Highlights from the 2021 ASCO Annual Meeting, with Lisa A. Carey, MD, FASCO

Lisa A. Carey, MD, FASCO

The Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research

University of North Carolina – Chapel Hill
Lisa A. Carey, MD, FASCO, is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research in the department of medicine at the University of North Carolina. In 2020, Dr. Carey assumed the role of deputy director of clinical sciences at Lineberger Comprehensive Cancer Center. Dr. Carey’s research interests include the clinical application of laboratory findings in breast cancer, with a particular interest in the clinical implications of different subtypes of breast cancer. Read more. 

Catherine L. Ormerod, MSS, NLSP

Chief Executive Officer, Living Beyond Breast Cancer

Catherine L. Ormerod, MSS, NLSP, is responsible for overseeing the implementation of all direct service and partnership initiatives for Living Beyond Breast Cancer. This includes leading efforts that increase public awareness of LBBC’s mission, overseeing the development and implementation of educational programs and services for those affected by breast cancer, and helping to cultivate and develop LBBC’s relationships with new and existing partner companies. She has more than 20 years of experience in the nonprofit and academic sectors, especially in the areas of communications and program and organizational development. Read more.

Catherine L. Ormerod, MSS, MLSP (00:01):

Hello everybody. I'm Cathy Ormerod. I'm the executive vice president for strategy and mission here at Living Beyond Breast Cancer. And we have a presentation on some of the key findings from the 2021 ASCO meeting annual meeting. Generally, this meeting takes place in person in Chicago, and there are about 35,000 and counting people attending. However, of course this year it was virtual as it was last year, but we're fortunate the research has gone on and the findings have gone on, and we are also fortunate because we have Dr. Lisa Carey with us today to provide some detail on the key takeaways from that meeting. So thank you for joining us, Dr. Carey.

Lisa A. Carey, MD, FASCO (00:49):

It's my pleasure. Thank you.

Catherine L. Ormerod, MSS, MLSP (00:51):

I'm going to give you a quick bio for Dr. Carey. She is the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research in the department of medicine at the University of North Carolina. And she is also the deputy director of clinical sciences at the Lineberger Comprehensive Cancer Center. A mouthful. Welcome again. So, Dr. Carey, let's jump in. Our community is always like other oncologists and patient advocates: we're always looking for kind of the big takeaways. Were there any practice-changing headlines that we can start with? And we can get into some of the more nuanced details, but some say that the OlympiA trial was one of those practice-changing ones. Would you agree?

Lisa A. Carey, MD, FASCO (01:49):

I do agree. And OlympiA is distinguished from OlympiAD, which was the one that came before it in the metastatic setting. So Olympia is the adjuvant use of olaparib, which is a PARP inhibitor in women with early-stage breast cancer — so non-metastatic breast cancer — that's what we call BRCA associated. They have an inherited germline mutation in either BRCA1 or BRCA2, the two main familial cancer (breast and ovarian cancer) susceptibility genes. I think it was practice changing because it showed an advantage to using more than 40 percent to giving a year of olaparib after chemotherapy to these women.

Catherine L. Ormerod, MSS, MLSP (02:39):

So, after treatment is done, you add another. And so this is for the inherited BRCA mutations, as you mentioned. When are people generally tested for BRCA mutations, and how do they know…

Lisa A. Carey, MD, FASCO (02:58):

People are tested at diagnosis and increasingly so because it changes our therapeutic approaches. For example, many women make different choices about having a lumpectomy or mastectomy if they know they have an inherited kind of breast cancer and they're at risk for getting another cancer, right? A second or a third, or whatever. It clearly plays a role in surgical decision-making and has for many years. So that's probably the time in which most people are tested. It's not everybody, although there's a small, but increasingly vocal group of people that say we should just test everyone because occasionally, someone who doesn't fulfill the threshold criteria by virtue of their age at diagnosis, family history, things like that, does, in fact, turn out to have a germline mutation of these kinds. That's picked up through a blood or a saliva test. But that's typically when it's done. It informs surgical decisions. It informs decisions for families, right? Because you know, an ounce of prevention is worth a pound of cure. So if you know that you have this in your family, you can have testing done for other family members.

And now it informs treatment, not just in the metastatic setting, which it has for many years, but now also in what we call the adjuvant setting or the postoperative setting.

Catherine L. Ormerod, MSS, MLSP (04:20):

Great. And the drug is not currently available, is that correct?

Lisa A. Carey, MD, FASCO (04:25):

Not for this. It's available for metastatic disease. They just have to extend the indication. I would be surprised if that would take much time.

Catherine L. Ormerod, MSS, MLSP (04:35):

Okay, great. Good to know.

Lisa A. Carey, MD, FASCO (04:39):

It was pretty compelling data. The only thing they don't have is a survival advantage that's statistically significant, but they have distant metastasis differences that were similar to the overall trial findings. So I think it's likely to be relatively quick.

Catherine L. Ormerod, MSS, MLSP (04:58):

Great. In this meeting you discussed another PARP inhibitor, talazoparib, or Talzenna; it's being studied to de-escalate treatment. I'm wondering if you could tell us about that and why that's important.

Lisa A. Carey, MD, FASCO (05:17):

Yes. Talazoparib is also an FDA-approved PARP inhibitor that was also tested in a trial and metastatic setting, similar to the OlympiAD, and in this study, it was given neoadjuvantly as a single agent. So no chemo, just the talazoparib for 24 weeks, to women who have a germline mutation in BRCA1 or BRCA2. This is an all triple-negative trial. That was just by design the way they enrolled patients. They were going to enroll hormone receptor-positive BRCA carriers, but the trial ended before they were able to do that. So it was a triple-negative cohort of patients who just got this one drug. They were looking for a pathologic complete response that could be supported statistically — the findings had to exclude the possibility that pathologic complete response was less than 45 percent, which is kind of a weird way of saying it.

But I'm saying that deliberately, because what they found was a pathologic complete response rate of 45 percent, exactly. So technically it didn't meet their statistical endpoints because it was right at the line as opposed to well above it. But I have to say, I found that a pretty compelling number. It was a small study. There were only about 50 patients that were evaluable in it. But that's not far away from the kind of pathologic response rate we get with chemotherapy. And so, the question is: Can you use these highly active drugs to try and minimize the need for multiple chemotherapy drugs? I think this gives us a sense that along with the fact that these are going to be used in early breast cancer now on the basis of OlympiA, and it gives us a very good roadmap for trying to tailor therapy, using these drugs to try and eliminate drugs with greater toxicity and less targeting.

There is a downside. The downside in that study was a much higher progression rate than we expect with chemo. It was about between 15 and 20 percent where during the neoadjuvant or pre-operative phase, the cancer started to grow, and it just wasn't sensitive to those drugs. So I do think, going forward, we probably need to design trials that give us an early look at whether the tumor is really insensitive to these drugs, which may actually drive the pathologic response rate and the improved outcomes even higher for the ones that really are sensitive.

Catherine L. Ormerod, MSS, MLSP (07:57):

Great. So more research, but promising. Always more research. You had a poster I believe, on Trodelvy, and speaking of triple-negative, and it was a small group of patients, but it was also very promising in its conclusions.

Lisa A. Carey, MD, FASCO (08:18):

Yes. This is a subset analysis of the ASCENT trial. So the ASCENT trial was the pivotal trial of sacituzumab govitecan that compared it to treatment of physician's choice, meaning chemotherapy of various flavors, versus sacituzumab, in pretreated metastatic triple-negative breast cancer. And there was a nearly a threefold increase in the progression-free survival, a doubling of the overall survival in the parent trial — in the overall trial. But these patients had received a lot of therapy on average, about three chemotherapy regimens before they entered the trial. This subset was asking about a group that's of great interest. So, sacituzumab govitecan (Trodelvy) is what's called an antibody drug conjugate, and I consider it a Trojan horse. It takes a chemotherapy drug. In this case, it's a metabolite or an active form of a drug called irinotecan that we don't use much in breast cancer.

It's used more in gastrointestinal tumors, but it's very active. I takes this chemotherapy and it attaches it to an antibody that then targets a protein that's frequently expressed on triple-negative breast cancer cells called TROP-2. It delivers the chemotherapy selectively to those overexpressing cells, the cancer cells. In the parent trial, it was very successful, but those are very pretreated patients. The interest in this subset analysis was in those patients who had early relapse within a year of chemotherapy, meaning some evidence that their cancer wasn't sensitive to the chemotherapy. Those patients who had early relapse and only one line of therapy before entering the trial were examined. There were only 65 of them, but basically they appeared to have the same benefit of the sacituzumab over the free chemotherapy that you give either by vein or orally, as in the parent trial. It seems to supersede what we might consider to be kind of primary resistance, which I think is good. It's particularly good because sacituzumab govitecan (Trodelvy) is actually being studied, moving kind of earlier in lines of therapy, including in the residual disease setting. So that gives us some sense that it actually is going to continue to have equal efficacy across earlier lines of treatment.

Catherine L. Ormerod, MSS, MLSP (10:53):

Interesting. That is promising. So as in many past ASCO meetings, there has been news about CDK 4/6 inhibitors are. What was the news about CDK 4/6 inhibitors at the 2021 meeting?

Lisa A. Carey, MD, FASCO (11:15):

Yeah, I think the main news was a long-term mature evaluation of overall survival impact of adding CDK 4/6 inhibitors to a drug called fulvestrant or Faslodex in patients. In one study they had to have progressed on a previous anti-estrogen therapy; in the other, they could either be from the beginning or after progression, but always with fulvestrant. In both cases, the survival advantage was confirmed. It was a several-month advantage adding the CDK 4/6 inhibitor to fulvestrant. What that doesn't tell us is whether it's better to give it later or give it earlier. The two trials that were presented were called PALOMA-3 and MONALEESA-3. One involved the CDK 4/6 inhibitor is palbociclib; the other involved ribociclib.

Lisa A. Carey, MD, FASCO (12:18):

But they basically had very similar advantages in terms of survival improvement with the addition. If you looked at the group in MONALEESA-3, that were first-line, treated as the first anti-estrogen therapy that they received, it actually looked like they were doing particularly well, which is what we expect with first-line therapy. And to be honest in the United States, most people get their CDK 4/6 inhibitor added to their first-line therapy, which is usually not fulvestrant, it's an aromatase inhibitor, but, taken in toto, I think it suggests that these drugs are highly active regardless of prior therapy, regardless of which anti-estrogen therapy you add them to. And they do provide a survival advantage. I wasn't terribly surprised, but it's very reassuring.

Catherine L. Ormerod, MSS, MLSP (13:13):

It's good to see. And some of the OS [overall survival] numbers were pretty profound.

Lisa A. Carey, MD, FASCO (13:18):

Yes. And actually, the OS numbers for that first-line setting with fulvestrant looked similar in many regards to what we see with the aromatase inhibitor. So I think we've got a lot of choices and it's not necessarily true that you have to have an AI [aromatase inhibitor] first, if fulvestrant is on the table.

Catherine L. Ormerod, MSS, MLSP (13:35):

Great. Have we learned anything about which CDK 4/6 inhibitor patients should receive? Because there were three, and then there was another that may not be available in the U.S. as you and I were discussing earlier, but is there any sort of clarity for patients on which one they should receive?

Lisa A. Carey, MD, FASCO (14:00):

No. There's some emerging data at San Antonio. There was some interesting data from the MONALEESA trials done by a clinician scientist in Spain who looked at those trials and found that there's a subset of patients that seem to do particularly well with ribociclib. They have a subset of tumors that are called HER2-enriched. Ribociclib seem to be particularly active there, but we don't know really whether or not that's a selection process that should be used. To be honest, they all seem to have a very similar, powerful effect. I think among the main differences, abemaciclib, which was not one of the ones that was presented at ASCO this year, is a little bit different from the other two. In terms of the side effects, it's a little bit less of the low blood counts, which is something that we have to keep monitoring, and a little more gastrointestinal toxicity. So I think that's the one that's a little bit different in terms of the side effects that patients experience. The other two seem fairly similar, and they all are effective. So, at this point, I suspect there will be studies that will give us a little more clarity about reasons to choose one over the other, if there are any.

Catherine L. Ormerod, MSS, MLSP (15:26):

Okay. So more to come in the future ASCOs and San Antonios. There were also a number of studies looking into using genomic tests in early-stage breast cancer. What were, what were some of the key findings there?

Lisa A. Carey, MD, FASCO (15:43):

Yeah. There were a couple of presentations that were looking at how we can identify patients who would benefit from extended endocrine therapy. The Breast Cancer Index, which is a combination of genomic grade plus a ratio of two genes that are also relevant for relapse has been looked at and has shown some promise in this regard.

And the other is, of course, the MammaPrint, which was the study used in MINDACT. They were both applied to an American study of extended endocrine therapy. Extended endocrine therapy is an additional 5 years of anti-estrogen therapy with an aromatase inhibitor after an initial phase of 5 years.

So if you're still well, and your cancer has not recurred after 5 years, you know, there are data that there's a small, but real benefit of continuing for another 5 years now. I say “small, but real” deliberately because we have to be very cautious about this because there's are side effects of ongoing anti-estrogen therapy.

There's osteoporosis; many people have musculoskeletal symptoms or arthritis-type symptoms. So we don't want to just put it in the water. These efforts are to try and better delineate [who would benefit most]. I would say, you know, one of the problems with the study that they chose, which is called NSABP B-42, was it didn't show a particularly significant impact of the additional 5 years, probably because of the study population. So it's hard if that's not very compelling to try and tease out a predictor of that effect, and in truth, the breast cancer index didn't seem to perform very well. MammaPrint gave a little bit more of a hint that a genomic assay might be useful. There've been other tests. Um, the what's called the EPclin assay, which is mostly used in Europe and the Prosigna, which is, in fact, FDA approved here. Both seem, give us some hint off benefit of or at least risk of additional long-term relapses.

The BCI was the only one that had shown from another study that it might actually bring that risk down. But I suspect if you intervene on risk with the aromatase inhibitors, you will see it no matter what assay. If you treat all patients as if they were the same, then it's really hard for us to get a lot of important information out of these assays. I think there are calculators now that pick patients that are a little bit more at risk. Um, uh, there's a calculator called the CTS5 that was created by an investigator in England — Mitch Dowsett, who's very famous in this realm — and that combines a bunch of clinical features and gives you a high, medium, or low risk of late relapse. I'd love to see some of these data interpreted in light of higher risks so that you can actually get a better readout. If the risk stays low, it's hard to see any benefit.

Before we layer on all these expensive genomic tests, I'd like to see that they actually add value beyond a thoughtful application of clinical features. But this is an important need, right? We have these conversations with patients all the time about whether we keep going at the fifth year. And it's basically on a case-by-case basis. So, more data and a valuable test would be very much in order. I suspect in order to do this well, they'll have to take a bunch of these studies and put them all together so they have big enough numbers to actually be able to get through the noise and see what's really going on.

Catherine L. Ormerod, MSS, MLSP (19:31):

Speaking of patient-driven research, patient advocates are increasingly more vocal about getting involved in research and in all aspects of the discovery process. One very interesting study was delivered at ASCO and it was done by Anne Loeser and it was about dosage and she was joined by a number of oncologists. Can you tell us about this and what you think about the patient role?

Lisa A. Carey, MD, FASCO (20:11):

I have to say I loved this presentation. Their patient-centered dosing initiative was really patient advocate-driven. They had a medical advisory group that helped design it methodologically, using medical survey technology. They basically went to about 1,200 women with metastatic breast cancer. I think it was mostly women. There may have been some men, but mostly women with metastatic breast cancer, most of whom were somewhere between 1 and 5 years of, of treatment with metastatic disease. They had been treated with a variety of drugs: they'd had targeted therapies; they'd had endocrine therapy; they'd had chemotherapy. It was the whole gamut of treatment options that we use in the metastatic setting.

There were a couple of takeaways about the group. The first is they surveyed them about their own experiences over the time they'd had metastatic disease. Most of them had had what they consider to be a personally bad side effect. This is from the patient's perspective. Most had to have dose reductions, dose delays, etc. — some alteration of how their treatment regimen was prescribed. The alterations largely worked: 80 something percent said when they altered things, it made me feel better or made my side effect go away. What it came down to was that 92 percent of them actually would prefer that rather than the traditional way that we dose things, which is of course the way drugs are developed, as you start at the maximum tolerated dose, and then you back off from there.

That's been the way we do this all the time, but in the metastatic setting, as I always say to my metastatic patients, the goals of therapy are disease control and your quality of life? Because this is not considered curable. So it is really important for the patient's voice to be heard. And 92 percent of them said they wanted individualized dosing. They wanted us to not start at the top and start backing off. They wanted us to figure out ways to be much more thoughtful and rational about the way we give these drugs, taking into account mechanisms to reduce side effects. And I think that was a very clear message to the medical community — that we need to think this through and to incorporate that kind of approach.

Catherine L. Ormerod, MSS, MLSP (22:55):

That's great, and I love your enthusiasm for it, too. So thank you. The quality of life is something we always talk about here. You mentioned one other exciting study from China, I believe SYSUCC-002. Is that right? Yeah.

Lisa A. Carey, MD, FASCO (23:24):

This study is actually in the HER2-positive space. HER2-positive breast cancer; there've been four drugs in the last couple of years that have been approved for it. There are a lot of options and a lot of things that are available, but we have some fundamentals that we start with. In metastatic disease, because of a trial called CLEOPATRA, which showed a very long survival curve with patients who received a chemotherapy drug, a taxane, plus trastuzumab and pertuzumab, what we call the THP regimen has been the standard of care first-line therapy. And you give it until the patient doesn’t tolerate it. In the trial, they could give at least six cycles of the chemo, drop the chemo out, and then continue on the HP-based therapy.

And that's been the way we've done things for a long time because CLEOPATRA showed such a long survival. What's been a question that hasn't been answered is: If patients have HER2-positive breast cancer, that's also estrogen receptor-positive, which is half of them — it’s not a small subset, it's half — how would they do if you skip the chemo part and just gave them anti-estrogen along with the anti-HER2? This is a very biologically rational thing to ask because the two signaling pathways, ER signaling and HER2 signaling — so estrogen receptor and HER2 — actually talk to each other. So when you influence one, the other one tends to get influenced also. As a result, co-targeting is actually a very rational thing to do from a scientific standpoint. And the question is: Is it going to give you as good a result as giving chemo?

This study they were looking at is called a non-inferiority study. The reason we hate describing non-inferiority studies is because they are really hard to explain in a statistically accurate way. But in a non-inferiority study, in this case, they were saying, statistically, we'd want to prove that endocrine therapy with trastuzumab, or Herceptin, is not inferior to chemotherapy plus trastuzumab. And there were a couple of different chemos you could use, and a couple of different anti-estrogens. It was a very practical question. Not only was it not non-inferior, it actually looked like the patients who are randomized to get the anti-estrogen therapy plus trastuzumab in general might even be doing better. You can't say that with any statistical assurance because it was pretty close to even, but it certainly wasn't going in the wrong way.

And so I actually take that as very reassuring that if we have a patient with strongly hormone receptor-positive and HER2-positive metastatic breast cancer, it's very reasonable to skip the chemo part up front and start with anti-estrogen based therapy. Subsequent studies have added pertuzumab or Perjeta to the trastuzumab, and that worked. So that's probably what I would use and feel pretty good about it. It goes without saying that the arm that got the anti-estrogen therapy plus anti-HER2 therapy also had fewer side effects and less toxicity than the chemo-based one. That, for me, answered a foundational question that we really haven't had an answer to, so I really liked that study.

Catherine L. Ormerod, MSS, MLSP (27:03):

Great. Quality of life. Again, there it is. Well, Dr. Carey, any other closing thoughts on ASCO 2021?

Lisa A. Carey, MD, FASCO (27:14):

ASCO 2021, San Antonio, 2020 and ESMO breast 2021 — what you're probably getting a feel for is that all of these studies are tilting towards more rational ways of treating our patients and, and, you know, we're coming at it in practical ways, sort of like the one I just described. They didn't get too complicated about genetics or research biopsies or anything like that. Considering whether you can do this safely and well is incredibly useful. At the same time, there's a lot of research going on. There's great research. We have a better understanding of the biology of breast cancer now than we ever did before.

And what we know is that each of these groups — hormone receptor-positive breast cancer, HER2-positive breast cancer, triple-negative breast cancer — are all molecularly very heterogeneous in ways that are increasingly clearly relevant for treatment. And so I think it's kind of two tacks — one super sophisticated, one very practical — towards getting towards precision medicine. I think these have been really, these are really interesting and good times to be living in from the patient and the physician or provider standpoint, because I do think the focus is on the right endpoints, and the tools are getting better every day.

Catherine L. Ormerod, MSS, MLSP (28:41):

And with patients informing some of the research, it'll all be good —all to our advantage. Well, thank you. That's a really great note to end on, and thank you so much for joining us today. We really appreciate it.

Lisa A. Carey, MD, FASCO:

My pleasure.

Catherine L. Ormerod, MSS, MLSP:

We have more ASCO coverage on lbbc.org. And if you're looking to connect with other people in conversations, please check out the Living Beyond Breast Cancer Facebook groups. Thanks so much, and stay safe.