Dr. Jennifer Litton is a board-certified medical oncologist and professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, where she is also vice president of clinical research.
The 2021 American Society of Clinical Oncology annual meeting was held virtually June 4-8, and there were a number of studies on breast cancer presented. Dr. Litton joined us to talk about some of the most notable research.
Listen to the episode to hear her explain:
- results from the OlympiA trial, showing that Lynparza (chemical name: oliparib) offered benefits for early-stage breast cancer in people with a BRCA1 or BRCA2 mutation
- results from the NEOTALA trial showing that Talzenna (chemical name: talazoparib) offered benefits for early-stage breast cancer in people with a BRCA1 or BRCA2 mutation when given before surgery
- updated results showing continued better overall survival when advanced-stage, hormone-receptor-positive, HER2-negative breast cancer is treated with the CDK4/6 inhibitors Ibrance (chemical name: palbociclib) or Kisqali (chemical name: ribociclib)
Running time: 23:19
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Show Full Transcript
Jamie DePolo: Hello, thanks for listening. Dr. Jennifer Litton is a board-certified medical oncologist and professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, where she is vice president of clinical research.
Dr. Litton joins us today to talk about some of the most interesting and immediately applicable breast cancer research presented at the 2021 American Society of Clinical Oncology virtual annual meeting, which was held June 4th through 8th.
Dr. Litton, welcome to the podcast. It’s always nice to talk to you.
Dr. Jennifer Litton: Oh, thank you. It’s nice to talk to you, too, Jamie.
Jamie DePolo: So, I’m so excited you’re going to help us sort through all the stuff that was presented at ASCO, because there’s always a lot, and I know when I look through it I get a little bit overwhelmed. But in my opinion, some of the most exciting results came from the OlympiA trial, which showed that Lynparza, or olaparib, offered benefits for early-stage breast cancer in people who have a BRCA1 or a BRCA2 mutation. And I know that you personally have done research on Talzenna, which is the other PARP inhibitor used to treat breast cancer, so would you mind talking a little bit about the OlympiA trial results, and what do those mean for people with a mutation in early-stage disease?
Dr. Jennifer Litton: Absolutely. So, the OlympiA trial was a phase III randomized clinical trial of 1,836 patients, and the patients had to have a germline BRCA1 or 2 mutation. And as trials like this are built, there’s definite timelines where they look at the data and they decide, do they keep going or is the data so telling at a certain point that they should stop it and just release the results? And that’s really what happened with the OlympiA study.
So, the eligibility is a little bit complicated, but it really was a way to be very inclusive of all patients with early-stage breast cancer and a germline BRCA1 or 2 mutation. And so, they split it up into people who had surgery first followed by chemotherapy versus patients who had chemotherapy first followed by surgery.
So, if you had surgery first, if you had triple-negative breast cancer, if you had biopsy-proven disease in one of the lymph nodes, or the tumor was 2 centimeters or greater, or if it was hormone receptor-positive and there were four lymph nodes involved, you were eligible. If you got the chemotherapy first, if there was any residual disease at all, invasive disease; if you had triple-negative breast cancer; or if you had a hormone receptor-positive, they looked at different factors: the size of the tumor, how aggressive the grade was, and they had a score. And if it was greater than that, then you could be randomized to 1 year of olaparib versus observation.
And at about 3 years, there was a big difference of invasive disease-free survival, improved from 77.1% to 85.9%. And then distant disease-free survival — so stopping the cancer from spreading somewhere else in the body at 3 years — was improved from 80.4 to 87.5% of the people who participated. And given that is a big difference, the study was stopped and it was reported. It was also published at the same time in the New England Journal of Medicine. And I think this is really practice-changing for patients with germline BRCA mutation. And especially, what the investigators did is really look for those patients who had a high risk of relapse, and what could they do to change that?
One of the other things that was presented — and I did present this trial, for full disclosure — was the NEOTALA trial. And it was looking at something in a slightly different way. And that was, instead of chemotherapy, could there be a group of patients identified that if you just gave them that pill, that talazoparib — one pill per day for 6 months and no chemo and took them to surgery — could you get responses that were similar to that of chemotherapy? And the trial was actually truncated and stopped after halfway — nothing to do with the trial, the patients, the efficacy, anything, but just a decision by the company who was going to go a different way.
But I think what the trial did show was a significant response with pathologic complete response rates very similar to what we see to polychemotherapy. Because it was a small trial, it did not cross what they had hoped for the statistical significance, but I think showed that there was a group of patients who, when they took them to surgery, there was no invasive cancer left.
And I think that these two studies with the same class of drugs really looked at two ways that we’re thinking about research: how do you pick out those patients that have a more aggressive disease, and where and how should we add more? That’s the OlympiA trial. And then, is there a way that we can more target and tailor the trial to try to get the same results, but maybe not expose the patient to as much? And that’s the NEOTALA.
So, I think that you’re going to see a lot of work in both ways: instead of just giving everyone the same drug the same way, I think we need to be much more thoughtful of how we develop these trials, these drugs, and to make sure that we’re not just adding more and more and more. But really identifying the patients that could best be helped.
Jamie DePolo: Okay. That is very interesting and very promising, and it actually raises two more questions to me. Do you think that these two PARP inhibitors, that there may be applications put in to have the indication be for early-stage breast cancer?
Dr. Jennifer Litton: Well, I think that with the OlympiA trial, I certainly hope so. It was a randomized, well-run phase III trial that I think met all of the independent statistical set points and I think is practice-changing for someone with a high-risk early breast cancer and a germline BRCA mutation.
Jamie DePolo: Okay.
Dr. Jennifer Litton: I think that the preoperative alone, single agent is something that I think we’re going to see a lot more research going in that direction as well and expanding that prior to considering that just routinely standard of care.
Jamie DePolo: Okay. And I’m also wondering, given these results, do you think we’re moving in the direction of sort of immediate genetic testing for a BRCA1 or BRCA2 mutation if someone’s diagnosed? Because otherwise, right now — at least my understanding is — these PARP inhibitors wouldn’t be given unless you knew somebody had one of those mutations.
Dr. Jennifer Litton: Exactly. So, right now we’ve looked at PARP inhibitors by themselves for patients who don’t have a known germline mutation. The only other group of people that we’ve routinely shown them to work by themselves is people who maybe don’t have the inherited gene, but in their tumor itself the gene’s not working, and we certainly have seen that respond. The other group of people is — that have on these big panels, there are a lot of different mutations that kind of orbit around BRCA1 and 2, but they’re not all BRCA1 and 2, and they don’t all respond to PARP inhibitors in this class of drugs the same.
There’s a lot of research going there except for, I would say, in my opinion, one group, and it’s a very small group of patients who have a PALB2 mutation, PALB2, where this seems to be very similar. It’s linked in its function to BRCA2, and in studies in the metastatic setting, we’re seeing very similar results to PARP inhibitors.
So, I would hope that future studies looking at germline BRCA mutation carriers will also start including patients with PALB2 mutations. I don’t think it’ll be very hard, although I think efforts are ongoing to have a really large standalone PALB2 mutation carrier study in particular, but it is something I think we need to consider as we move forward with designing these trials.
Jamie DePolo: Okay.
Dr. Jennifer Litton: Oh, so that goes to your question about the genetic testing.
Jamie DePolo: Right!
Dr. Jennifer Litton: I really went all the way around that, didn’t I? But you know, I can only — and my personal belief on this — is that when we think about patients with metastatic breast cancer, 5% or less of the patients have a germline BRCA mutation. And yes, the vast majority of them we can identify from other hints in their tumor or their family history, but because they had a very effective option in the metastatic setting, most guidelines did warrant that germline testing should be happening for anyone with metastatic cancer. I think that if you have an aggressive early-stage breast cancer and this becomes available and approved, I suspect that we would definitely be moving to germline testing for early-stage breast cancer as well.
Jamie DePolo: Okay.
Dr. Jennifer Litton: But that is my personal opinion at this point. We’ll have to wait to see what all the guidelines feel about that.
Jamie DePolo: Sure, of course. And I know that even some of the professional societies have different ideas about what should be done when, but it’s just interesting to see this particular class of medicines being effective in early-stage disease. And so, it just got me wondering.
Dr. Jennifer Litton: Yeah.
Jamie DePolo: So, were there other studies that stood out for you? Other breast cancer studies that you think are either practice-changing or really noteworthy that maybe people are going to see it in their doctor’s office or talk about it in their doctor’s office soon, it’s going to make a difference?
Dr. Jennifer Litton: Sure. I think in the hormone-receptor-positive setting of breast cancer, we had two updates on the MONALEESA-3 and the PALOMA-3 trials. These were both trials for patients with metastatic breast cancer and had endocrine therapy plus a CDK inhibitor, and that was palbociclib and ribociclib in the two different studies. These have been around and have been approved and are widely used, because the progression-free survival of these early trials were so impressive. In fact, I can’t think of another group that had such an impressive progression-free survival, where we’re talking over 2 years on a single line of therapy in a metastatic setting. But these further updates with longer median — for the PALOMA-3 it was 73.3 median months follow-up — and we see now a significant overall survival benefit.
So, I think further solidifying not only improvement of progression-free survival, but really important and often really hard to prove in a metastatic setting is overall survival. I think if you dig down to the data and look at the time to response to these drugs and the depth of the response — you know, when I first started in oncology we were all taught that if the cancer is in an organ like the lungs or the liver, you had to go right away up to multiagent chemotherapy. And in fact, I think these studies and these further updates solidify for me that they really hold their place in the first-line setting for patients regardless of where the metastases may be.
Jamie DePolo: Yeah, those were very, very exciting to see that overall survival. Because I know that always takes longer and longer follow-up, and it’s basically just waiting to see what the data is going to show. So, to me that’s always exciting, yeah.
Dr. Jennifer Litton: I think that there was some talk in there, too, about progression-free survival, too, and measuring from the time of randomization to the time they moved on from whatever they got after the trial. And I think a lot of that was based on some early thoughts that maybe there were some rapid progressors and that maybe they would do even worse. Like, they would keep controlled but then do worse on the backend after you took them off the CDK inhibitor. And these trials really showed us that that wasn’t the case. So, I think it was also very helpful for that.
I think there’s a lot of really exciting drugs in that ER-positive metastatic space that are under investigation. Different in the class of drugs, like fulvestrant, where not just blocking estrogen but actually degrading the receptors. I think we’re seeing multiple phase III trials with these drugs, and hopefully we're going to see some new options out there for us to be able to use in patients in the next several years.
We’re looking at other drugs, SERCAs — so these are highly selective ERα covalent antagonists — so another whole new class of endocrine agents that are out there that we can be using.
I think that when I think of other trials, obviously I have a lot of interest in immunotherapy. We have two drugs in the metastatic setting — atezolizumab and pembrolizumab — that have been approved. And we have several trials — the NeoTRIP, the IMpassion031, and the KEYNOTE-522 — that all looked at neoadjuvant or preoperative therapy for patients with early-stage breast cancer. And although it improved pathologic complete response, the question is, well, what does that mean for long-term response and does that really translate into something meaningful for patients?
And the reason that’s important is because these immunotherapies really aren’t without toxicity. They can come with lifelong things like requiring thyroid replacement, other endocrinopathies, other side effects that, when you do get them, they can be quite severe. And so we want to make sure we’re not just adding them without actually adding benefit. Now, we’re waiting for the actual report from KEYNOTE-522. We had a press release saying that the event-free survival was improved, but we haven’t seen that data, and we’re waiting for that to be presented.
But the GeparNuevo, which is a European study, did present. It was a small study of 174 patients with triple-negative breast cancer, and with nab-paclitaxel and durvalumab followed by anthracycline and durvalumab followed by surgery.
And there was an improvement in pCR, or pathologic complete response, from about 44% to about 53%. But they presented the invasive disease-free survival with a median follow-up of 43.7 months, and that did show improvements in 3-year survival, distant disease-free survival, and starting to see signals with overall survival. So, really, also, as we think about pathologic complete response as a surrogate, we may have to rethink how we look at that also when we’re talking about immunotherapies where we may see even bigger responses after the fact.
So, I thought that that was really interesting from that GeparNuevo, and we’ll wait to see what the larger KEYNOTE and the IMpassion031 have in further follow-up. But the KEYNOTE is the one that was really set up to look at that event-free survival.
Jamie DePolo: I just want to ask, I just want to make sure — and I’m probably going to mispronounce it — but durva, the one that starts with a D.
Dr. Jennifer Litton: Durvalumab.
Jamie DePolo: Yeah. That is not approved to treat breast cancer yet in the United States is it?
Dr. Jennifer Litton: No, not in the United States.
Jamie DePolo: Okay.
Dr. Jennifer Litton: Yes. Well, none of those are FDA-approved for preoperative chemotherapy. We only have those — atezolizumab and [pembrolizumab] — in the metastatic setting only.
Jamie DePolo: Got it. Okay. Okay. Sorry, go ahead. What else exciting happened?
Dr. Jennifer Litton: I’m trying to think...
Jamie DePolo: Well, there is one study I wanted to ask you about, and I don’t know if you saw it. I thought it was interesting because it was — patients participated, and it was about dosing, especially for people who had been diagnosed with metastatic breast cancer. And the idea is that when the clinical studies are done it’s basically looking at, okay, what’s the maximum dose that is effective and can be tolerated? Because I think the thinking has always been more is better — like so much in American life, if one is good, 20 is better.
And so this particular study was taking the premise that, well, this is often looked at for early-stage disease, but with somebody with metastatic disease who may be on this particular medicine for 5, 10, however many years, is that dose really appropriate? And it was serving people with metastatic disease and asking, “Are you open to a dose reduction or at least talking to your doctor about changing the dose?” And I just wondered if you saw that, and what you thought of it? And if you didn't, that's fine, I was just curious.
Dr. Jennifer Litton: I’m sure I did, but I do think, I think this goes into how we traditionally did studies, right? You did a dose escalation until you had too many toxicities, and then you backed off one dose level, and that’s how you just rolled. And maybe that was the case for chemotherapy, although that’s still debatable. And we know, the high-dose stem cell transplant type of thing did not work consistently in breast cancer or is not considered standard for breast cancer. But as we start to think more about these more targeted and designed drugs that are very specific, I think that you’re going to see that many more of the trials have blood draws and also biopsies.
And one of the reasons is, what is the actual biologically active dose? And I think that that’s going to be a very important thing to look at — if you block a receptor at dose A, giving dose A plus 20 won’t matter if you’ve already blocked it, and you might just be gaining toxicity. So, how we think about measuring what the dose should be really depends on, are we actually hitting the target that we’re now looking at instead of just kind of putting something out there that just hits everything and hopefully the cancer, too? And really being thoughtful about that. And that’s why with clinical trials, you’ll often see a lot more companion information — blood, tissue, things like that — to try to better understand that.
We know from patients in metastatic cancer that for breast cancer, we’ve shown that actually, some of these aromatase inhibitors, which can have really life-altering side effects for our patients, sometimes taking a couple of weeks or a month break and restarting can help reset some of the side effects.
But I think that it’s a reasonable and important conversation to have with your caregiver as far as dose reductions when appropriate for your quality of life and side effects. When we looked at trials — and I’m thinking specifically the PARP inhibitor trials and the CDK inhibitor trials — a large portion of patients in both of these classes of drugs needed a dose reduction or a dose delay. And yet how well the drug worked didn’t change if you had that dose reduction or dose delay. So, I think that those aspects of trials are really important when you’re presenting that to a patient.
Jamie DePolo: This has all been really helpful.
Dr. Jennifer Litton: Thank you.
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