® program entitled, “Conference Review, San Antonio Breast Cancer Symposium 2020.” I’m Dr Adam Brufsky from the University of Pittsburgh, in Pennsylvania, and joining me today in this discussion is my colleague, Dr Erica Hamilton of Sarah Cannon Research Institute, Tennessee Oncology.

Our discussion today is going to focus on the San Antonio Breast Cancer Symposium coming up in December, what the year has brought, and what we hope to see at the conference to help women with breast cancer. Let’s get started.

Let’s start thinking of the last 12 months with approvals for some of the drugs. What do you think are some of the big ones that have been approved, Erica?

The biggest story has been probably HER2 [human epidermal growth factor receptor 2]. We had trastuzumab deruxtecan approved about a year ago, in December of 2019, and then tucatinib quickly on its heels. We also had a new drug for triple negative breast cancer, sacituzumab govitecan, and we’ve seen some of the data from that this year as well. It’s been a good year for breast cancer.

 I would agree with you. I’m intrigued by the approvals; they were pretty interesting. We’ll get to sacituzumab in a minute, but trastuzumab deruxtecan has a chance to be a total game changer in our business. We’re all excited when they showed us that forest plot or the waterfall plot at the San Antonio [Breast Cancer Symposium] last year. It looked dramatic, but what was even more dramatic was the progression-free survival and the overall survival. The progression-free survival was something like 14 1/2 months, and the overall survival wasn’t reached in people who had a median of 6 regimens for their disease. We’ve got the randomized trial coming up, and we may hopefully see it at ASCO [the American Society of Clinical Oncology annual meeting] in 2021, or somewhere thereabout. 

That is something that you don’t see. When you look at all the other trials, you look at tucatinib, which we’ll talk about in a minute because I always use your patient when we talk about tucatinib and what you did. But before we get there, trastuzumab deruxtecan is a big deal, and I’m curious to hear what you think of it.

I completely agree. It’s not often that we see curves like that in breast cancer. That reminds me of the TRK [tropomyosin receptor kinase] alteration curve, and we don’t get things like that in breast cancer. That was impressive. You certainly have to feel good putting a patient on a therapy when you’re almost guaranteed that they’re going to get some benefit from it.

You brought up an important point about the duration of response. For how heavily pretreated these patients were, that’s a meaningful response. We’re all getting a bit more familiar with the ILD [interstitial lung disease] or pneumonitis. Pneumonitis was certainly a concern, and it’s still a concern, but it seems to be true that there are more and more drugs across our oncology portfolio for which we’re having to keep a close eye on pneumonitis and caution our patients to let us know if they’re having any symptoms.

 I agree. The other big one was tucatinib. The cool thing about tucatinib is that they were really bold in the HER2CLIMB trial. I keep using your patient and what you said about it. You put people on it who had active brain metastases who weren’t getting radiotherapy, and you saw responses. I always use that. You had someone who had a 4-cm lesion. That is great.

Before I get a bad rap, that was an exception.

 No, it’s not a bad rap at all because the woman had a dramatic response, right?

Yes, absolutely. We all have those patients. When somebody asks you about how many patients you have who are actively progressing in the brain, and you say, “a handful,” right? That adds up, especially for people who have already had radiation, and their cancer is growing again. That’s a horrible prognostic situation. To have a drug like this that gets into the brain is meaningful.

The other thing I like about tucatinib is that it doesn’t add a whole lot of toxicity to the backbone with which it’s given: capecitabine and trastuzumab. We certainly see hand-foot syndrome, and we see diarrhea. In my experience, I don’t think tucatinib adds to the diarrhea of what I would expect to see in patients with capecitabine. Some have very little, and some have more; that’s my experience with capecitabine in the clinic as well. You certainly have to watch the liver function enzymes.

With brain metastasis, we’re curing more and more patients who are presenting with early HER2-positive disease, even patients who have had advanced disease, such as node positive disease. For those patients who have cancer that comes back, the new statistic is that up to 50% of them will have brain metastasis at some point. Making sure that we develop great drugs systemically is important, but making sure that we have options for brain metastasis is also important.

 I couldn’t agree more. I’ve seen a number of people now in my practice for whom it’s incredible. To think that you have people who progress through the radiation with multiple brain metastases, the scenario used to be that you’d say, “I could reradiate you,” and we all used to do that. We used to give a second course of whole-brain radiation, and you’re now talking about 5000 rad. You’re getting up there. To have something that can give them a decent response—we’re talking 12 months, maybe even longer on average, survival improvements—is a big deal.

I agree. I like the data that are also looking at patients who had a CNS [central nervous system] progression event, and they then stayed on therapy after radiation.

They continued to do better than the other arm as well. It’s encouraging us that tucatinib is going to be active for our patients with brain metastasis.

 I agree. The last big thing to talk about was the approval of sacituzumab govitecan. This is for a terrible prognosis of disease: people who have been through a third line of triple negative breast cancer treatment. Who survives to that? It’s incredible, and you see a doubling of the survival benefit. The hazard ratio was only 0.47 or something like that. That’s absolutely incredible.

Yes, absolutely. Unfortunately, the thing that also stood out to me on that trial was the progression-free survival of what we would consider standard of care chemotherapy.

These are chemotherapy treatments that we give third-line patients all the time, which have a progression-free survival of 1.6 months. We need better.

 We just scanned them, then we’re done, and they progress, right. It has no activity. I agree with you that this will be the new awful baseline that we’ll all be able to use as we figure out where to go next. A lot of people are thinking, there may be some immunosuppression going on. Can we believe it? We’ll be able to use that new baseline when we start to test out all these new drugs in that setting. That was pretty cool.

Breast Cancer Treatment: Year in Review

 Let’s go on to the San Antonio [Breast Cancer Symposium 2020] and what’s exciting. We’ve got a hint of a few things, specifically in terms of CDK4/6 [cyclin-dependent kinases 4/6] inhibitors in the adjuvant setting. Do you have any comments about what you want to see, or what you think you’re going to see in San Antonio?

We’re seeing a bit more data on CDK4/6. You mentioned that we’ve written the story as a metastatic disease, so these are early data. We saw the monarchE trial results. That was a positive trial of course, and all those patients were node positive with very high risk. That trial was a higher-risk population than the patients who were in the PALLAS trial.

You had to have at least 4 positive nodes. If you had 1 to 3 positive nodes, then you had to have an additional high-risk factor: either grade 3, a tumor size of at least 5 cm, or Ki-67 over 20%. This is our ultra-high risk of ER-positive adjuvant breast cancer.

We saw invasive disease-free status improved from 88.7% to 92.2% with the addition of abemaciclib; that was a benefit of about 3.5%. What one could argue is, is that some in-breast recurrence or distant recurrence? It did appear to be distant recurrence as that was a 3.3% difference.

We’re going to see an update of this, the final invasive disease-free survival. I’m eager to see that because the monarchE study was a bit of an early snapshot, so we’ll see how those data have matured over time.

Yes. With the monarchE trial, we were all excited about the presentation at ESMO [the European Society for Medical Oncology annual meeting]. Something that struck me was that the median time on trial was something like 16 or 18 months, and you have to be on abemaciclib for 2 years. Therefore, you’ve got to know that the problem with these CDK4/6 inhibitors is that, once you stop them in the neoadjuvant setting, suddenly the Ki-67 goes right back up. The question is going to be this: what happens when you stop the drug?

You’re really going to need some long-term follow-up. We’re all excited because we think the FDA is potentially going to approve these drugs based on these registration trials. But on the other hand, they may say, “We don’t know. We want to see a little more follow-up in the EFS [event-free survival] to be sure that the stuff we’re seeing is true.” I don’t know. It’s going to be an interesting dilemma here.

That’s why Joyce O’Shaughnessy, MD, is presenting these data. I think it’s the first presentation: it’s GS101 [general session 101], so it’s the prime spot on Wednesday morning, December 9, at the San Antonio [Breast Cancer Symposium]. I’ll be interested to see what happens with that. I don’t know if you have any more thoughts before we go on to the other trial, which is the more disappointing study, which is the palbociclib trial. What do you think about the monarchE study before we go on?

I completely agree with you. It could theoretically go either way. You certainly bring up that if we stop the CDK4/6 inhibitor, are those patients going to relapse, albeit a little bit later? Or are we going to see that separation grow? It may be that we are curing some of these patients.

We have to follow it. It’s an interesting time in breast cancer research in general because we have a lot of different end points to look at. With each of these trials, we have to think about what that end point means, and how it is going to mature over time, whether that’s pCR [pathologic complete response] for triple negative breast cancer with immunotherapy translating to disease-free recurrence, or whether it’s endocrine therapy here.

You’re right. I’ll go even further. It’s interesting. What intrigued me is that, when you do those neoMONARCH trials and give people abemaciclib for a long time, like 4 or 5 months, you start to see T-cell infiltration where you didn’t see it.

There’s going to be something to that. It may be that there’s something about being on a CDK4/6 inhibitor—with abemaciclib in particular, but who knows—that somehow leads to some sort of immune response that’s allowing you to have a PFS [progression-free survival] or an event-free survival. That’s where we may be going with this. It’s a crazy idea, but you need some crazy ideas in this business every so often.

Right. People who have been successful in history have been thought of as crazy at one point, right?

Exactly. The thing is that I’ve always been intrigued by that factor, you saw the serial biopsies, if you remember that trial. You do the ones at the end, and they start to see T-cell infiltration in a number of tumors.

Let’s move on to the other trial. I was shocked, I’ve got to tell you. We all looked, when the PALLAS trial was presented, I was looking with a microscope trying to see anything at all. I understand that 45% of the people in PALLAS came off trial because of typical neutropenia issues, which we don’t usually do in practice. Erica, what do you think? That is a totally negative trial.

Yes. It’s completely negative. There are a variety of things we could attribute to why it’s negative now. Speaking to what you were talking about with the neoadjuvant setting and the T-cell infiltration, we also see that same thing in Ki-67. In the neoadjuvant trials, you knock down Ki-67 considerably, but they stop the CDK4/6 inhibitor a couple of weeks before you go to surgery. Then in the surgical specimens, it’s back up where it was.

Right. That raises the possibility that we could be seeing some type of difference between continuous and intermittent dosing.

That hasn’t been borne out in the metastatic literature, but that doesn’t mean that it’s not different in the early literature. Immunotherapy benefit across early and late disease settings is certainly different. Then you bring up the discontinuation rate. That’s a shame. We have to be careful about the way we design our clinical trials now. We certainly see neutropenia, and yes, that neutropenia can be significant. However, we’ve proven, even across many metastatic patients, that it does not translate to clinical infections. Our febrile neutropenia rate is less than 1%.

If we’re saying that these patients are high enough risk that they need the potential addition of this agent, we need to be more liberal with the neutrophil criteria to allow them to get it. That was probably a bit of a mistake in the trial design.

The other thing is, if I had to put my eggs in a basket, this would be the basket I’d pick. It’s the risk. In the PALLAS trial, the patients with N2/3 [2 or 3 positive lymph nodes] were 37%, whereas in the monarchE study, the N2/3 patients were 59%, so a 22% difference. We’ve already talked about the fact that those N1 patients in the monarchE trial had an additional quite significant high-risk factor of a tumor size over 5 cm or a high Ki-67.

It may come back to the fact that, if we’re taking a population in which very few people are going to relapse anyway, you’re not going to see a big difference by adding another drug.

 I agree. I was even trying to look at the subgroup analysis, but I didn’t see anything there. This is getting to the PENELOPE-B study: importantly, they had people who got neoadjuvant therapy up front and then chemotherapy, and then in the adjuvant setting got either hormonal therapy or hormonal therapy plus palbociclib. They didn’t see any difference.

That’s predictive of PENELOPE-B, and then a couple of weeks later, the PENELOPE-B study announces. We only have the top line data in the press release, but it announces that it’s negative. I am now curious to see it. This is going to be the No. 2 presentation: it’s GS102, so it’s right after the monarchE trial. I don’t know who’s discussing it; it would be cool to see who is discussing it. The bottom line is this: I want to know if there is any piece of information that we can take from PENELOPE-B to learn about why it didn’t work because it would be interesting for us to figure that out.

Absolutely. The PENELOPE-B study was from the German Breast Group, and it was a pretty large study: it was 1250 patients. It was looking at the addition of palbociclib to endocrine therapy in patients with residual disease after neoadjuvant chemotherapy and surgery. You could almost think of it as the KATHERINE trial, but this time with ER+ disease. It started a long time ago in November of 2013, and we’re just now getting the readout of it.

I also found that a bit surprising. It goes back to clinical trial design too. I would have thought that it had been positive, but we have to ask ourselves—pCR and residual disease is a big deal for us in triple negative cancer and in patients with HER2-positive disease. But is this the right end point for the high-risk patient for ER+ disease? I’d argue that it probably isn’t.

I agree with you: no way. I don’t think it is going to be right. But I’m just looking for a biomarker. I’m trying to put all these data together. I like your continuous vs intermittent dosing concept here, and that may be it. It may be something else: some off-target effect. These things are tyrosine kinase inhibitors of a lot of different ones, so there may be one that we don’t know. The question is, this would have normally come out in the metastatic setting, and it didn’t.

The adjuvant setting is teaching us about the metastatic setting. It’s like vice versa.

Right, and it’s not only that. In the metastatic setting, those hazard ratios were all 0.55. They were identical.

It’s crazy. We’ll figure that one out.

SABCS 2020: CDK4/6 Inhibitors for Breast Cancer

 We’ll now talk about 3 more abstracts that are interesting.

With the first abstract, I’ve been involved with the team at Odonate Therapeutics for a long time. I’m sure that they probably talk to you a lot; they talk to a lot of us. The CONTESSA trial is pretty cool. I like the idea of an oral taxane. The alopecia is minimal. There is something that I didn’t like about this design, and I told this to them, as I’m sure you did, when they all talked to us a couple years ago.

Basically, when you’re on hormonal therapy and progress, we normally give you capecitabine. In this case, all they did in the CONTESSA trial was add a single dose of tesetaxel, I think it’s 27 mg/m2, every 3 weeks. The adverse effect profile was basically what you would expect: a bit more neutropenia and a bit of neuropathy, but not much more. It was dominated more than anything by the capecitabine effects. It apparently has some impact. We don’t know the results. They just showed some PFS [progression-free survival] and the usual signs by press release. I’m going to be curious to see those data. I think that’s going to be a big trial to see. What do you think of that trial?

I also think it’s interesting. It’s interesting that the oral taxanes have a bit of a different adverse effect profile, as you mentioned, compared to an IV [intravenous] taxane, so that’s important from a hair loss and a neuropathy standpoint.

The other thing that 2020 has taught us is about COVID-19 [coronavirus disease 2019]. It is attractive to have more oral therapies that patients can take on their own at home with some local laboratory monitoring or symptom checks. Even telemedicine is attractive in a time where, for some patients, it’s hard to get into the clinic, and it’s risky for others.

I agree. It’s always good to have that. To change gears for a second, I can never pronounce it, but they have Phesgo [pertuzumab, trastuzumab, hyaluronidase], or whatever they call it. It’s a combination of pertuzumab and trastuzumab as a subcutaneous formulation that can potentially keep people out of the hospital. Have you started using that at all [at Sarah Cannon Research Institute, Tennessee Oncology]?

No, I haven’t. We [at the University of Pittsburg] just received it. For now, we’re trying to figure out how to integrate it into our practice. Apparently, there are people who have started using it: I know Mark Pegram, MD, uses it a lot now at Stanford [Health Care], and he loves it. He says that patients like it, and they don’t mind it in clinical practice. They have this thing going on: they’re doing a quasi-trial where they have visiting nurses deliver it to patients within their homes. This is all big, it goes back to COVID-19, which is basically why they’re doing it.

The other thing to go on at the San Antonio [Breast Cancer Symposium], it’s in the same session. It’s GS402 [general session 402], this whole thing with entinostat. This is an ECOG [Eastern Cooperative Oncology Group] study for which Denise Yardley, MD, was the PI [primary investigator], apparently. It was weird that it was a randomized phase 2 trial of this HDAC [histone deacetylase] inhibitor with or without exemestane. That basically showed no PFS, but there was a survival benefit. It always got me scratching my head, but it led to this phase 3 trial, and I was surprised that it was negative, especially because they had that phase 2 data that looked so good. Do you have any thoughts on that study?

I agree. I feel like entinostat has been around for a long time. It’s resurrecting here in a result. It’s disappointing. We’ve certainly given it across multiple trials in a few different ways, and it looks like it’s had some activity. It certainly adds a bit of toxicity to the regimen that it’s given with, but I’m eager to see the entire results.

It was a big deal with the Stand Up to Cancer program. They did vorinostat and 5 days of azacitidine in a phase 2 trial in leukemia and breast cancer. It was this big Stand Up to Cancer study, and they got $10 million for it or something like that, and there were all these biomarkers that were done with it. It never worked; the phase 2 study never took off.

That’s why, when I saw this huge trial around the time when Denise presented that data from ECOG, we said, “Ok. Maybe it will work,” but it didn’t. Again, we have to learn from our failure here. That is going to be an interesting thing: why did it fail? Were there subgroups in which it worked? We’ll have to see.

SABCS 2020: Other Oral Therapies for Breast Cancer

 I want to end with another thing that is also going to be a pretty big mystery: AKT inhibition in triple-negative breast cancer. We’re going to see. We already saw the ER-positive part of the IPATunity130 trial. Ipatasertib has been promoted by Genentech/Roche as this AKT inhibitor that, with chemotherapy and hormonal therapy, could supposedly give some benefit. We already know that capivasertib in the FAKTION trial, when given with fulvestrant, does have activity. At ESMO [the European Society for Medical Oncology Virtual Congress], they did 1 section of this IPATunity program where they did the randomized trial with people with ER+ disease who did or did not have an 

 mutation, and then got paclitaxel with or without ipatasertib. That was negative.

They’re now doing it in the triple negative cohort, which they’re going to present. As you know, 10% to 15% of the patients have 

, or, or PI3 kinase mutations. Everybody gets paclitaxel with or without ipatasertib. I’m going to be curious to see. I’m worried that, based on the ER+ idea, they’re not going to see much. I thought this was going to work. They had neat phase 2 stuff that was presented by Peter Schmidt [MD, PhD,] a couple years ago. I saw the randomized phase 2 study, in which the patients who got this mutation seemed to have a survival benefit, and I was excited. I then saw the data from ESMO, and I thought “Uh-oh.” So, I don’t know, what do you think?

You mentioned this, but they did the triple negative study with capivasertib too.

These drugs are similar: they’re AKT1, 2, and 3, pan-AKT inhibitors. Although, it’s another trial like you were mentioning where we only saw an improvement of progression-free survival of about a month and a half, but there was a 7-month improvement of overall survival.

To be quite honest, I’m excited about this class of AKT inhibitors. They’re in a variety of phase 3 studies, whether patients are ER+ or triple negative, and a lot of studies are combining them there. We think of first-line triple negative cancers, and we now have immunotherapy. The reality is that, in my experience, I haven’t seen quite a 40% positivity on testing. It’s probably more like 30% to 35% in the real world, so that’s for a minority of patients. I would certainly like to be able to improve upon single-agent taxane for those patients. I like the idea of the AKT inhibitors because you don’t have to have a mutation to benefit like you do with PI3 kinase inhibitors. It’s an attractive class of molecules if we have benefit.

Right. I agree. There’s something there with this. Clearly, the FAKTION trial shows that there is activity, so we know there’s activity: it’s a question of where and how. The adverse effect profile is manageable. To me, it’s similar to the PI3 kinase inhibitors; they’re slightly different. The toxicities are hopefully going to be manageable, and hopefully, they’ll have some place somewhere. There may be differences between capivasertib and ipatasertib just like there are with the CDK4/6 inhibitors. We’re going to have to wait and see because we [at the University of Pittsburg] are participating in the CAPItello trial. I don’t know if you [at the Sarah Cannon Research Institute, Tennessee Oncology] are. We didn’t do the IPATunity; we decided to do the CAPItello trial, which is the AZ [AstraZeneca] with capivasertib. We’ll see what happens. We’ve got to wait and see on these drugs. I’m excited about it.

SABCS 2020: AKT Inhibitors for TNBC

 We’ve gone over some of the things we have. Do you have anything else that you are interested in that we’ve left out?

No. That hits the high points. The other things I’m interested in are some smaller abstracts or posters getting at these biomarkers. Can we tease out different populations that do or don’t get benefit? That’s the exciting thing about breast cancer care right now: it’s not one-size-fits-all. We know that all ER-positive breast cancers aren’t the same. We’d like to tease out who may benefit the most from therapies and attempt to get to true personalized medicine.

I agree. What’s going to eventually happen is that we’re going to have all these biomarkers, and unfortunately, we’re going to want to learn new stuff. Where we’re going to get that data is from the real world. It’s going to be from analyzing the large databases, whether they come from the biomarker people like Caris [Life Sciences], Foundation [Medicine], Tempus, or Guardant [Health]. We could be looking at the outcome measures of people who have had mutations, or looking at a big thing like Flatiron Health in people who’ve had a Guardant [biomarker test] or something like that. We could be comparing their survival or their PFS [progression-free survival] to agent X, Y, or Z vs the biomarker they’ve had.

Trying to do a prospective randomized trial in that setting is going to be difficult. It may be that the way it will happen, is with little tiny trials with maybe 50 patients or something like that, or 75 patients, that gives a hint. And we may do some sort of convenience trial that we do in a registry to back it up.

I don’t know. I’m waving my hands because we’re going to have to think hard about novel trial designs to be able to do this. I don’t think the trial designs of the past are going to be able to allow us to evaluate agents efficiently or quickly. We’ll just have to see. I agree with you: we’re going to a personalized kind of medicine now in breast cancer, which is pretty cool.

That’s a wrap guys. Thank you very much for listening to us, and we can’t wait to see you after the San Antonio [Breast Cancer Symposium] to see exactly what happened. Thank you. Thank you Erica, and again, thanks to our listeners.

Thank you. I’ll see you virtually at San Antonio.

Precision Medicine in Breast Cancer

Conference Preview: SABCS 2020

The most interesting developments and approvals in breast cancer treatment in the last year and expectations regarding data that will be presented on at the upcoming 2020 San Antonio Breast Cancer Symposium.

Conference Preview: SABCS 2020 | Investigator Perspectives

EP 1: Breast Cancer Treatment: Year in Review

EP 2: SABCS 2020: CDK4/6 Inhibitors for Breast Cancer

EP 3: SABCS 2020: Other Oral Therapies for Breast Cancer

EP 4: SABCS 2020: AKT Inhibitors for TNBC

EP 5: Precision Medicine in Breast Cancer