Episode 55: New Approvals for Breast Cancer

Dr. Virginia Kaklamani joins Healthcare Unfiltered EXPRESS to discuss the recent FDA-approved indications for T-DXd in breast cancer, and what this means for treating patients with the disease. A critical episode ahead of the annual ASCO meeting. Check it out, subscribe, rate, review, and join the conversation.

Transcript

SPEAKER_00 0:12

Enjoy the show. Well, excited to have you back. Virginia, thank you so much for coming on Healthcare and Fruit Tood Express. You always are very generous with your time, despite how busy you are. But that's a testament that you love teaching people and you love sharing knowledge with people. So thank you.

SPEAKER_01 0:34

Thank you. I just love talking to you, Charlie.

SPEAKER_00 0:36

I love talking to you as well. And uh we're taping this before ASCO, and we are gonna actually air it even before ASCO because certain things just can't wait. Uh, and I've asked you to come on the show to talk a bit about some approvals, recent approvals that came on in breast cancer. We're gonna try to put those in context of managing breast cancer as a disease, whether it's early stage or late stage. So, what are these new approvals that we just heard about uh over the past week or so?

SPEAKER_01 1:02

So, what the FDA did was it took two clinical trials, the Destiny Breast 11 and the Destiny Breast05, that looked at the early stage uh incorporation of TDXD into the treatment of HERT depositive breast cancer and then uh approved TDXD in that early stage setting. So, just a reminder to the viewers, uh DB11 was a neoadjuvant trial. It had three arms. The first arm was the standard of care ACTHP arm, and then the second arm was TDXD for eight cycles. That arm did not meet the um the pre-specified endpoints, and so the efficacy data has not been presented yet. But then there was the second investigational arm, which was TDXD for four cycles, fall fall by THP for four cycles. And what the trial showed, and it was presented last late last year, was that the arm of TDXD fall by THP had an improvement in pathological plate response compared to TCA to ACTHP. There was some update recently looking at the RCB rate, and that also was increased compared to in the TDXD arm. Now there's no long-term data from this study yet, it's not mature enough. Uh, but that's why the FDA was looking at the destiny breast 05 trial, which was the adjuvant use of TDXD. So here we're taking patients that have received new adjuvant therapy, have residual disease at the time of surgery, and then go on to either receive TDM1 per the cathering trial, which is the standard of care, or receive TDXD. And these were high-risk patients. And uh the trials showed that there was an improvement uh in uh in event-free survival with the use of TDXD compared to TDM1. So they took both of these trials that showed that uh that showed that TDXT is superior to just standard of care, ADC or chemo, and approved TDXD in this setting. Uh great for our patients. I think it raises a big question: where how do we use TDXD now? Do we use it in the neoadjuvant setting or do we use it in the adjuvant setting? And I think you're going to hear debates about each one of these approaches for the next year or so until we have event-free survival data from Destiny Breast 11.

SPEAKER_00 3:13

So the approval is for neo-adjuvant and adjuvant.

SPEAKER_01 3:16

Correct.

SPEAKER_00 3:18

Okay, so but but but essentially you can give it new, is it that you have to do neo-adjuvant and adjuvant, or you could choose and mix? You do a neoadjuvant.

SPEAKER_01 3:27

Well, you're gonna have to choose one of the two approaches, and that's the unfortunate uh thing about these trials because they were independent trials. So if you decide to use it neo-adjuvantly, you know, the argument that people make is first of all, it's just four cycles of TDXD followed by THB. So the safety is much better with that approach. You have a 67% uh PCR rate with that approach, which is much higher in the ER negative compared to the ER positives, around 80 so percent in the ER negative HER2 positives, 50% in the in the triple positives. And if you do achieve PCR, that's great. You can just give HP in the adjuvant setting. Now the question is, what if you do not achieve PCR? Right. Then what do you do adjuvantly? Do you give more TDXD? We don't have any data. Do you give TDM1? And we don't really have data of the efficacy of TDM1 after TDXD. So that's really the concern with that approach. Now, with the with the Destiny Breast of 5 approach, you just give whatever new adjuvant therapy you want to, which, you know, in this country, most of us would be giving TCHP for six cycles. And then if there is residual disease, which is again in around 40% of patients, then you give TDXD, but now you give it for 14 cycles. So a lot more exposure to TDXD compared to the Destiny Breast 11 approach, where you just give four four cycles of TDXD. So it's a little, you know, the inclusion criteria are a little different. The FDA didn't really go into all that, just at high risk. Uh, but if you look at the inclusion criteria for the Destiny Breast 05 trial, these were patients that had uh either inflammatory breast cancer, node positive disease at the time of presentation, or inoperable breast cancer to start with. So these were your very high risk hertopositive breast cancer patients.

SPEAKER_00 5:15

So a general oncologist who's not seeing breast cancer only, who's just seeing it's a general oncologist. How do you think what do you predict how they're gonna take this data and how they're gonna approach patients? Because I think real-world data will be interesting with this information you described, actually. I'm trying to put the hat of a general oncologist. Uh I'm, you know, some of them will be calling you and say, hey, what should I do? But but some will probably, I don't know.

SPEAKER_01 5:44

I I think there's such a such a big movement toward antibody drug conjugates this day these days. There's the the re the the responses and the and the benefit from TDXD as well as others has been so big that our general oncologists love using them. So I have the feeling many of them will try the new adjuvant approach, giving TDXD for four cycles fall by THB. That's also an anthracycline-free regimen. Um, you can always make the argument if you don't get a PCR, you can just give AC adjuvantly. So a lot of different approaches people will do. Just a reminder that none of this was built into the clinical trial. Yeah. And also that we don't have long-term outcomes with uh with this approach.

SPEAKER_00 6:26

Um, so I suspect some people will get TDXD adjuvantly if they don't have PCR.

SPEAKER_01 6:32

That's what I will likely uh um move towards until we get the the the long-term data from the Destiny Breast 11 approach, uh, because we do have longer uh data with uh DBO5.

SPEAKER_00 6:45

Great approvals, helpful for patients, as you said, may create some temporary confusion, I think. Hopefully this will uh the dust were settled. But maybe uh sticking on the theme of uh either ADCs or something else. Uh, we just recently had the ESMO breast also concluded. Anything that might that uh intrigued you, aligned with the ADC specifically, TDXD, anything that might kind of like have the same theme?

SPEAKER_01 7:11

I think yeah. So the CETIN trial was presented, which is a smaller trial, it's a phase two trial, but it looked at HERTO positive breast cancer patients that had received TDXD. And after progression on TDXD, they were given sacetismab govotican plus strastisimab. Now, this is the first data that we have on sacetismab in her topositive disease, uh, but obviously sacetismab does, you know, targets um uh TROP2. So when we know that there's TROP2 receptors in in any breast cancer, including HER2 positive. So the the trial was very disappointing, but taught us a lot of lessons. So when you look at the response rate from the trial, only 3.7% response rate with sacetismab. Progression-free survival, 2.3 months. So basically, this approach did not work. And this is really the first clinical trial data that we have on ADC fall by ADC. And the lesson that we're learning is that if you have an ADC with the same target, and the target being a topoisomerase one inhibitor, and the patient's cancer has already progressed on one topo one inhibitor, the likelihood of having a response with the second one is really low. And I'm not sure why it's taken us all of these years to figure this out because we've known this with chemotherapy for a long time. We don't usually give dositaxyl after paclitaxyl because we the target is the same. So I this is a valuable lesson. This is also important for the pharmaceutical industry to start looking at ADCs that do not use topoisomerase-1 inhibitors as their payload, because it's important that we find better ways of sequencing these ADCs.

SPEAKER_00 8:51

But you could imagine ADC that has a different payload may work after another ADC.

SPEAKER_01 8:57

Absolutely. And this is where the mechanisms of resistance of ADCs come to play. We know that one of the mechanisms is a Topa 1 uh mutations, but obviously another mechanism is HER2 mutations or TROP2 mutations and so forth. So if in the future you know we we have uh a nice tool that shows us in real time what the generation of mutations is, then that'll help us find a better ADC approach. Uh but right now we don't we don't have that, we can't predict that in real time.

SPEAKER_00 9:29

Anything else?

SPEAKER_01 9:31

Um another interesting uh data set was from the pre-Copera study. And this was a window of opportunity trial in patients that have estrogen positive uh early stage breast cancer with the use of geodesterin. And they looked at gerodesterin in premenopausal women with and without an LHRH agonist, as well as an AI with an uh with an LHRH agonist. And the bottom line is as predicted, if you give geodesterin with an LHRH agonist, you're decreasing the key 67 more. Um, and and so we you know we've kind of suspected that, but we also know that some patients may not be able to tolerate ovarium suppression. And in those patients, the use of gerodesterin by itself still decreased the key 67, just not as much as uh in the patients that also uh had uh received an LHRH agonist. So I think again, this is a nice small study, uh thought-provoking, and and and will help us in the future in how we plan uh to use these oral surge a little bit better.

SPEAKER_00 10:36

Yeah, I'm I'm very interested in oral surges because they're like completely seemed like a new class that's gonna really take over pretty much the entire world of breast cancer. Uh, anything else before I let you go back to your busy schedule?

SPEAKER_01 10:49

I I think the last uh uh study that I liked was the TRAC ER study. And this was a study in patients with high risk disease, ER-positive breast cancer, early stage setting. And they looked at CT DNA, so the the the role of MRD. And a couple of interesting things that came from this. So even though this was a high-risk patient population, four more positive lymph nodes, one to three positive lymph nodes with high-risk features, more than five centimeter tumors, only 11.6% of these patients actually had or at some point had a positive CT DNA test. So a very small number. Out of those, 11%, 42% already had positive scans at the time of a positive CT DNA test. The majority of those had distant disease, 87%. So there were some local recurrences that were caught with that approach, but the majority was metastatic disease. So uh this study is also going to be randomizing patients to receiving uh a CDK4-6 inhibitor or not. So we'll see some long, longer uh term results from the study. But this is something that we need to think about, especially for the people that are already using MRD in breast cancer, because we do not have any predictive data. We had prognostic data, and and this study confirms the prognostic significance of MRD, but no predictive data. We don't know what to do if there's a positive ct DNA test. So in my practice, I don't usually uh I don't use uh MRD.

SPEAKER_00 12:15

Before I let you go, just one quick thing because I saw only 41% of patients with CT DNA positive had positive scans. The remainder also was CT DNA positive, false positive?

SPEAKER_01 12:30

They had positive scans at the time of the first CT DNA positive result. There's usually a lag time, and for ear positive disease, it's longer than for ear triple negative. For triple negative, around 70 to 80 percent of these patients will have positive scans. So at some point, these patients, the majority, will develop metastatic disease, but not at the time of diagnosis of that positive CT DNA. And so the thought is maybe we can salvage the patients by changing endocrine therapy. We don't have those results yet, but uh hopefully they'll get generated in the future.

SPEAKER_00 13:02

Yeah, well, I'll stay, I'm gonna try to be not biased, but I I do think in the future that is going to move from prognostic to predictive. Today you're absolutely correct. It's we don't have that data, but it's hard to believe that we can it is disease. I mean, CDDNA positivity is actual disease. It's a matter of whether you need to intervene today or tomorrow, kind of thing.

SPEAKER_01 13:24

Agreed.

SPEAKER_00 13:25

Dr. Virginia Caklamani, always wonderful to have you on Healthcare Unfiltered Express. Thank you.

SPEAKER_01 13:31

Thank you so much.

SPEAKER_00 13:33

Thank you for listening to this edition of Healthcare Unfiltered Express. Until next time. Take care.