if you meet a patient who has metastatic disease with oligometastatic sites — and they defined that as four or fewer sites — that might be amenable to local therapy, either surgical resection or focal stereotactic radiosurgery, would zapping or removing all of those oligometastatic sites improve the long-term outcomes in addition to systemic therapy?

It was a randomized phase 2 study. The idea was to generate both feasibility and safety data and to look for outcomes. They showed no benefit to prophylactically removing a lung nodule, zapping a bone lesion, or going after up to four sites with a very focal approach in these oligometastatic patients.

Standard of care remains systemic therapy and, obviously, using local therapies for palliation, whether it's a painful bone lesion, paracentesis, thoracentesis, or other areas that need to be addressed. The operating practice should not be to try and remove what is otherwise asymptomatic metastatic disease.

Miller: These patients with oligometastatic disease are not that common in practice, but they provide a common source of argument at tumor boards. It's hard when the radiation oncologist says it would be easy, with low risk and low toxicity, or the surgeon says they could take this out via video-assisted laparoscopy.

Burstein: It's a great point.

Miller: It's hard to say no.

Burstein: Patients understand that point. I think one of the interesting things here is that there was actually no benefit in progression-free survival, which I think is important. Let's say you had a liver lesion. If you zapped that liver lesion, would that buy you extra time before you needed chemotherapy or something like that? It just didn't play out that way.

By the time breast cancer has metastasized, unfortunately, it's almost always an event that has disseminated tumor cells throughout the body. The good news is that we're getting better and better therapeutics, but this is a very important negative result demonstrating that going after individual spots won't change the long-term outcomes.

Miller: Well, it's been a pleasure, as always, to have you here and talk about some of the updates. It's been a good year for breast cancer.

Burstein: It's always a good year to be a breast cancer doctor. Thanks, Kathy.

Miller: Thank you for joining me. To our audience, thank you for joining this episode of Medscape Oncology Insights.

Kathy D. Miller, MD, is associate director of clinical research and co-director of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University. Her career has combined both laboratory and clinical research in breast cancer.

Harold J. Burstein, MD, PhD, is a professor in the Department of Medicine at Harvard Medical School and a medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts.

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