2023 ASCO Takeaways

This podcast episode is made possible, in part, by a grant from Lilly.

Jamie DePolo: Hello, thanks for listening. I’m podcasting from the 2023 American Society of Clinical Oncology Annual Meeting. My guest today is Dr. Stephanie Graff, director of breast oncology at the Lifespan Cancer Institute at Brown University and co-leader of the Breast Cancer Translational Research Disease Group. She is going to explain the most applicable research on breast cancer presented at this conference.

Dr. Graff welcome to the podcast. Thanks so much for doing this.

Dr. Stephanie Graff: Thanks so much for having me again, Jamie. It’s a pleasure to be here. 

Jamie DePolo: So, in your opinion what was the top breast cancer research we heard about this week?

Dr. Stephanie Graff: I feel like CDK4/6 inhibitors stole the show, again. And, of course, then ADCs were in, I guess, kind of a never-ending circle in the story of breast cancer with those two themes continually…

Jamie DePolo: And ADCs just to let everybody know, antibody-drug conjugates. 

Dr. Stephanie Graff: Antibody-drug conjugates, exactly, yeah.

Jamie DePolo: Okay, perfect. So, tell us about the CDK4/6 inhibitors. To me, from the presentations I listened to, I thought it was, there was some controversy, but I’m not an oncologist. So break it down for us. 

Dr. Stephanie Graff: Yeah. So, let’s start in the early-stage disease. So, when I say early-stage disease, I mean curable breast cancer. And this week we saw the results of the NATALEE trial. NATALEE looked at the use of ribociclib for patients with early-stage breast cancer. Specially, NATALEE was expanding the patients that are potentially eligible for a CDK4/6 inhibitor with early-stage, hormone receptor-positive breast cancer. We already have abemaciclib approved in that space, based on the results of the monarchE trial, but the monarchE trial took patients that either had lymph node positive breast cancer -- that was four or more positive lymph nodes -- or patients with one to three positive lymph nodes and additional risk factors. 

Jamie DePolo: So, high-risk.

Dr. Stephanie Graff: Very high-risk patients. So, NATALEE, the trial we learned about at ASCO23, included patients that had any lymph node positive breast cancer. So, if you had one to three positive lymph nodes, four or more positive lymph nodes, you were just eligible. It also included patients with T2N0 tumors. I’m going to say that not using my doctor shorthand. T2 means a tumor bigger than 2 centimeters, N0 means negative lymph nodes. 

So, if you both had a tumor larger than 2 centimeters and were lymph node-negative, you would have been eligible to be on the NATALEE trial if you also had an additional risk factor, which included a grade 3 tumor, or a Ki-67 of over 20%, or a genomic test that was high risk. So, a MammaPrint, an Oncotype, like, something that said you have a high-risk tumor.

Jamie DePolo: Okay.

Dr. Stephanie Graff: So, a much wider population, including even some lymph node negative patients, and randomized those patients to receive ribociclib plus adjuvant endocrine therapy or adjuvant endocrine therapy alone. Now, ribociclib has some drug-drug interactions, so no patients received tamoxifen because there’s a drug interaction with those two compounds. And because all of the patients were on aromatase inhibitors, all of the patients were post-menopausal. Pre-menopausal patients were allowed, but they had to be given ovarian function suppression to be eligible. 

And that outcome, we got the results of the, the second interim analysis, which met its primary endpoint. So, this was actually an early meeting of the endpoint, so at a relatively short time point so the vast majority of patients are still taking the medication. They have already met the primary endpoint of invasive disease-free survival. And what they saw was that there was a 25% -- 25.2% if we want to be nitpicky -- reduction in the risk of breast cancer recurrence -- invasive disease-free survival -- for patients that were randomized to receive ribociclib. 

Now, patients in the NATALEE trial took ribociclib for three years. And so at this short time point like 99% of the patients are still actively in that three years of therapy. And so, you know, going back in time at the first analysis of the monarchE trial, the abemaciclib trial, which they gave us also at about 24 months, everybody was like, “Well, we’ll just wait to see what happens after people have been off that drug for a while.”

Jamie DePolo: Right.

Dr. Stephanie Graff: But now we’ve seen that monarchE curve continue to separate over time, where at that first interim analysis the delta, the difference, the change, was 2.4, I’m sorry 2.8%, and it’s continued to widen to 6.4% and now I think it’s at 8.3%. It just keeps getting wider and wider as they get farther out. The delta on NATALEE is 3.3%.

Jamie DePolo: So, it’s already higher than the monarchE trial.

Dr. Stephanie Graff: Yeah, well, again that’s a dangerous cross trial comparison, right?

Jamie DePolo: Yes, yes. 

Dr. Stephanie Graff: We don’t do it, we don’t compare that.

Jamie DePolo: Right.

Dr. Stephanie Graff: But it’s, at the very least, comparable to the monarchE if you look at the same basic time point even with a smaller, like, a potentially lower risk population.

Jamie DePolo: Right. 

Dr. Stephanie Graff: So, you know, I think Nadia Harbeck, who’s, you know, a worldwide, internationally recognized breast oncologist, did the discussion of the presentation and her conclusion was that we now have two standards of care in this space. And I agree with that. I think that this gives us, we don’t have an approval yet so I can’t write a prescription for it tomorrow, I think insurance may balk at us.

Jamie DePolo: Right.

Dr. Stephanie Graff: But I think that this really is going to open up the possibility. I hope to see that we move toward that. I think that what’s going to fall into our thinking then is the individual choices of two years versus three years, cost of drug, side effects, because there’s a difference in what to expect with abemaciclib versus ribociclib. Eligibility, whether somebody is monarchE eligible versus NATALEE eligible.

Jamie DePolo: I see.

Dr. Stephanie Graff: I tend to be a purist in who I choose for which treatment.

Jamie DePolo: Sure.

Dr. Stephanie Graff: And we’ll wait to see how the medical oncology community, and perhaps more important, regulators and payers, react to this early data.

Jamie DePolo: Right. Okay, yeah, no I thought it was very exciting. It seems like it could expand a CDK4/6 inhibitor to a lower risk population.

Dr. Stephanie Graff: Yeah.

Jamie DePolo: So, as you said we have to wait and see. What, I know there were a couple of other CDK4/6 inhibitor presentations.

Dr. Stephanie Graff: Yeah.

Jamie DePolo: Did you want to talk about those?

Dr. Stephanie Graff: So, just to, just to sort of stay in the early-stage disease space.

Jamie DePolo: Okay.

Dr. Stephanie Graff: The other two may be, actually, let’s do the other three early stage topics that I think are important to talk about. We saw an update on the monarchE trial, the abemaciclib in curative breast cancer that we just talked about. And that trial showed us that it was an analysis of the, I hate to say, elderly because we define that, right?

Jamie DePolo: Right.

Dr. Stephanie Graff: You laugh. We define that as age over 65. And I jokingly always tell people you’re not old until you’re older than my parents who are in their 80s now, so the over-65 population. And the over 65 patients derived the same benefit. Their magnitude of benefit, the efficacy, how well the medicine worked, was identical. So, I think that what that told us is that there’s no reason to shy away from treating a 65-year-old, a 70-year-old exactly the same, offering them the same treatment. 

Buried in that presentation was a single slide, that I think was so important, that wasn’t in just the age over 65 population it was in all comers. And that slide, so the presenter taught us that patients over the age of 65, despite having the same rate of side effects, were more likely to have dose reductions, which is probably bias on the part of physician investigators, right? 

Jamie DePolo: They assume they’re going to have more side effects or…? 

Dr. Stephanie Graff: Yeah, or they interpret their side effects more harshly and so dose- reduct…reduce off-protocol, I don’t even know how to interpret that. Anyway, as a counter to that, they gave us the data for the whole population, not just the age over 65, that showed that the outcomes of patients treated with adjuvant, or curative abemaciclib, regardless of dose reduction, was identical, which is amazing. 

Jamie DePolo: Right.

Dr. Stephanie Graff: That’s such a helpful pearl for me, as someone who prescribes these medicines, to be able to say, you know what? If you’re having side effects we can reduce your dose and your outcome’s going to be the same. Because I think especially when we’re talking about curative disease a lot of people feel like, gosh, if I lower my dose am I still going to be able to, you know, beat this thing? 

Jamie DePolo: Right. Right.

Dr. Stephanie Graff: Yeah, I think it really supports that.

Jamie DePolo: Yeah, no, that was, I thought that was very great too, especially if it’s going to help decrease side effects.

Dr. Stephanie Graff: Yeah. The second one, which is now the third one we’re talking about, is Dr. Richard Gray gave us a follow-up on a meta-analysis of over 15,000 patients, just at 15,000 patients, all pre-menopausal, to, again, look at the question about whether or not ovarian function suppression was beneficial. And the resounding answer is, yes. Offering ovarian function suppression reduces the risk of recurrence and death by about 18%. Ovarian function suppression is inexpensive. It certainly comes with side effects, for some, not all. 

And so, I think that with that magnitude of benefit that it’s always a conversation that we should be having with pre-menopausal patients, especially when you layer on top of it that we also know that aromatase inhibitors are better, and CDK4/6 inhibitors also continue to improve outcomes. So, for a pre-menopausal patient we can just layer, and layer, and layer, and each of these incremental steps continues to offer us a better and better outcome. But that magnitude of benefit, that 18% reduction, is really important. 

Another pearl that came out of that meta-analysis was that not only did it reduce the risk of breast cancer recurrence and death, there was no increase in other causes of mortality. I think that what we often think is that, well, if we do ovarian function suppression surely we’re going to cause other negative health effects. And we didn’t see that those pre-menopausal patients then had an increased risk of, you know, cardiovascular deaths or other, you know, ill-health effects. And so, I think…

Jamie DePolo: Bone problems.

Dr. Stephanie Graff: Yeah, I think we can, we can rest assured that, you know, it doesn’t cause, and I don’t want to say significant impact on their risk -- their health -- because obviously, again, there are side effects, but it doesn’t negatively impact the risk of death. 

Jamie DePolo: Okay.

Dr. Stephanie Graff: Last was just a poster that I want to mention, because I think it’s a simple thing to think about. There was a poster, poster number 376, that looked at the time of day that people take their medications and how it intersects with the sort of complex hormonal environment that is our bodies, the petri dish that we walk around in, and what that poster shows was there that there’s really no difference with aromatase inhibitors. But that for patients taking tamoxifen in the evening as compared to patients taking tamoxifen at night. I’m sorry that’s the same thing. 

Patients taking tamoxifen at night have a better outcome than patients taking tamoxifen in the morning. And you know, it doesn’t cost a darn thing to change your tamoxifen to a nighttime dose. And you know I don’t know that we’re ever going to design a phase III randomized trial to have people switch their pills to nighttime dosing. And again it’s such a simple switch for most people currently taking tamoxifen to take that, and I clearly have no evidence that it would harm anyone to take it at night, that I think that even though that was just a poster it’s worth considering. 

Jamie DePolo: Were there any ideas why the time?

Dr. Stephanie Graff: Yeah, I mean, it’s complicated. There’s a lot of really, really elegant biochemical reasons that have to do with our clock hormones. I mean, we’ve known for a long time that our hormonal regulation has a lot to do with our circadian rhythm. If you think back, shift workers actually have a higher risk of breast cancer, which probably has to do with circadian rhythm dysregulation. We also know that things like cortisol balance and our hormonal cascade surges and troughs at different time points based on what is happening with our hormone levels that regulate our sleep cycle. And so, we think that maybe just taking tamoxifen at night has the biggest impact on that estrogen balance in, as a pre-menopausal woman. And so, here we are.

Jamie DePolo: Okay. Well, then that kind of makes sense if that’s kind of the rationale behind it. 

Dr. Stephanie Graff: Yeah.

Jamie DePolo: Because I mean aromatase inhibitors are either in post-menopausal women or women who have ovarian suppression.

Dr. Stephanie Graff: Yeah.

Jamie DePolo: They don’t have as much estrogen so that makes sense.

Dr. Stephanie Graff: Exactly. Exactly. 

Jamie DePolo: Okay. All right, what else was exciting?

Dr. Stephanie Graff: So, now, I mean, we can move to the metastatic space if you want.

Jamie DePolo: Sure.

Dr. Stephanie Graff: Yeah. And so, continuing our CDK4/6 inhibitor theme, right, so the metastatic setting. I think that in the metastatic space, you know, I guess maybe the controversial presentation is the SONIA trial. The SONIA trial was done in the Netherlands, which randomized patients to first-line CDK4/6 inhibitors followed by second-line hormonal therapy versus first-line hormonal therapy followed by second-line CDK4/6 inhibitors, okay? In the first-line CDK4/6 inhibitor followed by second-line hormonal therapy, the second-line hormonal therapy was mostly fulvestrant, okay? 

And it showed that there was no difference between first-line CDK4/6 inhibitor and second-line CDK4/6 inhibitor in terms of progression-free survival, overall survival, or quality of life. And that there was a significantly increased number of grade 3 and grade 4 toxicity events in patients that got a first-line CDK4/6 inhibitor, because patients that received a CDK4/6 inhibitor in the first-line took it for a longer cumulative time. Like everybody’s first-line treatment, no matter what their first-line treatment was, was longer. 

Jamie DePolo: Okay.

Dr. Stephanie Graff: And also patients that got a first-line CDK4/6 inhibitor had a substantially increased cost, again, because they took it for longer. 

Jamie DePolo: Right.

Dr. Stephanie Graff: And so, the presenter’s conclusion was, for no benefit in outcome, only an increase of toxicity both medical and financial, that this is a harm to people and society and that we should stop doing this. I think that the discussant then did a very nice job saying we see you, this is beautiful data, but it’s complicated.

So, first of all, the control arm, the first-line endocrine therapy followed by second-line CDK4/6 inhibitor did really, really good. Like, better than even historical controls in, like, the phase III randomized trials that brought drugs like ribociclib, palbociclib and abemaciclib to market. 

So, the fact that the control arm performed really well is unusual and it may raise questions about, you know, the patient characteristics. It was, you know it was entirely a one-country trial. How would that look in an international population? In a U.S.-based population? I mean there’s all sorts of comments. The study was entirely done with palbociclib.

Jamie DePolo: Right, that was something they had said.

Dr. Stephanie Graff: Palbociclib has largely fallen out of favor, in the U.S. at least, because ribociclib has an overall survival advantage. Abemaciclib is trending dangerously, I mean, we’re closer and closer. And Palbociclib does not have an overall survival advantage. So, I think that a lot of U.S. medical oncologists have switched to using ribociclib as the standard first-line CDK4/6 inhibitor in the metastatic setting because of that clear advantage. So, how substituting ribociclib would have played in that landscape. 

And then the next point is that the second-line therapy being fulvestrant for the after CDK4/6 inhibitor is complicated. 

We’ve seen in all of the post-CDK4/6 inhibitor trials that fulvestrant after CDK4/6 inhibitor doesn’t perform well. Patients have a relatively short duration of response to fulvestrant as a single agent, and now in the U.S. that’s rarely our approach. Often, you know, now we have SERDs, medicines like elacestrant for patients with ESR1 mutations, for patients with PIK3CA we do things like alpelisib. We have Afinitor that we’ll add for patients agnostic of any biomarker. We also, you know, as the landscape continues to evolve we now have the New England Journal of Medicine paper for capivasertib, so we need to see what the official approval, if it ever comes, for capivasertib looks like if it’s for the AKT altered pathway or all comers. 

And we’re still waiting on the results of the post-monarch trial to give us a better idea of after progression on CDK4/6 inhibitor number one, do we continue on CDK4/6 inhibitors? Or can we even predict who a continuation strategy is reasonable for? And so, I think that right now, the SONIA trial is probably not going to change the standard of care in the U.S., and may not change the standard of care in Europe.

It certainly already reflects the things like the ESMO and ASCO guidelines for low- and middle-income countries where access to things like CDK4/6 inhibitors is much more limited and needs to be considered in a much more complicated cost paradigm. You know societal cost is far outside of my area of expertise. You know it’s a completely different question of whether that’s something we should be considering or grappling with on a societal scale. 

Jamie DePolo: But yeah, no, it was, it was just a very interesting presentation. I was there, too, and as you said, I thought that the discussant did a nice job of sort of incorporating everything into his presentation. But it still, I guess, I’ll ask you this because what I took away from it was we kind of need more biomarkers to figure out who’s going to benefit from a CDK4/6 inhibitor after a CDK4/6 inhibitor, like, if that’s even possible. What do you think?

Dr. Stephanie Graff: Yeah, I think, yeah I do. And I think that, that is increasingly true now that CDK4/6 inhibitors are arguably the standard of care in the curative setting. Because now one of the questions that we’ll all grapple with is, so what happens when you see a patient who progressed six months, a year, five years, two years, after receiving an adjuvant CDK4/6 inhibitor? Like, where is that spot where you give them a CDK4/6 inhibitor again versus say, okay, they’re resistant to that therapy? What’s the biomarker that helps you decide? I’m, I’m on, I’m doing some of that work on the translational science teams for some of these studies, and I think we’re, hopefully we’re getting closer to being able to answer some of those questions, but we’re not there yet.

Jamie DePolo: Okay. Okay. And was there anything else in the metastatic setting that was, caught your eye?

Dr. Stephanie Graff: Yeah, I mean, I think the other metastatic topics are that patritumab deruxtecan is coming. It was a HER3 antibody-drug conjugate. Like so much these days, HER3 doesn’t matter at all, it’s the target, but nobody cares about targets apparently in breast cancer. I would love to have precision medicine in breast oncology, but we just don’t. So, so, we saw that the HER3 antibody-drug conjugate was effective in hormone receptor-positive breast cancer, and triple-negative breast cancer, and HER2-low breast cancer, and it didn’t matter if you were HER3 high, HER3 low or HER3 absent, you responded to the HER3 deruxtecan, which is called patritumab deruxtecan. So, I think we’ll see more of that drug, which for those keeping track at home, gives us four antibody-drug conjugates in the, in the breast cancer space that the target doesn’t really matter. 

So, sacituzumab govitecan, which targets Trop-2, we don’t measure Trop-2. Trastuzumab deruxtecan, which targets HER2, yes we use for HER2-positive breast cancer, but we now also get to use for HER2-low breast cancer, which is actually secret code for triple-negative and hormone receptor-positive breast cancer. And we now have datopotamab deruxtecan still in clinical development, but it targets…is another Trop-2 ADC. Again, Trop-2 doesn’t matter. And now we have patritumab deruxtecan, which is a HER3 antibody-drug conjugate, and HER3 doesn’t matter. So, we’re really good at making antibody-drug conjugates where the antibody doesn’t matter. 

Jamie DePolo: Right. And it’s just, just for people listening I want to explain, like, HER3 it’s just, it’s a protein, right? 

Dr. Stephanie Graff: Yes.

Jamie DePolo: And the drug is just aiming at that. 

Dr. Stephanie Graff: Yes.

Jamie DePolo: It’s just leading it to the protein.

Dr. Stephanie Graff: Yes. It’s a homing beacon on the surface of the cancer cell, yeah. 

Jamie DePolo: Okay. And most.. I can’t remember the exact stat from the presentation, but I want to say it was like 60%, is that right? 

Dr. Stephanie Graff: Yeah, 60% to 70% of breast cancer expresses it. But again if you don’t its fine, because we, it seems like we don’t care, right? We’re just going to give it to everybody. The other things that happened were we saw the results of the, updates on TROPiCS-02, which was sacituzumab govitecan in hormone receptor-positive metastatic breast cancer, it still works. We saw updates on the progression-free survival and overall survival. It’s a heavily pretreated patient population, but it has met overall survival endpoint, which is fantastic. 

They gave us some analysis looking at whether or not Trop-2 expression mattered. Again, spoiler, it doesn’t. And then just as a side note, one of the other things that was happening synchronously was the survivorship presentations were happening at the same time as the breast cancer presentation, and there was a presentation looking at the application of topical diclofenac.

Jamie DePolo: What is that?

Dr. Stephanie Graff: It is just a gel that you’re going to…it’s just a gel, that’s what you need to know. It is, it’s technically a pain medicine that doesn’t really work very well for pain. And adding topical diclofenac to your hands significantly decreased the risk of hand-foot syndrome for patients that were prescribed capecitabine, or Xeloda, the brand name. And I think we can all agree that that’s terrible when you get it. And so, to see a reduction in that with something as easy as a fancy hand gel is, is wonderful. So, I think, Dr. Maryam Lustberg, who was attending that session, tweeted out that it’s practice changing and if the president of the Multinational Association of Cancer Supportive Care says its practice changing, then I’m onboard with agreeing with her.

Jamie DePolo: Sure.

Dr. Stephanie Graff: Yeah.

Jamie DePolo: Oh, that sounds great. And I’m assuming it’s maybe inexpensive or you don’t, do you need a prescription for it or?

Dr. Stephanie Graff: You’ll need a prescription for it. And you know I’m sometimes shocked when, I don’t actually, because I’ve never prescribed it, because I didn’t know until today.

Jamie DePolo: Right.

Dr. Stephanie Graff: I’m sometimes surprised when we reformulate things or have to compound things how they change the cost. I mean, diclofenac is dirt cheap, it should be affordable, but we’ll see if making it a gel somehow changes that. 

Jamie DePolo: Okay. All right. Well, Dr. Graff, thank you so much.

Dr. Stephanie Graff: Yeah.

Jamie DePolo: This has been so helpful. I really appreciate it.

Dr. Stephanie Graff: Thank you.