William Gradishar, MD, Department of Medicine, Betsy Bramsen Professorship of Breast Oncology, and professor of medicine, hematology and oncology, Northwestern University Feinberg School of Medicine, discusses the significance of drug development in HER2-positive breast cancer. 

HER2-positive breast cancer has been an area of ongoing research efforts in the last few years, Gradishar says. For example, the introduction of novel therapies represents additional options for patients with HER2-positive disease, Gradishar continues. Despite the improvement in outcomes for patients with early-stage disease, patients with HER2-positive breast cancer often experience disease recurrence. Therefore, additional effective options are needed for patients with metastatic or 

These transformative agents are improving survival for this patient population, Gradishar says. However, additional research regarding drug development is needed in HER2-positive breast cancer to further prolong survival for patients, Gradishar concludes.

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William Gradishar, MD, discusses the significance of drug development in HER2-positive breast cancer. 

Dr. Gradishar on the Significance of Drug Development in HER2+ Breast Cancer

Claudine and Bill, what’s your experience in terms of what kind of considerations you or your practices use in terms of the subcutaneous vs the intravenous? How is COVID-19 [coronavirus disease 2019] factoring into it? It hasn’t been around that long. Have things changed quickly, or is it evolving? How about your, Claudine?

 It just went on formulary for us a few months ago. We started to convert most patients, and we are having the same overwhelmingly enthusiastic, yes-please response to it that others are. It’s going to be the way we do it. It’s a winner for the patients, and it’s a winner for everyone.

We are participating in a study that was looking at home administration, and that started early on in COVID-19. It was a real plus for us because we were on the East Coast and we got hit early on with COVID-19. A lot of patients wanted to participate in that study because it kept them out of the hospital; it kept them at home. But being in the hospital for shorter is a win-win.

How about you, Bill? What is going on at Northwestern? Has COVID-19 played a role?

It was relatively recently approved, so we’re just starting to use it. I’ve done it in a few patients. I can see absolutely no reason why it wouldn’t be the win-win that everybody is describing. I don’t know why anybody wouldn’t want to do it, unless they had a child at home they needed to escape from. Short of that, it seems completely reasonable.

For COVID-19, anything that keeps people away or limits their time is attractive to patients. That’s another reason, but I don’t think we’ve treated enough people to say what our experience is in any big way.

 We really covered the waterfront. We hit all the new data and all the new things people have to know to optimize 

 [human epidermal growth factor receptor 2]–positive patients’ care in the early stage metastatic phase. Thank you. It’s really been a rich discussion and very comprehensive.

Let’s finish by going around the room. If anybody wants to leave with a parting thought: what you’re really happy to have in the clinic, something you’re interested in or excited about, what you’re looking forward to, or an unmet need that we’re looking for. VK, do you want to start?

Two thoughts. One, I was sitting next to an advocate in 2019 at the San Antonio Breast Cancer Symposium sessions, where all these amazing abstracts about 

 disease were coming by. She does not have 

+ disease, and she turned to me and said, “I have 

 MB [metastatic breast cancer].” That captured the sentiment of what we’ve done and what we’ve been able to achieve for this patient population with so many options. Many of these patients will still die of this disease. This is more optimistic than I’ve been about a space in a long time. For that I’m grateful.

I’ll close with 1 bit of data they kind of snuck in at the San Antonio meeting, which was from the SUMMIT trial. This had to do with neratinib. I know we don’t think about it in the same way, but there are patients who have 

-activating mutations. If we look for them, we’re going to seem 5% to 10% of the time in all these different disease settings—that’s triple negative, ER [estrogen receptor] positive.

It turns out that neratinib and probably some of the other HER2 tyrosine kinase inhibitors will work well for these patients with activating mutations, and I’m looking forward to more of that data so we can expand the net of patients who we use the HER2-targeted therapies for.

A couple of thoughts. First, I’ll double down on what VK said: Our friends who take care of patients with pancreatic cancer are not having conversations or arguments about whether to call it optimizing, de-escalating, tailoring, or precision. The armamentarium and the explosion of opportunities in treating this disease is really so remarkable. The trajectory that we’re on, which is to start peeling back in a rational fashion, is exactly the right direction to go.

Rather than just depending on drug evaluations combined with clinical variables, it’s going to involve biological information, either through the tumor or through circulating identification of parameters that are controlling disease behavior. We’re going to get there. We actually are going to have a menu that’s going to be driven by real risk and by likelihood of responsiveness to less toxic things.

We’re going to get rid of chemotherapy. In 5 to 10 years down the road, we may feel like we have a shot at—in some, not all—actually converting some metastatic patients with 

+ disease to cure. The drugs are that good, and there are many of them. Some of the tumors that we started this conversation talking about are exceptional responders, and we all have them. It’s not like, “I’ve heard of 1.” We all have these patients. This is a real possibility. The armamentarium is going to keep growing.

I’ll leave with 1 last anecdote. I had a patient, she was 1 of my favorite patients, a wonderful person, and she always was always dressed to the nines and ready for her evaluations. She would come in and I could always tell when her tumor was progressing because she had this big liver metastasis. It was her dominant site. When it grew, it would start to give her pain. She would come in looking more bedraggled. You could see her walk in the door, and you could tell that her tumor was progressing. She would get symptomatic. Whatever I did, every time I changed up her HER2, new drugs would come in or a trial would come in with a drug, just as her disease was growing. She must have gone 6 years with symptomatic liver metastasis, because we kept having drugs to change. As we figure out how resistance patterns come up, we’re going to be able to recycle if not the actual drugs, then the approaches. We’ll see more of that.

I would echo some of the sentiments that others have already mentioned. Many of us have been around long enough that we’ve seen the arch of how this disease has changed. It’s not unlike when there was carboplatin-paclitaxel: When you’re in private practice, you’re pretty much covered. You could hit about half the diseases you took care of. The challenge and the gift we have now are all these new therapies. It provides an understanding of how far we’ve come because we were treating patients before there was trastuzumab. We’ve seen the evolution of our ability to extend the survival of patients just like the anecdote that Lisa just mentioned. We have a lot of patients like that, where it’s not 2 years anymore. It may not be forever, but it’s 6 and 8 years, and for some patients 10 years.

I suspect that 10 years from now, what we’re doing will make us look like cavemen because we’ll have a lot of new therapies and different ways of assessing the disease than we currently do. It’s a remarkable evolution over a period of our careers.

Thank you, Bill. Claudine, how about you?

It’s hard to add much on top of what Bill said. I echo most of these sentiments, and I think the concept of individualization and optimization is there. Whatever we want to call them—neoadjuvant, adjuvant based—these trials that have been designed and are available through the cooperative groups. When Lisa talked about the CompassHER2-pCR trial and the escalation trials for the patients who only achieve a pCR [pathologic complete response], we’re really going to have better and better markers to figure out who needs what and who doesn’t need other things. We’ll get to a point where we are much more tailored in our treatments.

In the metastatic space, we all have a series of patients who are long-term responders. With all these drugs that are prolonging life, we’re offering better and better options for our patients. We’re going to figure out how we can peel some of it back. I’d love to give tucatinib without capecitabine. We need to figure out those things, because we’re talking about prolonging life and quality of life for as long as we can.

Yeah. Thank you, guys. It’s been nice talking to you all. Thanks for sharing your experiences and your thoughts and everything. I want to thank our viewing audience as well. We hope you found this 

® discussion to be useful and informative. Thank you.

Decision Factors for SubQ Therapy and Unmet Needs  

Let’s finish on subcutaneous approaches. That’s something new. Europe was doing this a lot with subcutaneous trastuzumab for a long time. We haven’t done that much in the United States, but now we have subcutaneous trastuzumab and pertuzumab. You have fixed-dose combinations. Lisa, you could tell us about the FeDeriCa trial, and VK, the PHranceSCa trial. We can see what’s going on in the real world with your experience.

FeDeriCa was the trial that got Phesgo, the subcutaneous Herceptin plus trastuzumab, approved. It was a neoadjuvant study. They had done individual studies with each drug, and this was a neoadjuvant study. It was a decent-size study. It was 500 patients, and it was AC [doxorubicin, cyclophosphamide] followed by THP [paclitaxel, trastuzumab, pertuzumab] in the usual fashion, or AC followed by THP with HP [trastuzumab, pertuzumab] being Phesgo, which is the subcutaneous version.

Then the adjuvant phase continued whatever they were assigned to up front. They looked at pharmacokinetics and found very similar pharmacokinetics. In fact, as I recall, the trough trastuzumab levels were actually maybe a little better in the subcutaneous formulation than in the IV [intravenous] formulation. They were very similar. PCR [pathologic complete response] rates were virtually identical, right? It was basically 60% for each. They looked like they were doing well. Their cardiac signals were not particularly different. They checked off the boxes, and this is where the approval came from.

Separately, when they’ve done studies of patient preference, the vast majority of patients would prefer the subcutaneous formulation. When the cost-effectiveness people get hold of it, it’s more cost effective. There’s a bunch of reasons. I’d be interested in hearing other people. I haven’t heard of anybody having strong dissenting reasons for this move. It’s going to be good for everybody and good for cost effectiveness and quality of care.

VK, say a few words about the old patient-preference PHranceSCa study.

 You guys may have heard about this investigator by the name of Joyce O’Shaughnessy. She presented this data at ESMO [European Society for Medical Oncology Congress]. In this trial, my understanding is that patients got preoperative therapy with PH, pertuzumab-trastuzumab; got surgery; and then were randomized. Half the patients received 3 cycles of subcutaneous and the other half continued with IV. Then they switched over for the next 3 cycles. After that they got to pick what they wanted to do. This is a small study, 160 patients. There aren’t any big differences that we’re going to see within terms of events of that nature, but patients preferred it. They liked the subcutaneous: 88% picked subcutaneous when given the option about what to do to continue. Overall, we’re looking at about a fourth of the time required to do subcutaneous administration in clinic vs the full time it takes to do pertuzumab and trastuzumab together as a combination, individually in the bag.

For those reasons, as you cited Lisa, the cost is going to be lower. Less chair time means less cost. Subcutaneous is going to need different resources in the clinic. The minute the drugs were available at our clinics, our formulary looked very hard to get these onboard. This is a slam-dunk winner.

I’ll share 1 anecdote. I had a single patient who, when offered this, said, “No, I want the IV version.” I asked her why. It turned out she had a baby during therapy, and this was her only time to be alone by herself. For that patient she picked the IV therapy. Otherwise, everybody else has been subcutaneous.

Phase 3 FeDeriCa and PHranceSCa Trial Overviews  

Before we leave the metastatic setting, what’s coming down the pike? What other agents are going to be coming our way potentially in trials?

With the new drugs, there’s a bunch of drugs that are percolating out there. For margetuximab, we saw Hope Rugo present those data. In TBCRC [Translational Breast Cancer Research Consortium] we’re actually going to do a neoadjuvant trial that looks at margetuximab.

It’s just to see in the appropriate low affinity FC receptor subset. Maybe you could build a better mousetrap than trastuzumab. Many of the others are versions of irreversible pan-HER inhibitors that looked good in either large or small studies, like pirotinib and poziotinib, where they look reasonably good; however, they look a lot like neratinib to me. This is an opinion. They are pan-HER inhibitors, and they perform well, but they also have the same toxicity issues.

For them to get traction is going to be tough because neratinib already, certainly in many practices, is now where capecitabine-lapatinib used to be, which is behind trastuzumab deruxtecan. They would have to demonstrate that they’re essentially better than tucatinib, which could be really hard to do, but at least better than neratinib. That is also going to be hard to do.

Novel Agents for Late-Stage HER2+ MBC

It’s very important, tucatinib for the brain. Does anybody have any pearls or words of wisdom in terms of cutting down toxicity? So many of these things have more toxicity when we start them in the first month or two, and then there is tachyphylaxis, or we tweak the dose. Does anybody have any particular thoughts? Anybody using any escalation strategies, for example, rather than going in with the full dose as they did in the protocol?

With neratinib, I feel very comfortable with an escalating strategy, and it does seem to increase or maintain compliance. I don’t know that we have that option with tucatinib yet. I haven’t seen data, and I’m still a little worried about starting with 1 tab instead of 2. They come in different increments, and I don’t know how we’re going to fix that. It’s so much easier with neratinib, where you can go 3, 4, 5, 6 pills. The other drug I have a hard time with is capecitabine and what’s the dose of capecitabine here in these regimens.

It’s slightly a little bit on the higher end of what I like to use in the metastatic setting, and we’ll use it, but a lot of the toxicity from the regimen that’s described in the studies is from capecitabine. It’s hand-foot syndrome, it’s diarrhea. Some of that could be tucatinib, but I think it’s really the capecitabine. If you look at the data deeply, the patients who are on capecitabine longer are more likely to have those toxicities. Big surprise. That’s the drug I struggle with the most in these combinations.

Yes, thanks. Lisa, what were you going to say?

I agree with VK. Tucatinib is an easier drug because it is a much more HER2-specific drug. So you don’t have, in this sense, off-target effects with the GI [gastrointestinal] toxicities. I haven’t had that struggle, where you do have it with neratinib. We’re all looking for strategies to manage neratinib better, and we think dose escalation is a good one because it’s proactive, and we need it to be proactive.

I haven’t had that need, and I think that a good deal of the toxicity is capecitabine. We’re going to have tucatinib added to T-DM1 [trastuzumab emtansine]. We’re going to have tucatinib added to trastuzumab deruxtecan. There are going to be all these trials; we may have other options that allow us to avoid capecitabine if we want to. But I think you basically strategize around capecitabine the way you always do.

Start, and go down. But nobody gives it at the same doses that the FDA thinks we do.

Right, and I can start a little low on the capecitabine and try to get the full dose of tucatinib in because we’re trying to get to the brain, and then work my way up on the capecitabine. Sometimes I’ll do that to have a better experience, a more positive win for the patients early on.

Practical Advice for Toxicity Management in HER2+ MBC

Let’s talk about brain metastases a little bit more. We talked a little bit about possibly throwing in some screening when we’re at a decision point in the road, and you go A or B, which way do I go? That might be one piece of data, particularly in a higher-risk person who has a lot of metastatic disease, a heavy tumor burden that’s probably been seeded as she’s been progressing through a prior line. There may be times, and I haven’t done it routinely, but I’ve done it a few times recently where I’ve thought, “Oh, which way do I go?” Let’s talk a little bit about what you do. Is there anybody who you wouldn’t rush into SRS [stereotactic radiosurgery]? Do you get to see the patient sometimes if she’s developed CNS [central nervous system] metastases? Sometimes she’ll be seeing the radiation oncologist back because she’s already had SRS let’s say, but now she’s going forward and now we have the tucatinib tool. Would you generally have chance to think about tucatinib before she gets more SRS? How do you balance the systemic therapy vs the brain therapy? How do you think through that in terms of when to change? Add a few general thoughts about brain metastases and how things are evolving in their management.

Claudine mentioned this earlier. Patients with brain metastases fall into 2 categories. There are those that are symptomatic, at which point you need dedicated local therapy, particularly if they haven’t been previously treated, and that’s typically with radiation. Although Priscilla Brastianos, MD’s, paper a year or so ago suggested that the actionable mutations and DNA aberrations may be different in a brain metastasis than in the rest of the systemic compartment. We shouldn’t give up on taking them out because then you can look at them a little more carefully. Certainly for larger ones, we still do it, but for a while we were shifting away to radiating everything. We may start to see a move back to some of the larger ones, where we go back to taking them out, but some local approach.

My own impression and practice recently has been, with all the HER2-directed therapies that we have in asymptomatic patients, so we’re pivoting away from the symptomatic ones. In asymptomatic patients, my radiation oncologists are perfectly happy to let me go first and to follow what’s happening in the CNS compartment. They have some concerns. A lot of times these patients will have multiple things and if you keep going, they live so long, sometimes you’re going back to the well with SRS over and over again.

They’re OK with waiting to do a little more medical therapy up front. At least at the University of North Carolina, that’s been an evolution. It’s a good one because we watch them like hawks.

Exactly. VK, you were going to give us some thoughts though on this.

This has changed a lot because of tucatinib. Us looking now proactively is a real possibility for these findings. The question becomes, do we try to achieve, very aggressively, sterilization of the brain environment of visible metastases, especially if there’s 1 or 2? If there’s a lot of small miliary disease, that’s a different challenge, and fortunately those are not very common patients.

What we know now from both the first-line therapy with THP [paclitaxel, trastuzumab, pertuzumab], but also in the second-line with T-DM1 [trastuzumab emtansine], is that there’s this principle of if you can keep the disease below the neck controlled, it looks like there’s a survival benefit even for CNS-related stuff down the road, just as a general theme.

If you can get to a point where you’ve used SRS, or some localized therapy, and ”cleaned up the brain,” and you get some really good below the neck therapy, these are patients who maybe do really well without additional CNS events. That was at least my initial way of practicing. But tucatinib for good reasons is throwing a wrench into this, and for those patients now I’m feeling more inclined to use tucatinib earlier in the sequence of therapies, especially if they have HER2-positive brain metastases. It’s hard to argue with data that have an overall survival benefit, and you do have an overall survival benefit even in the patients with brain metastases in the HER2CLIMB study, so you can’t exactly dismiss that. That’s a real finding.

It’s changed a lot. More of us are probably going to look. We’re going to find disease. It’s an interesting fact I think a lot of people don’t realize that 50% of the brain metastases that happen in patients with HER2-positive disease happen within the first 2 months of therapy.

It’s an early event, it’s not a late event like you might see in ER-positive, HER2-negative disease where 5, 6 years down the road there’s a brain metastasis. This is something that happens early in these patients. If they’re symptomatic, we all know what to do in that case. It’s the asymptomatic where we have to use our judgment. If it’s a bunch of small miliary lesions and you’re asymptomatic, I’m actually really worried about that patient. But if it’s prior to half a centimeter spots, maybe that’s the patient I watch like a hawk, then bring in my neuroradiation oncologist down the road to target these lesions, especially if I’m not seeing control like I want to see.

I was going to say one thing, and I agree with what VK said. It is nuance though too because there are those patients who he was describing, who have done well below the neck who had bad disease that the systemic therapy is holding them.

It may be in that patient, particularly if they have relatively limited brain involvement, that radiation therapy would be a first choice rather than abandoning what seems to be holding the systemic therapy completely in check. But I agree, if the disease continues, then I would switch to something that has more activity in the brain.

I would argue, this is a space that has to be highly personalized. It’s going to be very much a challenge to write guidelines that say do the steps in this context.

Yes. How about Claudine? Any evolving thoughts about treating brain metastases or management strategies?

Increasingly when this happens, we function in a very multidisciplinary way. Increasingly, radiation oncologists and neurosurgeons and medical oncologists are around this, it’s a discussion about what might be best for the patient. Increasingly, I have exactly Lisa’s experience that sometimes radiation oncologists, because they’re the ones who follow, and are ordering the MRIs, they’ll call me and they say, “Something is going on, do you have something for her?” As opposed to me calling the radiation oncologist and saying, “I have somebody, and we need some local therapy.”

I also agree with Bill. This is one of those spaces where we’re evolving, but we have those patients who had aggressive disease, it was really well controlled, you just have a few areas in the brain, do I really want to drop their systemic therapy that’s been holding things in check and go to tucatinib now? In those patients I’d probably be more likely to get the radiation oncologist to think about doing some stereotactic Cyberknife procedure and keep them on. If you had a patient where things were more significant, I would, like everyone else has been saying, I’d be thinking about tucatinib here. Everyone has alluded to this as well, many of these drugs have some CNS activity. There was some CNS activity with T-DM1. There certainly was CNS activity with lapatinib, there is with neratinib, and with tucatinib.

It is a very individualized space. The other thing is, my sense is that in general, in speaking to people out in the community, the radiation oncologists and medical oncologists are talking together about the next best step. That’s probably the most important thing because this is so individualized; nobody jumps the gun first but talk about it together.

Brain Metastases Therapy in Second-Line HER2+ MBC

Now we’ll talk about some scenarios; we’re in a data-free zone because we don’t have randomized trials, except what we just went over. We don’t have any clear guidance on how to sequence. We have to go in part by the patient populations that were studied in the phase 3 trial. We have to go in part by antecedent therapy they had, maybe in the adjuvant/neoadjuvant, and what the disease-free interval might be. We have brain metastases, we have toxicities to consider. What are you doing? This might be a good time if you had any interesting observations or anything like that, it would be interesting and to hear about it. Who wants to start? How do you think about sequencing?

I can start. If you build off what is viewed as standard, and you’re more likely to use a CLEOPATRA-like regimen, then follow it by T-DM1 [trastuzumab emtansine]. The reality is that in the adjuvant setting some people get TH [paclitaxel, trastuzumab]. If they develop progressive disease, would that make you not give a taxane with HP [trastuzumab, pertuzumab]? It would be dependent on how recently the patient progressed and last received their therapy. I wouldn’t exclude the possibility in that kind of scenario of using HP with a taxane.

As for the newer agents, it’s to a large degree influenced by whether CNS [central nervous system] disease is present. That certainly would influence my thinking. We’ve used a lot of trastuzumab deruxtecan, and I’ve been impressed with its activity. Obviously if somebody had bad pulmonary disease for whatever reason, I’m not talking about cancer-related disease, it may be somebody who I would avoid it in, but not because they have cancer in their lungs. There’s also, obviously if somebody has active brain metastases, tucatinib would be very attractive. I’ll stop there so others can comment.

I’ll go. I do start with the CLEOPATRA regimen, and typically if somebody had a lot of CNS disease or something going on, I might think tucatinib, it’s approved as second line and beyond. There are instances where I might think a bit, but I would typically do T-DM1 next. It’s a really well tolerated drug, and we have good data for it.

In the third-line setting, I think it’s going to really depend on the patient. I have to say I was a little bit skittish about trastuzumab deruxtecan because of the interstitial lung disease and because it came just as coronavirus disease 2019 was hitting. Getting more used to everything, I’ve used it as well. I would probably think of tucatinib in the third line and then trastuzumab deruxtecan. Which way we do it, I don’t think we have evidence for; it ends up being individualized on the patient’s adverse effect profile, what’s more tolerable. It’s a lot of medication to take with the tucatinib and the capecitabine. There’s diarrhea with it, so it carries with a very different adverse effect profile. As usual, we now have 2 good, very solid options for third and fourth line, and it’s an individualized decision in my mind with the patient in terms of their preference, their adverse effects, their comorbidities, and other things that come into play.

Let me ask you Claudine because you make the point about the tucatinib being FDA approved and on National Comprehensive Cancer Network guidelines in the second line, which distinguishes it from the trastuzumab deruxtecan in the second line, which distinguishes it from the trastuzumab deruxtecan and the neratinib, not that we have to rigidly follow that. Sometimes we don’t for individual patients. Nonetheless, it’s nice to know where the guidelines and FDA stand. Having said that, is there any patient for whom you might consider the tucatinib in second line? Would you ever consider any kind of a brain MRI? We have a little ostrich effect here; we’ll look at the liver every day, but we’re not looking at that brain, we’re not going there. The question is, is there anybody we should, if you think they may be at particularly high risk for CNS metastases?

I’m not aware of what would predict for a higher risk of CNS metastases with HER2-positive disease. I don’t know if my colleagues are?

Yes, Nancy Lin, MD, taught me. I don’t know that it really pertains to the sequence of metastatic, but for those who recur in the brain, or who start off, it’s probably the same, it’s T3/T4 disease and ER [estrogen receptor]-negative. If you’re T3/T4, even ER-positive, you can be at risk, or if you have more sizable cancers, ER-negative—like node-positive, ER-negative. So, ER negativity and the bigger cancers would be the ones that would tend to seed back when these things were developing.

There you go. I always listen to what Nancy Lin says, so I’ll take that one home too. I’m debating whether we should be doing scans. I have to say, I have had that ostrich-like response. I didn’t want to know, and now that we have a drug that’s active, I think we need to rethink that strategy. I haven’t quite figured it out yet. I don’t know whether it’s something that we should be doing every X-period of time, whatever that might be, and to do it when it’s time to change therapies. It feels a little different when we know that we have something beyond repetitive local therapies for these patients to think about something. That could influence me if I had a patient who had CNS disease in the second line, and I thought I could spare and push off radiation if I chose a systemic therapy that had CNS penetration, that could influence things. I haven’t quite figured it out. I’d be interested to hear what my colleagues have to say about, if they’ve developed an algorithm for this. I’m still trying to get used to this playing field and figure out how to best strategize around that.

I don’t know that I have an algorithm, but I think it’s like alpelisib. We wouldn’t be looking for PI3 kinase mutations if we didn’t have something to do with the information. The practice is going to be as time goes on, we will be looking for more brain metastases, even in the absence of symptoms. But it does raise the issue, if there’s lead time that we’re creating, and we’re starting therapies that may or may not impact on very tiny or very indolent CNS disease. I don’t know the answer to that, but I bet we’re going to be looking more than we have in the past.

There was that subset analysis. It was Nancy Lin who did this one too, where she looked at a combination of patients who did have brain metastases and those who didn’t have brain metastases, and then looked on the tucatinib vs placebo for time to development of new brain metastases. A little preventive. There was a real nice separation in that curve where it certainly gives us hope in the curative setting. That’s helpful, but probably for right now I think if people have brain metastases, we’d all be thinking about tucatinib sooner than later, probably. Sometimes, even in my practice, leapfrogging over the T-DM1 if they had substantial brain metastases. I don’t mean necessarily 1 brain met. How about you, Lisa, how do you sequence these so far?

I have to say, I share the sequence that Claudine just outlined. I’m fairly conservative about that way. There’s some reassurance in that when they’ve done many of the trials, like EMILIA for example, they did include patients that had stable brain metastases. They did have some of them for whom they could see a response rate, and it didn’t look terribly different from the parent trial.

I suspect for a variety of reasons that tucatinib is going to outperform all of them, specifically in the CNS compartment, but I’m not so worried about it that I’m leapfrogging or rearranging my normal lines of therapy at this point. I do share Bill’s concern about routine screening in asymptomatic patients. If you look, you will find. Once you find, then you’re stopping and reconsidering, and you’re doing stereotactic radiosurgery here, there, and everywhere. I’m not sure that we’re helping patients if we do that. We might be, but I always get a little leery of it. You’re right, there is a disconnect because I’m imaging the systemic compartment all the time. But I typically don’t image asymptomatic patients for the CNS.

I echo what Claudine put out there as the framework. I am thinking about this disease now as a today problem and a tomorrow problem. The today problem is a lot of my patients have been through 1 or 2 lines of therapy. It’s a slam dunk to say I’m going to use tucatinib or deruxtecan, and maybe there are small, subtle reasons why I might pick one over the other, certainly brain metastases being present, one of the big ones. My concern is as we project forward, the patients who recur, those who had residual disease after THP [paclitaxel, trastuzumab, pertuzumab], and then we know that the patients who get T-DM1 in the adjuvant setting are still the ones having the events, right? Now they’ve taken out my first 2 lines of therapy, and if you’re recurring within 1 to 3 years, as many of these patients will, then I’m worried about going back to these agents.

Now we’re looking at in the first-line metastatic setting trying to get access to drugs like tucatinib and neratinib as well as deruxtecan. I don’t know how this is going to shake out. I’m just throwing out my hands with concern about what the near future is going to look like in these patients who are heavily pretreated in the adjuvant setting. Now we’re delivering them, and certainly if they get neratinib, like I said earlier, I’m a little worried about cross-resistance to tucatinib. Neratinib is a very potent HER2 inhibitor, it just inhibits a lot of other stuff as well. Now if you try to go back to the well and target HER2 kinases with tucatinib, will it work? We don’t have these data of course. It doesn’t exist. These are my fears and my worries for the coming days.

Can I ask VK a question on that? You go all the way out to; I’ve taken myself to a year, a year-and-a-half out and said after that I can think about reusing old agents. Does that?

I’m just worried. My anecdotal experience is that these drugs don’t maintain the same way as if it were a pristine patient in the metastatic setting who gets these drugs. I think that patient, you can very easily say, this is a person who’s going to be on these drugs for 2 years. But when those patients have been that experienced in that early phase setting and they have a metastatic event, I might, just my back of the envelope sense, is that they’re not getting that type of mileage.

Well the good news is that as we get better and better in this adjuvant setting, and we’re already seeing this in some of the modern things, they’re all de novos. All of these metastatic patients, there are like 45% in the most recent studies. That’s a testament to what we’re doing in the adjuvant setting. I share VK’s pessimism about patients with early relapse following poly-HER2 targeting, although I have to say I retry things unless there’s a compelling reason not to.

Sequencing Therapy in R/R HER2+ MBC

Let’s go on to the metastatic setting. Bill, you could lead us off with the standard of care. How do you see the standard of care, in the first and second line? 

It’s an area in flux based on some of the prior comments. There are a lot of trials that are trying to position the new drugs closer to the front than the back. Everybody wants to be up front. Today if you said, what do we typically do? We tend to give a taxane with trastuzumab and pertuzumab for most patients as the first line. We still follow that for most patients with T-DM1 [trastuzumab emtansine], and most of those data were generated from randomized trials.

In the last question, the issue is, can we move up trastuzumab deruxtecan? Can we move up tucatinib and replace T-DM1 as a standalone drug as a second-line best choice? Those trials are addressing that. For most patients, at least in our practice, we would follow the standard off of a trial, CLEOPATRA-like followed by T-DM1, and enroll in some of the trials we’ve been alluding to, to see if there’s an advantage.

Great, thank you. We’ll come back and talk about some of those different strategies for different patients. Let’s go through the data, a brief update from folks about what’s new that’s come out in 3 big new phase 3 trials that led to 3 new options in the metastatic setting—tucatinib, trastuzumab deruxtecan, and neratinib. Claudine, could you update us on what’s new with HER2CLIMB?

We have this abundance right now of options, which is great, as Bill was alluding to. For years we knew we had good data tell us what to do in first line and second line. Then third line was sort of a free-for-all, and it was really just choosing what chemotherapy partner with trastuzumab.

In the last year, we’ve seen the approval of 3 drugs in this space. Just to remind everyone about HER2CLIMB, because I stand in awe of people who do more than just breast cancer. I can barely keep up with breast cancer let alone trying to treat a multitude of different malignancies. The HER2CLIMB trial was a randomized trial looking at the role of tucatinib, which is a HER2-specific TKI [tyrosine kinase inhibitor], and was looking at it given with capecitabine, trastuzumab, looking what it added over and above that. It showed a benefit in terms of progression-free survival [PFS]. But the thing that we have now grown used to in the HER2-positive world and the metastatic HER2-positive world is that we expect to see survival benefits. We saw it with the addition of tucatinib. There was about a 4.5-month prolongation of overall survival.

The other thing about this trial is everyone who went on the trial had to receive prior trastuzumab, pertuzumab, and T-DM1. It’s asking what I think was practical for us as clinicians because that’s how we were treating most of our patients, and it showed the benefit of adding tucatinib on top of the trastuzumab and capecitabine with that survival advantage.

The other thing that we’ve talked about already is that we know that one of the issues for our patients with HER2-positive disease is that there unfortunately seems to be a predilection for the CNS [central nervous system]. In the HER2CLIMB study, they allowed patients who had stable CNS metastasis to enroll. It turns out they actually looked for it. They mandated a screening MRI to go onto the study, and what ended up happening is around half of the patients had CNS metastases.

Now to be eligible, you had to have CNS metastases that did not require immediate local intervention. These were patients who either had known CNS metastases that were stable, were found to have CNS metastases but they were small and did not require radiation, or they had had CNS metastases, and we saw they had a bit of progression, but they didn’t need immediate intervention.

The thing that came out in the trial is that there was benefit in the subpopulation, which was a pretty large one, about half of the trial altogether that had control and had the same benefit as the patients who didn’t have CNS metastasis. Then Nancy Lin, MD, presented at ASCO [the American Society of Clinical Oncology 2000 meeting], and showed that if you looked at CNS progression-free survival, it was also prolonged substantially in the group of patients who got tucatinib, cementing that this drug had activity in patients with CNS disease. So it clearly has CNS activity. It also had benefit in patients who did not have CNS metastases. It really positioned itself with this randomized trial as a drug that we need to figure out how we sequence in our armamentarium, but one that we really want to be using.

Great, thank you. We’ll come back. We’ll hear about the 3 trials, and we’ll come back and talk about sequencing strategies and your own experience with things. Thanks a lot. That was terrific. How about Lisa? What about trastuzumab deruxtecan? What’s new with that?

The most recent thing is the update of the DESTINY-Breast01 trial, which is the trial that generated the FDA approval for trastuzumab deruxtecan. That was updated at one of the recent meetings. Shanu Modi, MD, was presenting it, but I can’t remember where. I think it was recent, so it was at the San Antonio Breast Cancer Symposium. They looked at the outcome. This is a single-arm trial in heavily pretreated patients with HER2-positive metastatic disease at 20 months out. What they found was that, again, the progression-free survival was excellent. It was about 19 months. The range was still invaluable in the upper end. This is a very active drug with more than 50%, around a 60% response rate.

Counter to the enthusiasm is that it does have some significant toxicities, and in particular, the ILD [interstitial lung disease]. The numbers of the ILD were up a little. It was about 13% the first time it was presented, and it was about 15% this time, and they did have some deaths that were related to it, which we knew before. There’s some caution but it’s a wildly active drug, and we have to figure out if we can manage the ILD, who’s at risk for it, and trying to figure out where it goes.

Thank you, thanks a lot. VK, what about the NALA trial?

NALA you will recall was presented at ASCO 2019, but the paper is already out, and you can read that in the

. This is a funny trial and it’s a funny approval, and it’s hard to figure out how we’re going to use this in the modern world, so to speak.

This trial was designed as a comparator with lapatinib and capecitabine. This is a trial with neratinib and capecitabine. Keep in mind both molecules are small inhibitors of HER2 TKI, but also hit a lot of other tyrosine kinases as well. They’re not as clean and direct as tucatinib.

When they did the study, the trial had to be designed in a way that fully anticipated that the medians were not going to be very different. Because just inhibiting HER2 as neratinib does as opposed to the irreversible inhibition from lapatinib would mean that the biology of the disease could change over time.

What they did is they looked at landmark analyses at 12, 24 months, and so forth. Basically at those time points you see the curves separate and stay apart. When you integrate the area under those curves, and you look for a benefit for PFS, you see one. It’s modest. It’s only a couple of months, but it’s there and it’s statistically significant. This of course then gets registered with the FDA, leads to an approval, and now we have this molecule on hand.

The challenge is of course, you have now 3 HER2-targeting TKIs and how you position them. We’ll talk about this more. Tucatinib is probably a molecule that could be used first and maybe neratinib afterward. But I suspect if you get neratinib before and you’re resistant to neratinib, and this is just conjecture on my part, that you’re probably going to have cross-resistance to tucatinib.

Obviously the adverse effect profiles of these molecules are very different for that same reason, that they tend to hit multiple tyrosine kinases, so you’re going to have a lot more toxicity with neratinib. We’ll talk more about that, it’s an interesting study, and just out of necessity it had to be a funny looking trial.

Yes. Neratinib, capecitabine is in the NCCN [National Comprehensive Cancer Network] guidelines not only for HER2-positive breast cancer metastatic, but also for patients with CNS metastasis, as is paclitaxel plus neratinib. Just so we know because we don’t go necessarily looking at the CNS NCCN guidelines that much. Those are there, so that’s helpful to be able to get for patients. Thank you guys for updating us.

Newly FDA Approved Therapies: R/R HER2+ MBC

Taking out the crystal ball, how do you think the curative setting might change? What other newer agents do you think might make their way into the curative setting? Second, is there any role for the T-DM1 [trastuzumab emtansine]–pertuzumab KAITLIN regimen? Is there any patient who maybe that would help? Maybe they just have comorbidities or what have you. It wasn’t as effective as the TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] in the KAITLIN trial. It’s not a standard of care, but do you see any role for that for any patients? Do you think about that at all? What agents do you think will maybe move up in the future?

I do think that for our optimization, personalization, and tailoring efforts, we have a couple of trials that are actually trying to leverage this pCR [pathologic complete response] thing, right? There’s CompassHER2-pCR, which is an ECOG-ACRIN trial. In Europe there’s the DECRESCENDO trial, which is a very similarly designed trial in which they’re giving just a taxane and HP [trastuzumab, pertuzumab]. If the patient achieves pCR, they just get the HP and never get additional chemotherapy.

Those are maneuvers in which we serially try to eliminate the chemotherapy, right? You could argue what we should eliminate. Do you eliminate pertuzumab? Do you eliminate the duration of the 

 target? When you poll patients, they want us to get rid of the chemotherapy. One thing we did take away from KAITLIN is that although the pCR was different—and this is a small number, but it looked like it didn’t matter a huge amount whether you got a pCR through a T-DM1P [trastuzumab emtansine–pertuzumab] mechanism or a more traditional TCHP mechanism—they all had about the similar event-free survival. There is an argument, a testable hypothesis, that pCR achieved by whatever is pCR. Then we have to figure out who can we get away with just giving anti-HER2 therapy with endocrine therapy. There have been trials of this, and there’s always a low but real pCR rate. If we could figure who they are, that’s a way forward.

Because it’s a trial that’s about to open and we’re super excited about it for those who have residual disease—as we were just saying, there are groups in the residual disease setting who in spite of KATHERINE, in spite of T-DM1 still have a high relapse rate. You may remember that KATHERINE did not have an impact on brain mets. There’s an Alliance trial that is about to open that is with residual disease is T-DM1, or the same with tucatinib, and so it’s a very straight up. Can we build on that in high-risk residual disease?

That’s great. Hopefully it’s going to be a strategy for both cure and brain. What do you think VK?

 Lisa, I have 1 other thing. With these trials you mentioned, the 1 other neat feature is in the correlative work. They’re using circulating tumor DNA as a measure of deep molecular remissions. I hope that something like a deep molecular remission would track well with pCR. For those who didn’t, you can see the circulating tumor DNA that still suggests there might be cancer cells. Then having some adaptive therapy, based on that in some of these novel agents used, would be a future possibility. That’s really early science. I was heartened to see the collection of those specimens so we can assess for those things.

The things that were—the integrative biomarker that’s in these is actually the intrinsic subtype. Some are more 

 driven than others, so we may get a little more bang for the buck out of looking more closely at the tumor. Also, I would argue, although it’s a secondary thing: exploratory, immune microenvironment, getting back to Claudine’s comment about TILs [tumor-infiltrating lymphocytes].

Thank you. I want to mention the DESTINY-Breast05 trial too. We have tucatinib trying to improve overall outcome, but also brain, and then the DESTINY-Breast05. It’s just opened, T-DM1 vs TDXD—that’s trastuzumab deruxtecan. Just a head-to-head, and there’s a head-to-head going on in the metastatic, which we don’t know the answer to. It just opened in the curative setting as well. We don’t know much about TDXD [trastuzumab deruxtecan] in the brain. That’s still an unknown area, but another candidate isn’t it for the curative setting.

Moving Metastatic Therapy to Early Stage Setting

 Let’s say you have a patient who, for example, comes in and has some bone metastases, de novo metastatic disease. She’s young and triple positive, and she does really well with CLEOPATRA and with a THP [paclitaxel, trastuzumab, pertuzumab], and PETs [positron emission tomography scans] are now clear, with no FDG [F18-fluorodeoxyglucose] uptake. She goes in, gets her ovaries out, gets on an aromatase inhibitor, and continues the HP [trastuzumab, pertuzumab]. Maybe she even has local control because you’re hoping she’s going to be 1 of the ones who goes long term.

Just a show of hands in terms of the HP. The question is, we keep the endocrine therapy going, but how long do we keep the HP going? It depends. Someone’s got multiple mets, for example, or maybe just had like 1 or 2 bone mets or something like that. Who would like to speak from their experience? We obviously don’t have randomized data, but does anybody have any experience on that? What do you tend to do?

 It’s always easy to be an authority when we have no data. Everything is an anecdote, but the reality is the longer a patient maintains stable disease, the more likely I am to probably take 1 of the anti-HER2 therapies away. I don’t know when that is. It’s different with each patient. The younger the patient, if they’re tolerating it, fine. If they start having any gastrointestinal symptoms from the pertuzumab, I’d probably get rid of that first.

 And probably with lesser disease. This could all be individualized. VK, what were you going to say?

 I know it’s not data. It’s retrospective, and it’s from 2 centers. Rashmi Murthy published a paper not too long ago showing that if your best response to HER2-targeted therapy is a CR [complete response], most of the patients maintain that. They don’t speak to whether they de-escalate or get rid of drugs along the way. It certainly suggests that patients can do really well for a very long period of time, and some may actually be cured in that setting.

I’m just making that point, that we do have a little—not randomized controlled data, but there’s a little bit of—

I’ll have to take a look at that, yeah. How about Lisa or Claudine: Any experiences or sense from a practical standpoint of what you do every day?

 We grapple with that. It really is an individual case-by-case situation. The patient’s view of it is obviously of incredible importance as well. For those patients who have a great response—you’re still doing it 2 or 3 years out, and you’re still wondering what you’re doing—if they have adverse effects, I happily get rid of 1. I spread it out a little, so when they can go places, they can go more easily. I’ve had some patients who have been champing at the bit to stop. Others are saying, “There is no way I’m stopping this. I want to come in because it makes me feel better,” and I don’t have any data.

If you want anecdotal experience, I just had a patient who had a great response, and she really wanted to come off. She was convinced that if she did other things it would be a better way to go. She changed her whole diet, and she felt great. She came to see me, and everything was great. I was feeling I should do this more, and her disease just started to grow again. It was 2½ years later, and she got 2½ years without anything, and she has a little lung progression. She was probably right.

We don’t know the answer to that, and it’s obviously something we need to study. We all have these phenomenal responders, and we wonder what we should be doing in that situation. We really don’t know.

 I tend to agree. I have to say, this really comes down to the goals of therapy are to control the disease and not to make the patient sick. If you’re doing well 2 years into it, and they’re having diarrhea or they hate coming in—and you’re in the middle of a pandemic—it’s perfectly reasonable to take a break. You’re going to be following them anyway.

That said, I have had very little success in convincing patients who are doing well and having excellent tolerance of these drugs to stop them. I had 1 patient, and it took me years to get her to let me stop the Navelbine she was on. She was on Navelbine-trastuzumab. She was on that. She died of myeloma years later, still taking it. I might have gotten rid of the Navelbine, but it took a long time. She’d say, “I forget about my disease most of the time. I come in to see you guys intermittently, and you give me an infusion. I don’t get sick. I don’t get constipation.” She just happened to tolerate it really well. She said, “Why would I change everything? You know I have metastatic disease.” She had very diffuse visceral symptomatic disease up front. She remembered what it was like to have bad metastatic cancer. You have to individualize it. It wouldn’t surprise me if it never comes back for a few patients we’re able to take off it. We don’t know who they are. The anticipation is that they will, but a holiday isn’t necessarily a terrible thing.

I just wouldn’t count on it. You count on great longevity. I’d be very careful about the patients you choose it in. We know that with chemotherapy you’re better on maintenance doses than you are with intermittent dosing and coming off and on and stuff.

I did it in 2, but I won’t do it again. I took 2 off after zillions of years. One came back in the liver in the same spot. She had been on Navelbine—at least it took forever—and she was on it 8 years. Then she did great on trastuzumab for X number more years. It came right back in her liver. Then I got her right back, thank God, to a CR, but now she’s on HP for life.

I had another patient in the pre-pertuzumab, and we stopped after a couple of years. We had 1 solitary bone met. We radiated it, and she was NED [no evidence of disease] 2 years later, so we stopped it. She came back in her brain. She lived a long time, but we couldn’t salvage her back. You know what I mean? I’m like, “That’s it. I’m not doing it anymore.”

Hormone Therapy in HER2+ Breast Cancer

VK, we don’t know if we want to call it de-escalation, but personalizing the amount of treatment. People are calling it some response adapted as such. Say a little about where we are with that. What’s your take? Anything new there?

 I’ve heard the same feedback. De-escalation is so 2019. In 2020 we used optimized, personalized, and there are probably better words. I get the sentiment. It feels like we’re holding something back that might be important, whereas personalization and optimization makes more sense. These response-adapted strategies are fascinating.

There was a couple presented at San Antonio Breast Cancer Symposium in non-

 [human epidermal growth factor receptor 2–positive] disease this year as well. The idea that you’re letting the disease teach you which direction you go is very dynamic. What’s hard in practice is to get those strategies to a point where people are uniform and thinking about this instead of shooting from the hip. That’s going to be something we need to coalesce on—ideas on how to define these things.

For example, in recent meetings you’ve seen somebody use FDG-PET [fluorodeoxyglucose–positron emission tomography] imaging of the primary breast tumor to see if you are having a clinical response. If you’re having a clinical response, those patients might then go on to surgery right then, and if they don’t, they escalate to chemotherapy. There are a lot of trees and decision points here. At the end of the day, patients who got chemotherapy typically got the advertised pCR [pathologic complete response] rates of like 60%-plus. For patients who were randomized to the endocrine therapy plus HP [trastuzumab, pertuzumab] options up front, depending on what happens—maybe they got a pCR eventually, but that was a small group of patients. If they didn’t, then they got chemotherapy in the adjuvant setting and potentially 2 monoclonal antibodies in some of these trials for the fixed amount of time that we offer this.

It’s a little messy to look at these data and try to extract and come out with a uniformed message. When we don’t have that concretely defined for a community practitioner where breast is 1 of the many things they’re seeing, this becomes a challenging thing to memorize and to know. I don’t want to hamstring our doctors that way just yet until we have more mature data about these pathways. I agree, in principle, that if we can optimize our therapy and minimize toxicities, financial and physical toxicities, that’s very important. We’re still a little early for that outside the academic setting.

 Yeah. A lot of the response was adapted very early, before pilot feasibility trials, as opposed to randomized trials. It’s very interesting, though. People are clearly taking note of these high-level pathologic CRs and saying, “Wait a minute. What can we do a little differently?” That’s the major message.

De-Escalation of Adjuvant Anti-HER2 Therapy and Chemo

Let’s turn to Claudine. Maybe you could refresh and update for us about APHINITY, ExteNET, and KATHERINE. I think we all know what the data are, but is there anything new around those 3 particular topics?

Absolutely. For APHINITY we’ve already alluded that the differences were pretty modest. There were groups where we saw the differences on the patients with hormone receptor negative or node positive disease were where the differences emerged, but they weren’t huge. They were a few percentage points in terms of evasive disease-free survival.

There was a presentation at San Antonio Breast Cancer Symposium. There was a poster that tried to look at which populations were the ones that derived the greatest benefit and tried to get estimates based on treatment or patient subpopulations. What came out was very much in keeping with what we thought that the group that derived the greatest benefit were the patients who had higher clinical risk. Then they also looked at other parameters. They looked at TILs [tumor-infiltrating lymphocytes] and 

 [human epidermal growth factor receptor 2] fluorescence in situ hybridization copy number. They found that the patients with the highest TILs were also the group that seemed to derive the greatest benefit from pertuzumab. Something else to put in there, not that we’re necessarily getting TIL numbers when we’re getting path specimens on patients who are getting core biopsies on patients, but the concept that the patient was at higher risk, and still incorporating what we’ve been incorporating like the node-positive or the hormone receptor–negative patients.

I know I’ve heard others say that they started with TCH [docetaxel, carboplatin, trastuzumab]. I’d say in that the neoadjuvant setting, if I’m treating somebody, I do tend to give TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] except in an older patient or somebody where there would be a reason for me not to. But I realize I’m probably a little more conservative on that than I need to be, and I’m trying to figure out how to pull back on some of that.

That is what was new on APHINITY. On ExteNET, this is a study that we’ve seen a lot. This is a study that is looking at the role of neratinib, pan-TKI [tyrosine kinase inhibitor], in patients who had completed HER2-targeted therapy. This is a pretty old trial, so the patients typically got trastuzumab as their treatment, and it was a wide-open trial. We talked about that trial, and we thought about opening it, and it was a trial that basically allowed anyone at any time who had gotten trastuzumab. You could have been 2 or 3 years out, and then they shortened the time frame. It’s really a very wide-open trial.

What they showed us over the past couple of years is that the group that appeared to benefit from that year of neratinib after having completed trastuzumab and chemotherapy were actually the patients who had hormone receptor–positive disease. All patients with hormone receptor–positive disease also got endocrine therapy. We know there’s a lot of cross talk between those pathways, so you can think that there might be a rationale, particularly if you’re starting it later in the course.

That was really the subset that seemed to come out. The other thing is not surprising: The patients who were started more closely into completing their adjuvant trastuzumab were the other group that seemed to really get the benefit. The hormone receptor positive started within 1 year of completing their trastuzumab.

We hadn’t seen survival data and Frankie Holmes presented that at this past San Antonio Breast Cancer Symposium. Looking at that group, there was no benefit overall in terms of overall survival in the intent-to-treat population. These become exploratory analysis when they looked at the patients with hormone receptor positive. There emerged a survival benefit—about a 2% survival benefit—if you looked at the super-highest risk. The hormone receptor–positive patients who started within a year of completing their therapy, and the ones who didn’t achieve a pathologic CR [complete response]. We’re getting to really small numbers, so let’s be careful. There was actually a pretty significant benefit that emerged in that group in terms of overall survival.

It takes us back to the discussion of where we think about this drug now. What do we do with this drug in the era of KATHERINE and in the era of pertuzumab? That’s something that maybe we want to come back to as a group and talk about. That was really an interesting finding and it’s one that we debate in practice. I don’t know if you want to talk about it now, Joyce.

Let’s do it. What do you do? Do you use neratinib in some patients?

I’d be really interested to hear what my colleagues think. Like most of us, I was really impressed by the KATHERINE data. It showed this really big 3-year invasive disease-free survival benefit for the patients who just didn’t achieve a pathologic CR. It’s about an 11% absolute benefit. What also struck me is those patients weren’t doing that great—even the group that got T-DM1 [trastuzumab emtansine], right? At 3 years there was about 11% to 12% of them who developed a recurrence.

It was 3 years so it struck me that there was still room for benefit in that group. In those patients, particularly in the really high-risk patients, and particularly if they have hormone receptor–positive disease—and we all have some patients who have multiple nodes, 2 or 3 nodes—I tell them, and I do tend to give them neratinib.

I always tell people when we start on a drug, particularly 1 that has adverse effects: This is not a moving train; you can’t get off. Let’s try it, and let’s see how you tolerate it. If it’s tolerable, we may as well try to get benefit from it. If it’s not, we try it, and obviously they go on endocrine therapy and everything, but that’s the group for whom I still think about using neratinib. I recognize that we have a paucity of data to support my recommendation, except that there’s still a place for improvement in that group of patients.

I agree with everything that Claudine said, and the 1 other element that has to go into the mix is that it has to be a highly motivated patient partnered with a highly motivated oncologist because it’s going to take a lot to get them through it. I frankly don’t use it a lot. It would be in those patients that Claudine described. Of the handful of patients who did go on, half discontinued, and that’s even with the antidiarrheal maneuvers. It’s not for the faint of heart oftentimes.

Yeah, and I just want to make the point about how important it is to escalate the agent. In case somebody hasn’t seen the results of the CONTROL trial, a lot of things were looked at. Loperamide, which we certainly want to use for more prn as needed with the escalation strategy, plus budesonide and colestipol. Starting at 3 or 4 pills, from 120 to 150 mg, and then every 1 or 2 weeks as tolerated, increasing it by 1 pill has made a substantial difference. In the CONTROL trial, only 2% or something stopped for toxicity. I’ve really been pleased with that. That’s really the only way to go. People are going to try to give patients a shot at this, and using the escalation strategy is really important. How about you, VK? What do you think about neratinib?

I’ve actually found myself using it increasingly of late. That’s because of the cross talk issue. I believe that ER [estrogen receptor] disease is fundamentally different from the kind that’s ER negative. If we don’t address that cross talk, and we don’t do that with T-DM1 [trastuzumab emtansine], I’m still worried about these patients having events down the road.

The other thing, and we learned this from tucatinib in the metastatic setting, having that molecule that can cross the blood-brain barrier even in this context may actually have benefit. I know that trials are underpowered for CNS [central nervous system] as a first site of recurrent type event. It’s my suspicion that those are patients who are vulnerable to those events when you have residual disease, have done T-DM1, have ER-positive disease. I’d like to give them that extra bit of coverage for that as well as for prevention for those CNS events. I’ve gradually shifted: I was not at all using it, and now I find myself more often using it. Now that we have the ability to give it, start with a few pills, work our way up…. It’s not for the faint of heart, to steal Bill’s words.

I’ll be honest: I know practices that don’t let their doctors use it in off pathways and stuff. I’d love Bill to change this for us, the NCCN [National Comprehensive Cancer Network] has it like it’s a footnote—on the top, Bill, just as an option. It’s down in the fine print, it’s the argument that the ExteNET was done with pertuzumab and T-DM1. That’s the argument, and I totally get that.

It’s a non-cross-resistant agent, and you’ve got the cross top coming. To me, it’s like a totally different drug, and I don’t know why antecedent pertuzumab and T-DM1 make a difference. What do you guys think? Lisa, do you ever use this drug?

Rarely. The thing I struggle with is that the cross talk is certainly something that’s preclinically important. We haven’t seen that direction of effect by hormone receptors with any of the other small molecules or, in fact, with neratinib itself in the metastatic setting.

I struggle a little with it because it didn’t quite seem to hold true. That said, the ExteNET data are what they are. If I have a very high-risk patient, I have occasionally reached for it, and I’ve been happier with the option of dose escalation. In the CONTROL trial they did quite well. They escalated relatively quickly. I was actually surprised. It seemed like the low hanging fruit of managing your diarrhea, and it was the most effective 1. If I was going to do it, I would do that.

We’re going to talk about it in a little bit, but NALA and HER2CLIMB are the only studies we have in the metastatic setting. Both did not permit endocrine therapy usage. Personal opinion, it would have been nice to have studies that just said, “We are just managing 

+, ER-positive patients with the anchored regimens with endocrine therapy.” We do have studies in the early stage metastatic setting, like in the PERTAIN trial, and you see that synergy there. I think there’s still room.

Adjuvant Systemic Therapy Data Updates

Bill, how do you define patients at high risk of recurrence after their neoadjuvant therapy? What do you do with them? Who is high enough risk in your practice to get a pertuzumab up front? Do you know what I mean? When you start it, do you ever stop it? Do you just keep it going because you feel patients are high enough risk? Then in the adjuvant setting for people with residual disease.

Right. To piggyback on some of the other comments, we’ve more or less exclusively got away from anthracyclines preoperatively. There may be exceptions where that’s an appropriate thing to do. For most patients, they are getting TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] upfront, particularly if they have bigger disease at the outset. We do use TCH [docetaxel, carboplatin, trastuzumab] for those where we’re trying to avoid some of the excess toxicity.

In my mind, the fundamental thing that defines risk after receiving neoadjuvant therapy is what the residual disease burden looks like. If there’s significant disease, particularly in nodes, that would be very worrisome, as it would be if there’s a significant amount of disease in the breast. I would also say as a caveat, quite frankly, I haven’t seen that many patients in my own personal experience getting TCH or TCHP who actually progressed on that preoperatively. I know it happens, but I don’t see it very often.

For those that have significant residual disease, and Lisa was already alluding to KATHERINE with those patients switching to T-DM1 [trastuzumab emtansine] and good results, even in those patients where the subsequent 

 [human epidermal growth factor receptor 2] assessment is negative, we continued the idea to switching to T-DM1 in those with residual disease makes sense.

That’s the strategy we employ. With respect to those who get a pCR [pathologic complete response] at the outset, for most patients—not all—we’ve continued or at least started with the idea that they would complete HP [trastuzumab, pertuzumab]. Who would we not do that in? Certainly, anybody who’s having excessive toxicity. Anybody who’s ER+ [estrogen receptor positive] I would be reluctant to do that in because I don’t think they’re getting as much benefit. There are some nuances to how it would be used.

Bill, do you think that if somebody has residual disease after a TCHP or occasionally a AC-THP [doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, pertuzumab], that T-DM1 is really the real standard of care? I say that because not long ago, say a few weeks ago, I saw a patient who had some residual disease and didn’t get T-DM1. Frankly, I was surprised, you know what I mean? It’s become a must-do standard. What do you think? Do you think there’s some room for maneuver with a tiny amount of cancer left?

I think it is the standard. Just as we can find exceptions to everything we do if we look hard enough, I suppose if somebody had a millimeter of disease, would I feel obligated that they must get T-DM1? Maybe not. Maybe if they’re a little older. For most patients, it really is the standard. Most patients do OK with it, so I would try to leverage that benefit that we saw in KATHERINE and confer to whoever has residual disease.

Yeah. Does anyone else want to make any comments about KATHERINE? We’re going to come back and go into it a little more deeply, but any other issues around the adjuvant?

I’ll share a struggle. In our patients who are node-positive preoperative therapy and get a pCR, what’s the thinking around continuing HP? Even in those pCR patients who were node positive, knowing that there’s a little benefit there when they’re node positive. I found a presentation at San Antonio Breast Cancer Symposium by a very young scientist from Europe looking at pCR rates across a lot of different diseases and saying, “pCR equals pCR.” These are people who have good outcomes. You look at some of the trials, and you start picking at them a little. There seems to be a suggestion that maybe you should continue the HP. I have to be honest. I don’t find that data compelling, but I’m always curious what others think.

I have to say, I don’t think we know the right thing to do. I stay with whatever brought you. You know? If I got a pCR out of an HP-based regimen, I tend to continue the HP. Your point is well taken. The patients can do very well. In our experience, CALGB-40601—which was designed deliberately—is very similar to the European analog Neo ALTTO; the pCR is different. It’s about a 10% absolute benefit difference between the 2 of them in the pCR group, with the event-free survival around 90%-plus for the American trial. But it’s in the 80s for European trials, without a particularly good explanation if you dive into it. I’m not sure that I have, because I don’t feel I can take a pCR to the bank. And so if I gave HP up front, I’d give HP out back, but I don’t know if that’s right.

I tend to continue HP as well if somebody is tolerating it and there’s no compelling reason to stop it. I have Lisa’s take on it that. If it’s not causing much harm—and I’m not sure what it would do for me to take it back—I’ll continue it. I agree. I wonder about de-escalating from the patient’s perspective and then the time and the inconvenience and everything that goes with it to continuing the therapy.

I also think that the other thing that figures into it is APHINITY, though we can’t jump up and down about this huge gap between the lines. That gap was identified with a full year of therapy, particularly in node-positive patients. That has to figure into it at least a little. It is a struggle for the patient.

Yeah, I did also want to point out that the FDA label for pertuzumab talks about the neoadjuvant. In the label there’s a section called neoadjuvant, and talks about pertuzumab preoperatively. What it says is interesting. It says that if you start it preoperatively, you should finish the year of it. It’s really interesting. Even though we honestly don’t know. If somebody has a pCR, do they really need it, or you don’t even know. If they’re clinically node negative, they start off with it, but they’ve got a big cancer. You decide to use it; we just don’t know this so much.

Bill does the NCCN [National Comprehensive Cancer Network] have a statement about this anywhere, if somebody starts with pertuzumab preoperatively and gets a pCR, are there any recommendations in NCCN Guidelines?

No, we haven’t gone to that granular level. We wanted to let doctors be doctors.

That’s a beautiful thing. I love that. Thank you. It’s refreshing.

Joyce, I’ll point out 1 thing that does make giving both therapies in the adjuvant setting now—and we’re going to talk about this later this evening—is the ability to give both as a single injection.

Yeah, there you go. That might help too, VK.

Adjuvant Systemic Therapy Decision Factors

® titled “Refining Treatment Approaches for 

+ Breast Cancer.” I am Dr Joyce O’Shaughnessy from the Baylor University Medical Center, Texas Oncology, and US Oncology in Dallas, Texas. I’m delighted to have 4 friends and longtime colleagues with us to debrief after San Antonio Breast Cancer Symposium and find out what people thought about some of these data.

I have with me tonight Dr Lisa Carey from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina; Dr VK Gadi from the University of Illinois College of Medicine in Chicago, Illinois; Dr William Gradishar from Northwestern Memorial Hospital in Chicago, Illinois; and Dr Claudine Isaacs from the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.

William Gradishar, MD, Northwestern Medicine

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