Case: A patient in her late 40s with ER-positive, HER2-positive, node-positive breast cancer experiences a near complete response after treatment with neoadjuvant doxorubicin, cyclophosphamide, paclitaxel, trastuzumab and pertuzumab (AC-THP)

DR KROP: This is a 48-year-old woman who presented with a clearly locally advanced cancer. She had I think palpable, about 4 or 5 centimeters, and there was clear bulky adenopathy. We treated her with what we typically use in patients with high-risk HER2-positive cancer, in her case it was ER-positive as well, with neoadjuvant AC followed by paclitaxel and trastuzumab and pertuzumab.

DR LOVE: Could I just ask, was it your sense that she delayed coming in, was aware of this? Or would you think this is just a rapidly growing lesion?

DR KROP: That’s a good question. In this particular patient I don’t think — I mean her cancer, she had relatively large breasts and so on exam it was clear this was a good-sized cancer, but it wasn’t causing any change in the breast shape. And she wasn’t doing breast exams up until she found this incidentally.

This is not breaking through the skin. There was no obvious manifestation of this. I mean, I treat patients in Boston, and so certainly this may not be completely generalizable, but I think the number of patients now who ignore breast cancer is pretty small. I think it’s just there are cancers with pretty bad biologies that grow under the radar fairly quickly. And when they present, they’re already fairly significantly advanced.

Choice of neoadjuvant chemotherapy for patients with HER2-positive breast cancer

DR LOVE: I also want to ask you about your choice of neoadjuvant therapy. I was mentioning we had just done this survey of 50 general medical oncologists and we were comparing it to practice patterns in a survey your participated in — had 30 clinical investigators and 1 thing I noticed was there was more anthracyclines used by investigators.

Can you talk about at what point you start bringing anthracycline into neoadjuvant therapy? And also, what about the out-back approach? Is that still valid?

DR KROP: Yes. Those are 2 important questions, and I think there’s going to be some shift, or I think there should probably be some shift based on the evolving data. On the anthracycline question, there clearly are 2 very reasonable either neoadjuvant or adjuvant regimens that can be used in HER2-positive breast cancer these days. One is the anthracycline regimen, which is, for most of us, AC and either paclitaxel and trastuzumab and pertuzumab or docetaxel and trastuzumab and pertuzumab. And that’s been tested in multiple adjuvant studies and also been looked at in neoadjuvant trials as well.

And then the other is the nonanthracycline regimen, which is docetaxel, carboplatin and trastuzumab and pertuzumab. Again, been tested in a large adjuvant trial. Been looked at in multiple neoadjuvant trials.

It’s pretty clear that both types of regimens result in very good outcomes in either the adjuvant setting or the neoadjuvant setting. In the neoadjuvant setting, we have studies showing path CR rates of 60+% with both types of regimens. I mean, I think a case could be made that either approach is very reasonable for the moderate- to high-risk patient.

DR LOVE: Just out of curiosity. Are there direct comparative data to show the exact value of adding an anthracycline? Or is this pretty much indirect comparison?

DR KROP: I mean, we have a randomized trial from BCIRG 006, which was comparing AC followed by docetaxel and trastuzumab versus the TCH regimen. There’s no pertuzumab in that trial. It was an older trial. And in that trial, which — I want to make very clear — was not designed to compare those 2 chemotherapy regimens. Both of them showed good benefit compared to the nontrastuzumab regimen. But if you look at the absolute outcomes in those 2, the nonanthracycline and the anthracycline arm — in absolute terms there was a little bit numerically better outcome with the anthracycline. We have a number of other anthracycline-based trials.

And so our group does tend to use anthracycline still in the higher-risk patients. Obviously, anybody who has an increased risk for cardiac toxicity we use nonanthracycline regimens.

DR LOVE: You’re bringing back flashback memories of Dr Dennis Slamon presenting — this is like, what, 2005, that trial, I think.

DR KROP: Yes, right around there.

DR LOVE: But it wasn’t like a very big difference. And I don’t think it was statistically significant.

DR KROP: No, and again, as I said, it was not even designed —

DR LOVE: Right.

DR KROP: — to test that question.

DR LOVE: Right.

DR KROP: But that’s really the only true randomized data with long-term outcome that I know about comparing anthracyclines versus nonanthracyclines.

We have neoadjuvant trials that have compared, like TRYPHENA, which looked at anthracycline/taxane versus TCH, both of those had pertuzumab. And again, both of them had very high path CR rates, pretty similar in the mid-60s.

Pertuzumab toxicity with or without chemotherapy

DR LOVE: I’ll be curious, once we get into the KATHERINE data, whether that’s affected whether you use an anthracycline. Now, then you’ve kind of got another tool out there.

But anyhow, what happened with this lady?

DR KROP: She had a very good response, still had a little bit of residual disease, but very good response. We continued the trastuzumab and pertuzumab for a year, to complete a year of HER2 therapy. And she’s done very well since then.

Even though she started out with quite high-risk disease, she’s now, I guess, about almost 3 years out and has done very well.

DR LOVE: Any tolerability issues with treatment, either the antibodies or chemo?

DR KROP: Yes. I think most of us are familiar with the potential toxicities of the chemotherapy part of the regimen and she, overall, did fine with that. Adding pertuzumab does add some toxicity. In this particular person, she had trivial amounts of diarrhea, especially early on. It was responsive to loperamide. She didn’t have to take substantial time off of her teaching job. And, like most patients, once she got to the antibody portion, once the chemo was completed, the diarrhea essentially became a non-issue. And all the studies have shown that most of the added diarrhea associated with pertuzumab happens in the period where they’re getting concurrent chemotherapy.

DR LOVE: I can’t believe that I never heard that stated before. That’s really interesting.

DR KROP: Yes. I mean, again, I think that that’s not only what’s been seen in the trials, but also in our clinical experience.

DR LOVE: It makes sense.

I guess, of course, the issue here is what was seen at surgery?

DR KROP: Yes. She had a small amount of cancer. She did not have a pathologic complete response. I think she had less than a centimeter of invasive cancer in the breast and she had 1 lymph node that still had invasive cancer, but multiple lymph nodes had shown treatment effect. She clearly did have substantial disease at baseline.

Management of the axilla in patients with clinically node-positive breast cancer who achieve a pathologic complete response to neoadjuvant systemic therapy

DR LOVE: What did you do about her axilla?

DR KROP: She ended up having a complete dissection and then got radiation, post-lumpectomy radiation after that.

DR LOVE: If she had negative nodes, what would you have done? And let’s say a path CR completely.

DR KROP: Yes. Right now there’s a question amongst the local therapy groups of, for somebody who starts out with known positive lymph nodes and then has a path CR at the time and sterilization of the lymph nodes, what the appropriate therapy is.

There is a cooperative group study going on in the United States that’s asking that question of whether those patients need radiation or not, in a randomized fashion, which I think is really nice that it’s being tested in that way. And similarly, there’s another trial looking for patients who still have residual disease after neoadjuvant therapy in the axilla, what’s the appropriate management? Do they need further surgery, or is radiation acceptable?

DR LOVE: As you know, a lot of times what we do is when trials are ongoing, we are also asking people what they do. And I remember another survey we did about neoadjuvant therapy and in terms of the axilla, the surgical and medical oncology breast investigators were saying at that point, it was a couple of years ago, was after, in general, after neoadjuvant therapy, negative sentinel nodes, no axillary dissection; positive sentinel nodes in contrast to the adjuvant situation, axillary dissection. Is that, kind of, your algorithm outside trial?

DR KROP: Yes. No, I think it is. And again, I think that’s why it’s really important that we have some data from randomized studies telling us what to do. Especially given the effectiveness of these systemic therapies now, that arguably, hopefully, will change how much local therapy these patients need. And it will be great to have definitive data to confirm that.

Design and results from the Phase III KATHERINE study evaluating adjuvant T-DM1 versus trastuzumab for patients with HER2-positive early breast cancer and residual disease after neoadjuvant treatment

DR LOVE: When I saw this case I was thinking, 2017, and now were going to talk about 2019, but, also, I think we should talk about 2021 and whether or not we’re going to be starting to look at tissue predictors to identify patients like this before they ever even get treatment. But we’ll get to that in a second.

Let’s start out with 2019, which, really, 2018 December, the KATHERINE trial. Can you explain the design of that trial, the eligibility, how it was executed, and what they saw?

DR KROP: Yes. I mean, I think this was a very visionary study, to be honest. I remember when this study was initiated, many of us weren’t sure that it was actually a feasible study. But basically, the design of the study was it looked at patients like this, who received any number of standard neoadjuvant therapies, so it was patients with HER2-positive cancers, regardless of hormone receptor status, who received some type of neoadjuvant HER2-directed therapy. It just had to be 6 cycles of something. It had to contain a taxane.

It had to include trastuzumab. It didn’t exclude patients who also received pertuzumab, although that was only about 20% of the patients who actually went on the study. But it was patients who received some neoadjuvant HER2-directed therapy off of trial, but then had residual invasive cancer, and it could be any amount of residual invasive cancer.

They were then eligible for this trial.

You have a relatively heterogeneous population, patients who received some anthracyclines, some patients received nonanthracyclines. As I mentioned, 20% of patients received pertuzumab and trastuzumab; most just received trastuzumab.

And then they went on this trial where they were randomized to what was considered the standard, which was, at the time, completion of a year, essentially 14 cycles, of trastuzumab, or switching to T-DM1, the antibody-drug conjugate, against HER2, again for the same duration of therapy.

And when they looked at invasive disease-free survival at 3 years, the difference was quite striking. The hazard ratio was 0.5 in favor of T-DM1. That translated to about an 11% difference in disease-free survival. Really stark, an unequivocal benefit to switching to this antibody-drug conjugate compared to just continuing the trastuzumab. And that was irrespective of whether they had had neoadjuvant pertuzumab or not, irrespective of hormone receptor status. The subgroup analyses on the forest plots were remarkably consistent in terms of this hazard ratio of 0.5 being across the board.

DR LOVE: I was curious. You said you weren’t sure whether or not it would be feasible to do the study. What were the concerns?

DR KROP: Just that at that time, this was before the CREATE-X study, which was kind of a similar design in triple-negative patients. It was not a situation where clinical trials were being done after — we had trials in the adjuvant setting and we had trials in the neoadjuvant setting. We didn’t have this kind of hybrid approach.

Perspective on the benefits and risks of T-DM1/pertuzumab versus T-DM1 alone as adjuvant therapy

DR LOVE: I guess 1 question is, you have done work on T-DM1/pertuzumab, which we can talk about, in the neoadjuvant setting. What would you say if you saw a second opinion, assuming there was a way to get it paid for, for somebody who had significant residual disease where the first doc recommended T-DM1 plus pertuzumab as adjuvant therapy?

DR KROP: Yes. We really don’t have data on that particular combination in a way that tells us that it’s better than T-DM1 alone in that situation.

We have now several neoadjuvant trials looking at T-DM1 plus pertuzumab showing good pathologic complete response rates but not clearly showing that the addition of pertuzumab adds to the efficacy of T-DM1.

We have data from the metastatic setting, which seems to suggest that adding pertuzumab to T-DM1 did not result in improved outcomes. That’s the MARIANNE trial in the first-line setting.

You look across at the data we have, the evidence that we have, I really don’t see anything that says that this particular patient in whom we have the KATHERINE data showing good outcomes with using T-DM1 alone in the adjuvant setting warrants adding pertuzumab to that. And it certainly probably adds some toxicity. Obviously, it adds cost. I think it’s really hard to justify doing anything else in the neoadjuvant setting other than T-DM1 alone for a patient like this.

Benefit of T-DM1 compared to trastuzumab irrespective of the extent of residual disease at surgery in the KATHERINE trial

DR LOVE: Another thing I’m curious about, I don’t know if it really makes any difference anymore because of the tolerability/safety of this strategy and the efficacy. But prior to this, there were these systems out there — I think 1 of them was called RCB, residual disease systems, to try to predict. I’m curious how that played out in the trial, particularly in the control group? And I’m guessing that even in the lowest amount of residual disease there was still significant absolute benefit?

DR KROP: Yes. I’m not sure that was such a given. I mean, I think, intuitively, you could have made the argument, as you suggested, that if you look at how much cancer someone has after neoadjuvant therapy, which can be quantified in a very standardized way using this residual cancer burden algorithm from MD Anderson and Fraser Symmans, the amount of residual disease, it’s quite prognostic. And so you could imagine that if you looked at patients with very small amounts of residual cancer that the benefits of something like T-DM1 would be miniscule.

But in the data from KATHERINE, that doesn’t seem to be the case. That the relative benefit of T-DM1 over trastuzumab was very similar regardless of how much cancer was left. And even if you looked specifically at the patients who only had less than a centimeter of cancer and node-negative disease at time of surgery, the hazard ratio was still quite good. I think it was 0.6. And that translated to an absolute benefit of 5%.

It really does seem like, at least from the data we have at this point, that basically any amount of residual invasive cancer — I’m not talking about residual DCIS — but residual invasive cancer I think you should think strongly about using T-DM1 in that situation.

DR LOVE: I’m really glad because I never really understood that RCB system. And it sounds like it’s maybe not going to be as relevant any more. Or at least it was kind of hard to figure out for me anyhow.

DR KROP: It’s hard. I mean, the mathematical equation is actually very complicated. Fortunately, they put a website that does the calculation for you. You just plug in the pathologic data.

I mean, I think there is still a lot of interest in using RCB, and in other cancer situations, it can be very helpful. But I think for HER2-postive, postneoadjuvant, you’re right. The KATHERINE data kind of says that it’s more of a dichotomous situation: You either have invasive cancer residually or you don’t. And if you do, then it doesn’t really matter how much.

DR LOVE: That’s interesting. I never thought about it, but did they break that down based on ER/HER2 subtype, like triple-negative versus HER2? Or is it just 1 number?

DR KROP: The RCB is independent of —

DR LOVE: Right.

DR KROP: — receptor status.

But just to be clear, having an RCB of 2.1 is associated with a different prognosis whether you are ER-negative, ER-positive —

DR LOVE: Right.

DR KROP: — or triple-negative.

DR LOVE: Yes, you would certainly expect that.

Clinical implications of the KATHERINE trial results

DR LOVE: Getting back to the question I was bringing up before about choice of neoadjuvant therapy and this kind of case of this woman that you just presented. Now that you’ve got this in your back pocket, a 50% knockdown after therapy, are you going to change the way you approach using anthracyclines?

DR KROP: I think that’s an excellent question. And the ability to leverage this, have use of T-DM1, does that allow us now to de-escalate therapy? Having T-DM1 out back and knowing that patients who get trastuzumab and pertuzumab-based chemotherapy neoadjuvantly now having good path CR rates, can we use those tools to cut back on treatment in those patients who have very HER2-sensitive cancers?

We don’t have specific data on that. Actually, we now do, actually after ASCO, indirectly at least, but there is now a clinical trial that’s going to be getting underway within the US Cooperative Group system called the COMPASS trial — it’s going to be led by ECOG. It’s basically taking patients with Stage II and III HER2-positive cancers and treating them neoadjuvantly with 4 cycles of paclitaxel plus trastuzumab and pertuzumab, a very well-tolerated regimen. No platinum. No anthracycline. And if they have a pathologic complete response then they will not get further chemotherapy. They’ll just get the dual antibodies to complete a year and will be done.

And that’s asking this question of, if you have a pathologic complete response with lesser chemotherapy does that still translate to very good outcomes? And we have a number of studies that would suggest that’s the case.

Results from the Phase III KRISTINE study evaluating neoadjuvant docetaxel, carboplatin, trastuzumab and pertuzumab (TCHP) versus T-DM1 and pertuzumab for HER2-positive breast cancer

DR KROP: The most recently we have KRISTINE, which was another T-DM1-based trial. This one was comparing TCHP versus T-DM1/p, which did show increased path CR rates with the conventional chemotherapy arm compared to T-DM1. But what we learned recently, presented by Sara Hurvitz at ASCO, was that in the long run the patients who were on the T-DM1/p arm did just as well as those who got TCHP with 1 caveat, and that is you had to take out those patients who progressed during their neoadjuvant therapy. Which was about 6% or 7% of the patients on T-DM1/pertuzumab, and 0 on the TCHP.

Clearly there were some patients who did not respond very well at all to TCHP. And those patients don’t do well in the long run unless they get additional therapy.

But if you take those patients out and you took the patients whether they got a PCR or didn’t get a PCR, overall, the outcomes were the same whether you got TCHP up front or T-DM1/p up front.

That would support this idea that if you have a pathologic complete response it doesn’t really matter how you go there, that you’re going to do well.

DR LOVE: The next thing I had written down here was this issue of paclitaxel/trastuzumab/pertuzumab. Because I’ve been starting to hear about cases, mainly a lot of them coming out of your institution from various people, where people were doing that. It kind of made complete sense. It kind of goes back to the adjuvant APT trial that you all did. It kind of sounds like this is the neoadjuvant version of that.

DR KROP: It is. I mean, it’s with pertuzumab.

DR LOVE: Right.

DR KROP: Which is slightly different than —

DR LOVE: With paclitaxel.

DR KROP: Right.

I think the general idea here is we know that there is this group of HER2-positive cancers that are just exquisitely sensitive to HER2-directed therapy. And they need a little bit of chemotherapy, but they probably don’t need that much. And we’re getting these path CR rates in the 40+% range from just getting 4 cycles of paclitaxel and trastuzumab and pertuzumab. And, again, the data from KRISTINE would support this idea that it doesn’t really matter how you get to your path CR. If you get it, you’re likely to do well. And adding on extra chemotherapy isn’t really needed, isn’t going to make a big difference.

DR LOVE: There are very few quality-of-life or patient perspective outcomes that are reported comparing paclitaxel versus, say, carbo/docetaxel as partners for anti-HER therapy. Maybe you’re aware of some that are convincing. But when you talk to patients and you talk to docs, it sounds like a substantial difference.

How much data do we have to show there’s a difference, and in your own clinical experience how much of a difference is there?

DR KROP: I can’t off the top of my head think of a randomized trial that compares just a taxane/pertuzumab or a taxane trastuzumab regimen to a combination chemotherapy/trastuzumab regimen, but, I mean, I think if you’ve used these regimens in a reasonable number of patients, it’s pretty clear that adding an anthracycline or adding carboplatin to docetaxel, or even just using docetaxel compared to paclitaxel, it’s a very different experience for many patients.

Paclitaxel is remarkably well tolerated when you’re just giving 12 weeks of it at 80 mg/m². And now with the usage of cold caps, you can alleviate the alopecia in a large number of those patients. It’s a remarkably well-tolerated regimen.

Some patients get into some issues with neuropathy, but that’s usually something that’s very manageable with dose reductions if it happens. Again, without randomized data, the gestalt is that this is a much better tolerated regimen than either TCH or ACTH.

Use of cold caps to reduce the risk of alopecia with chemotherapy

DR LOVE: I am curious about the cold strategy, how it plays out at Dana-Farber. How do you do it? How often do people elect to do it? And how effective is it?

DR KROP: I mean, the randomized data would show that it’s quite effective for nonanthracycline regimens; that’s been our experience. It’s not effective in everybody, but in the majority of patients, they really have very little, if any, noticeable alopecia when they’re using it.

It does add to the cost to the patient, in most cases. There are some ways to try to help with the cost, but it’s still a nontrivial financial burden for patients. And so that’s oftentimes a decider for patients whether they want to do it or not. But we offer it to all patients who are getting nonanthracycline regimens.

DR LOVE: What about the experience itself? How uncomfortable is it?

DR KROP: I mean, with the mechanized versions that don’t require the patients to bring in tubs of dry ice and things, some patients notice some mild discomfort, but, other than that, it’s not really a big issue. It does add the time that they’re in the clinic because you have to pre-cool and keep the cold caps on after the infusions, as well for a period of time. But I think most patients feel that the trade-off is very worthwhile, patients who really are concerned about the risk of alopecia.

Side-effect profile of T-DM1 in the adjuvant KATHERINE trial

DR LOVE: Before we get into where we’re heading, a little bit more about KATHERINE. Can you talk a little bit about what was seen in terms of tolerability and toxicity with T-DM1, and what some of the issues of using T-DM1 now in the adjuvant setting?

DR KROP: We’ve had experience now with T-DM1 in the adjuvant setting now through a number of trials, only 1 of which has been reported up until KATHERINE, which was a pilot study that we did a long time ago showing that it was feasible to give a year of T-DM1 in the early disease setting. But, I mean, it’s quite tolerable. I mean, I think those people who’ve used T-DM1 in the metastatic setting are pretty familiar with the toxicity profile. There was no unexpected toxicity seen in KATHERINE or in our pilot trial.

About 18% of patients stopped the T-DM1 prior to completing the full 14 cycles, and the reasons for discontinuation were kind of the expected things you see with T-DM1, many of which were laboratory abnormalities that didn’t substantially affect the patients’ quality of life.

I mean, for most people it’s pretty tolerable. There is more toxicity than just a year of trastuzumab, but I think for most people it’s quite manageable and not a big impact on quality of life.

DR LOVE: What specifically do you expect or counsel a patient in terms of risk related to thrombocytopenia and LFT abnormalities?

DR KROP: I mean, we know from the studies that it does happen and it requires dose modifications in some percentage of patients. But the clinically meaningful consequence is quite low, bleeding events have been very low. And I’m not sure they specifically called that out in KATHERINE. But I think the main reasons for discontinuation were, as you alluded to, thrombocytopenia, transaminase elevations. But in most cases those were not clinically impactful. They’re just something that we see and we modify the dose to try to prevent a clinical complication.

DR LOVE: T-DM1, I think, really was the first major commonly used antibody-drug conjugate that was utilized I think. But subsequently now, we have B-vedotin out there and a bunch of other antibody-drug — and T-DM1 is kind of always thought about as being the poster child of how nontoxic it is. But I have heard people claim, and of course it’s very, very hard to figure this out, that there are quality-of-life issues — I don’t know, like chemo kinds of feeling bad, fatigue type. I mean, obviously it’d be hard to figure that out. Do you think that happens?

DR KROP: I mean, I think there are some patients who do have real clinically meaningful toxicities from T-DM1. And you’re right, they’re the kinds of toxicities that are a little hard to tease out. But there are patients who definitely have nausea with each cycle. There are patients who have fatigue. Headache is seen. And whether the kind of cognitive effects, that you’re kind of — the chemo brain kind of things. I mean, I’ve had patients tell me that they’ve noticed that things feel a little different, but that’s hard to tease out.

I have never seen a neurosite type of analysis prognostic factor patients on T-DM1, which I think you’d have to do to really try to do that, to really kind of tease that out like has been done with chemotherapy. But there are patients who do notice something on T-DM1. But I think if you look in the totality of experience with T-DM1 compared to any chemotherapy, T-DM1 tends to be better tolerated. And that’s what’s been seen in all the randomized trials.

Compared to trastuzumab alone, which has very little toxicity, T-DM1 does have more. But for most patients, it’s a very manageable thing. And doing a year of it or 14 cycles of it is manageable for most patients.

DR LOVE: Not to mention that the benefit really is spectacular, so what a trade-off.

Perspective on the use of neratinib in the post-(neo)adjuvant and metastatic settings

DR LOVE: Obviously neratinib is out there in the post-adjuvant space, so to speak. And with all these changes going on, I’m kind of curious how its effective, if at all and the way you approach that decision? In the adjuvant setting, what we’ve heard from investigators is they think about it for higher-risk patients, node-positive, ER-positive. A lot of people will think about it or maybe present it.

I don’t know exactly what people think about, but I’m curious what you think in terms of post-neoadjuvant. I have heard people say for higher-risk patients that even though maybe we don’t have the data exactly, that they would do it.

Right now, what’s your approach to using neratinib?

DR KROP: Yes. I mean, I think we’re all struggling with how to incorporate all of these new data, particularly KATHERINE, in to our treatment paradigm. And using neratinib after pertuzumab was already an extrapolation because in the ExteNET trial, which was the post-adjuvant neratinib trial, patients hadn’t received prior pertuzumab because of when the ExteNET study was performed. That was already an extrapolation. I think many people were comfortable with it in high-risk patients, just as you described. The high-risk ER-positive/node-positive patients, given that we really were trying to maximize benefit given their risk level.

And now we have T-DM1, which is going to be used, I would think, almost universally in such a high-risk patient who has residual cancer after neoadjuvant treatment. And that would require further extrapolations since we have no data on the effects of neratinib after T-DM1 or pertuzumab and these patients will have had both.

We’re again moving into this kind of data-free zone, where we don’t like to be particularly in the adjuvant setting where we can’t even tell whether our drugs are working for a given individual. But I do think that when you’re confronted with a very high-risk patient, someone who has multiple nodes positive after residual cancer, and if you look at that subset in KATHERINE, those patients still had a substantial risk of recurrence despite T-DM1. That in such a patient who’s ER-positive, I think it’s still worth considering neratinib, but again, it’s without definitive data that it’s effective because of their prior therapy. And it’s a relatively small population.

I don’t think neratinib is completely out of the question for these high-risk patients. And I would still offer it to such a patient. But it’s a pretty niche population at this point.

DR LOVE: But that ER thing is really interesting. And I guess if you think about it, they’re also on hormonal therapy at the same time really. You think you’re giving neratinib but you’re actually giving neratinib plus hormonal therapy.

What about in the metastatic setting? Has that strategy been used?

DR KROP: No, I think you raise a good point, and that’s been the hypothesized mechanism of action of neratinib in that setting is it helps block the crosstalk between ER and HER2 and that’s why it’s synergistic with hormonal therapy particularly in ER-positives where we didn’t see any benefit in the ER-negatives in ExteNET.

In the metastatic setting, we don’t have any data yet, as far as I know, of combining neratinib — if that’s what you’re asking — combining neratinib plus hormonal therapy. We actually have recently started an investigator-initiated trial looking at the combination of neratinib with or without fulvestrant to hopefully, definitively, ask that question, to see whether we can replicate what’s happening in the adjuvant setting in the metastatic setting where it’s a little easier to follow. We’ll see whether we can see that kind of synergy.

Interestingly, in the NALA trial, which was the metastatic neratinib trial that just got reported, virtually all the benefit was in the ER-negative/HER2-positive cancers as opposed to the ER-positives. Exact opposite of what was seen in ExteNET.

Now, just to be clear, that was done in the absence of hormonal therapy, so perhaps that is why we see this big difference and maybe that does say that you need a hormonal therapy around when you’re using neratinib, but it’s a little complicated with chemotherapy also in the mix.

I think this trial that I just mentioned that combining fulvestrant and neratinib is a little bit of a cleaner way to ask that question.

APHINITY: Phase III study evaluating adjuvant pertuzumab in combination with trastuzumab and chemotherapy for HER2-positive early breast cancer

DR LOVE: I want to start to move more toward where we’re heading the future, particularly in terms of new agents. But I also want to probe a little bit in terms of predictors of response to treatment. This is something that there’s been a lot of interest in breast cancer and all cancers for that matter — for a long time. And you’ve done some really interesting research, a lot of it was reported at ASCO, both in neoadjuvant, as well in the adjuvant setting, actually looking at the APHINITY data, which I thought was really amazing.

Can you talk a little bit about the body of this work and kind of what you think it means?

DR KROP: I mean, I think this is 1 area that, despite making a lot of progress in developing new anti-HER2 therapies, which have led to improvements in outcomes in both early- and late-stage disease, where we’ve come up short is coming up with true prognostic and predictive biomarkers that tell us who benefits from these therapies, whether you — a particular person is going to benefit more from an antibody versus a tyrosine kinase inhibitor versus a conjugate. We haven’t done a good job there. And I think there’s some — I think we’re starting to learn perhaps why that might be the case.

And we did present data form the APHINITY trial, which, as many of you may remember, was this large adjuvant, Phase III trial that was looking whether adding pertuzumab in the adjuvant setting to chemotherapy and trastuzumab led to improved outcomes. This was a positive trial, but the absolute benefit was pretty small. Hazard ratio’s only about 0.8, statistically significant. And in higher-risk patients it definitely was clinically significant, but the magnitude of the benefit was less than we would have hoped.

And the goal of this biomarker analysis was to try to identify patients who may particularly benefit from pertuzumab and differentiate those patients from those who might not benefit at all from pertuzumab, and therefore, the pertuzumab could be avoided.

Biomarker analysis of the APHINITY trial: Genomic correlates of response to adjuvant pertuzumab with trastuzumab for HER2-positive breast cancer

DR KROP: This was a pretty big undertaking. APHINITY was 4,800 patients. And we tried to be as comprehensive as possible. We looked at not only kind of standard things such as HER2 levels and amplification and hormone receptor status, but used an RNA seq analysis to look at how the transcriptional profiles changed or how transcriptional profiles were predictive of HER2 of the addition of pertuzumab. And we looked at mutations with the DNA analysis. Pretty comprehensive analysis. We also looked at immune biomarkers.

And what we found was that, despite this fairly exhaustive analysis, the things that really mattered were immune markers. And I think in some ways that was surprising, given that this is a HER2-directed therapy, and we’re very interested in HER2 signaling effects. We didn’t really see a whole lot there.

What we saw was these immune effects. And didn’t matter whether we looked at gene signatures of immune activation or just the very simple presence of immune cells using these tumor infiltrating lymphocyte analysis, which is a very simple thing that you can do just on an H&E sample. Either way, those cancers that seemed to have evidence of immune activation at baseline, either because they had a large number of TILs or because they had a strong immune gene signature, those were the ones who not only did better overall, regardless of which treatment arm they got, but those were also the ones who seemed to benefit from the addition of pertuzumab.

I think it was pretty conclusive, or we thought it was fairly conclusive in this study. We saw some similar data from the metastatic setting with CLEOPATRA, where high levels of TILs seem to predict benefit of pertuzumab. And it’s been seen in other settings with trastuzumab, both as well, although the data there have been a little mixed.

If you put that together I think what it says is that trastuzumab and now pertuzumab are working, at least in part, by helping activate the immune system and it’s not just its effect on blocking HER2 signaling. Which again I think is something that was a little surprising maybe 5 of 6 years ago, but now, when you start looking at the totality of the data, it’s all pointing in that same direction.

And now we have these data, pardon me if I switch gears quickly, but we have this data on margetuximab in the metastatic setting, presented at ASCO, which was a drug that worked solely by potentiating the antibody dependent cellular cytotoxicity, this ADCC effect, the immune effect of trastuzumab. That’s its main mechanism of action compared to standard trastuzumab, and you see again a benefit there, even in pretty late-stage patients.

I think what we’re seeing if you put everything together is that these HER2-directed antibodies are working, at least in part, through immune-mediated mechanisms. And I think that that’s kind of an interesting take-home message we’re seeing.

DR LOVE: Or could you state that the better the immune system, the better the activity, that it requires an intact immune system or it works better with an intact —

DR KROP: Yes. No. I think that that’s another way of looking at it. And I think if you just looked at APHINITY, that would be a very reasonable conclusion, that you need to have an active immune system. And if you already have evidence of that, then these antibodies can then potentiate that.

But then if you look at the margetuximab data, which says that these really are working via an immune mechanism, it’s not just that the cancers are already being recognized by the host immune system and that’s just a biomarker of that.

The benefit of margetuximab would suggest that there really is a clinically meaningful component to this immune effect.

Emerging data with immune checkpoint inhibitors in combination with HER2-targeted therapy for HER2-positive breast cancer

DR LOVE: Is there a thought, or do you have a thought of trying to combine immune stimulation, I mean checkpoint inhibitors, for example, in this setting?

DR KROP: Yes. I mean, I think certainly that’s been an idea. There are good preclinical data suggesting synergy between trastuzumab and between T-DM1 and immune checkpoint inhibitors. But so far, the data there have been a little mixed. Sherene Loi did a single-arm Phase II study of trastuzumab plus the PD-1 inhibitor pembrolizumab, which showed a pretty small benefit, only about 15% response rate, and that was only in the PD-L1 subset.

And then there was study called KATE2, which looked at T-DM1 plus/minus a checkpoint inhibitor. Again, a negative study overall. Looked like there might be some activity in the PD-L1-positive/HER2-positive cancers, but again, not a dramatic difference.

Just adding a checkpoint inhibitor to HER2 therapy doesn’t look like it’s going to be a real game-changer. Perhaps we need to do other approaches. There are now some studies going on looking at other immune-targeted drugs that may be synergistic with trastuzumab. One of which is a drug targeting an immune marker called 4-1BB, or CD137, which is important for this ADC effect on natural killer cells and T cells. That looks promising. And there are several trials going on looking at that antibody.

But it doesn’t look like just adding a checkpoint inhibitor, in the studies so far, has been substantially beneficial.

HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 and pertuzumab: Results from a prospective clinical trial

DR LOVE: What about the issue of trying to predict whether neoadjuvant therapy is going to be helpful? I know you’ve looked at HER2 heterogeneity. I mean, would there be a way to identify a patient like this upfront and say “We need to do a different strategy”?

DR KROP: Yes. I mean, I think that’s a good question. We did a study recently, which, a very simple trial, just treated 160 patients with 6 cycles of T-DM1 and pertuzumab, no conventional chemotherapy. And showed a pathological complete response rate of a little bit more than 50%, consistent with some other studies and consistent with KRISTINE, but the main goal of that trial was to look at whether levels of heterogeneity, and what we mean by heterogeneity is whether there were differences in the amount of HER2 expressed from 1 cell to another within the cancer. Which we know exists, but we really haven’t paid attention to that much before. But the hypothesis was that if we use a purely HER2-directed regimen, that if you have some cancer cells within the tumor that are not expressing HER2, that you’re not going to be able to kill those with the HER2 therapy. And, therefore, you’re going to lead to less complete responses in those tumors that were heterogeneous versus those that had homogeneous expression of HER2.

A pretty simple idea. The trial showed exactly what was hypothesized, which was that the pathologic complete response in those cancers that were homogeneous for HER2, which was the vast majority of cancers, the response path CR rate was 55%. And the path CR rate in the patients that were heterogeneous were zero. About as kind of black and white as you could imagine. And, it goes along with this idea that if you have substantial heterogeneity in your cancer for HER2 that using just a HER2 therapy alone is probably not going to be enough.

DR LOVE: Although, it looked like it was only, what, 10% of the patients.

DR KROP: Right. In this trial the true heterogeneous patients were only 10%. But in those 10% of patients, again, we saw no pathologic complete response. A lot of patients had substantial residual disease.

We’re now going back and looking at whether that was a very stringent definition of heterogeneity. If we use a more mild, more comprehensive, less stringent definition, do we still see big differences in path CR rates? We’re now going back to analyze that.

A simple thing we can look at is whether a cancer is HER2 3+ versus 2+. We saw similar kinds of differential activity if you were 2+ versus 3+. And actually, that was seen with KRISTINE as well, that those cancers that were 2+ had a much lower rate of path CR than those who were 3+. I think it’s, again, it’s not that unexpected that if you have less uniform HER2 expression that drugs that specifically target HER2 aren’t going to work quite as well.

DR LOVE: That’s interesting. I saw that there, but was it also corrected for the degree of amplification? In other words, you have 2 tumors that are amplified, whatever, but 1 has IHC2 or 3, is there a difference?

DR KROP: I mean, in our particular study we didn’t have enough numbers to say that it didn’t make a difference. But the effects of heterogeneity were independent of 2+ versus 3+. Even within the 3+ patients the heterogeneity still mattered. But you have all these different measures of HER2 expression, whether they’re all independent or whether they’re all pointing in the same direction, I think right now, we don’t know the answer to that.

Changes in HER2 status during disease progression

DR LOVE: What about changes in HER2 status over time? Where are we today with that? Do you ever biopsy people because they’re suspicious one way or the other? They’ve either gone from positive to negative or the reverse. How often does it occur? Is it really a therapeutically meaningful thing to look at?

DR KROP: I mean, I think that’s been looked in both, and just to be clear, there’s 2 situations where you might be thinking of that. One is in the neoadjuvant setting. When they get neoadjuvant HER2 therapy, how many of the residual cancers become HER2-negative? And that’s been looked at, and there are some. It looks like it’s less than 20%, but it’s not single digits.

And then there’s the metastatic setting, which is a cancer that starts out HER2-negative and becomes HER2-positive and vice-versa. In the metastatic setting at least, it doesn’t seem like there’s a large number of patients who start out HER2-positive and then become HER2-negative in the metastatic setting. It’s certainly less than 10%. You see a little bit more going the opposite direction, starting out HER2-negative and becoming HER2-positive. But, at least in that situation, in the metastatic, it doesn’t seem like it happens that much.

I think one interesting question is in the metastatic setting. When you’ve treated with multiple lines of HER2 therapy, and now we have a number of different HER2 treatments, and so patients often go through 5, 6, 7, 8 lines of HER2 therapy in the metastatic setting, do you start losing HER2 expression over time? And we really don’t know the answer to that. But it’s certainly something that needs to be looked into because you could imagine that after hitting the cancer with HER2 therapy, with regimen after regimen, that 1 escape mechanism could be that they start losing HER2. Right now we don’t have data in those late patients to be able to answer that.

Case: A woman in her early 60s with de novo ER-positive, HER2-positive metastatic breast cancer (mBC) experiences disease progression in the brain during treatment with T-DM1

DR LOVE: Let’s move on now and talk about new agents in the HER2 space. And also I want to get into the issue of management of brain mets. And I asked you to pull a case from your practice of a patient who had brain mets, and you brought up this 63-year-old woman diagnosed in 2010 with de novo metastatic disease. Gets a bunch of different therapies. And it looks like at one point she was getting T-DM1 for metastatic disease and then had progression in the brain but was continued on T-DM1 at that point. Let’s start there.

What was going on with the woman at that point?

DR KROP: That’s an interesting question. And this, I think many of you who treat these patients will be familiar with this situation, where someone is on a systemic therapy, and in this particular patient’s case, it was T-DM1. She’d already had brain mets in the past, but they were treated with whole brain.

While on T-DM1 she developed progression. I think it was a couple of those lesions that had previously been treated, but they were amenable to stereotactic radiosurgery, because she hadn’t received that before.

And so the rest of her disease was completely stable, based on your extracranial disease — based on CT scans. We treated her with SRS. We continued the T-DM1.

Activity of T-DM1 in patients with brain metastases

DR LOVE: Before you go on, could I just pick up on that point because that has been a very major issue that has been emphasized. I think ASCO brought it up with their consensus statement, this issue of the patient who’s stable or not progressing, but then progresses in the brain — the concept you just talked about — you keep the systemic therapy going.

In this situation what do you think is going on? Actually, I have a question that someone sent in who had heard interviews with Dr Hope Rugo and Joyce O’Shaughnessy, talking about the fact that T-DM1 “crosses the blood-brain barrier.” And this person says, “The only data I see with this large molecule conjugate crossing blood-brain barrier is the metastatic setting where maybe the blood-brain barrier’s already breached with radiation therapy.” Is there any data T-DM1 crossing the blood-brain barrier in the, let’s say, adjuvant setting, this person wants to know.

DR KROP: Right. That’s a very good question. And Hope is correct that we do have data in the metastatic setting suggesting that trastuzumab crosses the blood-brain barrier when there’s a tumor present, a parenchymal HER2 brain metastasis present. And we have case series and a cohort trial showing that in some patients, treating with single-agent T-DM1 is able to shrink brain metastases. But in the adjuvant setting, we really don’t have any data saying that, as you suggested, that if there’s not a tumor there and, therefore, presumably the blood-brain barrier is intact, that a large macromolecule like T-DM1 can get into the brain.

The 1 negative piece of data we have, which is very recent from KATHERINE, is that the 1 situation where T-DM1 did not seem to be superior to trastuzumab was in preventing CNS recurrence as a first site of progression.

DR LOVE: Hmm.

DR KROP: And there was absolutely no benefit. In fact, I think the T-DM1 arm was actually a little worse.

Fortunately, that doesn’t happen very often. It’s about 4% or 5% of patients. But in that situation it did not look like T-DM1, in the adjuvant setting, did anything to prevent those brain metastases. And that would speak to this concern that with an intact blood-brain barrier that T-DM1 is not efficacious in the brain.

DR LOVE: It looks like that’s about the point that you took over. You got involved with her care in 2017. She’s got progression in the brain and in the liver. What happened at that point?

DR KROP: Right. Just to go back though. She did do fine on continuation of the T-DM1 for some period of time, and we’ve all seen that studies have shown that the median after CNS progression is in the 4 to 6 cycle range. It’s not a trivial amount of time that patients can still be benefitting from systemic therapy if you treat locally the brain. And that’s why those ASCO CNS guidelines are what they are. Which is that if the extracranial disease is controlled, there’s not a strong reason to change your systemic therapy at that point.

DR LOVE: It’s kind of an escape lesion. How long did she stay on just the T-DM1?

DR KROP: For her, I think it wasn’t a year, but it was at least 3 or 4 months, which I think is pretty typical.

Some patients do well even longer than that. Which is why, again, it’s worth trying that. But eventually her liver disease progressed on the T-DM1. But at that time her brain metastases also were progressing, and she was not felt to be a good SRS candidate at that point.

Efficacy and tolerability of tucatinib for HER2-positive mBC; ongoing Phase II HER2CLIMB study evaluating tucatinib versus placebo, each in combination with capecitabine and trastuzumab

DR KROP: Fortunately, at our institution we have a number of clinical trials for patients who have progressive brain metastases. It’s a big research interest of our group. And so she went on a trial of trastuzumab plus tucatinib. And tucatinib is a new HER2-directed tyrosine kinase inhibitor. And what’s unique about tucatinib, which has gone by previous names — it used to be ONT-380 and before that it was ARRY-380.

But what’s unique about this molecule is that unlike lapatinib and neratinib and afatinib, most of the other HER2 kinase inhibitors, which hit, not only HER2, but also EGFR and HER4, tucatinib is very specific for the HER2 tyrosine kinase.

Because it avoids inhibiting EGFR, you don’t get a lot of the diarrhea and rash that come along with EGFR inhibition. And tucatinib gets into the brain quite well because, again, it’s a small molecule.

That was the rationale for using tucatinib with trastuzumab in this trial. And she went on that study and did quite well for I think 7 or 8 months.

DR LOVE: Could you talk a little bit more about tucatinib in terms of what’s been seen in terms of response and tolerability?

DR KROP: Yes. I mean, as it was billed, because of its preclinical data being very HER2 specific, rates of diarrhea are very low, rates of rash are very low, and it’s got some mild fatigue. But other than that, it’s really been quite well tolerated. And that’s what led to its registrational trial, which is called HER2CLIMB, which is an add-on strategy.

That trial was looking at patients who’ve had progressive HER2-positive metastatic disease, randomizing them to capecitabine/trastuzumab with or without tucatinib, or in fact, it’s placebo-controlled for tucatinib, and because it’s so well tolerated, an add-on strategy was feasible. And that trial has completed its enrollment, and we’re just waiting for the data to mature.

What’s nice about that trial is, it’s leveraged the ability of tucatinib to get into the brain and therefore, unlike, as far as I can remember any other large, randomized trial, it allowed patients who had progressive brain metastases on that study. And hopefully, we can look at that subset and really ask for the first time in a randomized fashion whether a drug is able to meaningfully control progressive brain metastases.

Emerging data with neratinib and capecitabine for patients with HER2-positive breast cancer and brain metastases

DR LOVE: What happened with this lady?

DR KROP: She did very well on the tucatinib and trastuzumab. She tolerated it extremely well. Just as a coincidence, she’s also a teacher and continued to work. Eventually her brain metastases started to progress, and so we happened to have another trial going on of capecitabine and neratinib, and then — again, another tyrosine kinase inhibitor that gets into the brain quite well. The difference between tucatinib and neratinib, other than the fact that neratinib also hits other HER family members like EGFR is that neratinib is an irreversible inhibitor of HER2. And, perhaps, maybe a little bit more potent.

And so she was on this study of capecitabine and neratinib, and she’s done very well on that and continues to be on that regimen with good disease control, now out more than a year.

Again, this is with chemotherapy. The previous trial was without chemotherapy. But she’s done quite well. And again, I think this speaks to this fact that there are some HER2-positive cancers that are just very sensitive to HER2 inhibitors of multiple types. And these people can do well for many years just sequencing the different inhibitors.

DR LOVE: How did she do on the neratinib/capecitabine? And how do people do in general? When I first heard about it, you start to think a little bit about the potential for maybe problems, at least thinking back to lapatinib. But in any event, how did she do?

DR KROP: I mean, she, like most of the patients on that regimen, had some diarrhea. We use loperamide as primary prophylaxis just as now is being done clinically. And she still had some breakthrough diarrhea, and I think in her we added diphenoxylate and atropine at some point. But eventually things settled down as usually happens with that. With neratinib, is that if you can get patients through the first few cycles, the diarrhea becomes much more manageable. And again, she’s been on it for over a year and actually, right now, has virtually no diarrhea. And she’s only taking the loperamide intermittently and is doing quite well.

There are certain foods that seem to stimulate her diarrhea. But, otherwise, she’s doing quite well.

And, this combination of capecitabine/neratinib, I should point out that the capecitabine is not full dose in this trial.

It’s 750 mg/m² twice daily, which is actually the same combination that’s used in the NALA trial that also was reported at ASCO. And in that trial, again, use primary prophylaxis, still had substantial amount of diarrhea. But the number of patients who had to discontinue was only a few percent because of diarrhea.

Again, it’s certainly a substantial problem. You have to educate patients very aggressively. You have to use antidiarrheals from the get-go. But most patients you can get through it.

Response to CDK4/6 inhibitors in patients with ER-positive, HER2-positive mBC

DR LOVE: I’m kind of curious. Hopefully, this response will continue for a long time. But what are you thinking in terms of next steps if she does have progression? Are there trials you might think about or nontrial strategies?

DR KROP: I mean, I think the underlying problem here is there are no approved regimens for patients with CNS disease with HER2-positive cancers. The NCCN has indicated that that neratinib/capecitabine regimen is a reasonable thing to try but there’s no specific FDA approvals for a regimen in the brain.

This patient will have already gone through several different tyrosine kinase inhibitors, which is something that we all think about using in this situation because we know they get into the brain well. She’s already had capecitabine.

After this, you’re kind of in a data-free zone in terms of what you can do. We hope to have a clinical trial for her. Right now we have trials looking at immune therapy in patients with brain metastases, looking at CDK4/6 inhibitors, which — like abemaciclib — has some data suggesting some activity in the brain. That could be another option for her.

But outside of a clinical trial, there really isn’t much that has substantial data to support its use. I mean there are chemotherapies besides capecitabine that can get into the brain that have shown some case series kind of responses. But it’s definitely an area that needs some work.

DR LOVE: That’s interesting. I didn’t pick up on the fact that she was ER-positive, but I see she had letrozole at one point. I mean that works in the brain. Has she had a CDK inhibitor even though she’s HER2-positive?

DR KROP: That’s what I was saying is, I think that we do have a trial of abemaciclib, and I think that would be something that would be very worth exploring.

DR LOVE: But she hasn’t had one outside a trial?

DR KROP: No. We generally haven’t been doing it because there is no label for and no large data series of CDK4/6 inhibitors in HER2-positive disease. But there are preclinical data suggesting that they could be quite effective. And there are small studies now showing efficacy in HER2-positive disease.

Hopefully, eventually there’ll be enough data to tell us one way or the other whether we should start using these CDK inhibitors in HER2-positive disease on a more regular basis.

DR LOVE: Although we never talk much about hormone therapy in HER2-positive situations. But, I mean, has she had fulvestrant?

DR KROP: She hasn’t and that would be something else to think about. Again, we have some data in early stage HER2-positive metastatic disease that a hormonal therapy plus trastuzumab and pertuzumab can be effective. There’s similar data with trastuzumab and lapatinib and hormonal therapy that have shown pretty good activity.

It is something that I think we forget about because of all of the HER2-directed therapies in the later line of – of treatment. But there are patients who seem to benefit quite substantially from hormonal therapy plus HER2-directed therapy, and there are now randomized data to support that, but most of those data are for early metastatic patients. Whether that still is effective in later lines we don’t know. It’s something that’s worth evaluating.

DR LOVE: I mean, if you’re running out of options.

DR KROP: Yes. No, I completely agree. Necessity is the mother of invention. And that would certainly be something that we would explore for a patient like this. And again, there’s a little bit of a preference for abemaciclib because of its ability to cross the blood-brain barrier, which hasn’t really been established so much for the other 2 CKD4/6 inhibitors.

Case: A woman in her early 30s with HER2-positive mBC receives trastuzumab deruxtecan on a clinical trial after experiencing disease progression on multiple lines of therapy

DR LOVE: Let’s finish out again along the lines of new therapies and hear about your 31-year-old lady.

DR KROP: Yes. That brings up an interesting new drug. I have a 31-year-old woman who had HER2-positive metastatic breast cancer, had progressed on multiple lines of therapy. She lives in upstate New York and so traveled here, traveled to Boston looking for a clinical trial. And we happened to have a Phase I study of a new antibody-drug conjugate, this one called trastuzumab deruxtecan, also known as DS-8201a, neither of which are very euphonious titles, but hopefully we’ll get a better name eventually.

But this is an antibody-drug conjugate that’s like T-DM1; it’s based on trastuzumab or based on the HER2-targeting antibody. But what’s different between this conjugate and T-DM1 is that the payload is a TOPO-1 isomerase inhibitor, which T-DM1 is a microtubule inhibitor, so this is a TOPO-isomerase inhibitor. Different class of chemotherapy; it’s a very potent payload. And unlike T-DM1, which has 3 or 4 payloads per antibody, for this conjugate there’s more like 7 or 8. Eventually twice as much of chemo per antibody, a very potent chemotherapy.

DR LOVE: In my naïve ears, I hear TOPO, I think of anthracyclines. Is that right?

DR KROP: This is more like topotecan or irinotecan.

DR LOVE: Oh, topotecan. Yes. Yes. Okay. Got it.

DR KROP: This is a TOPO-1 inhibitor.

DR LOVE: TOPO-1. Okay. Great.

DR KROP: Yes. And this is a class of chemotherapy that we don’t generally use in breast cancer, so none of the cancers typically have seen this kind of class of chemotherapy. And there’s, again, there’s a lot of them on each antibody so the amount of drug that’s delivered is quite high. And, this one is structured to have what’s called “bystander effect” meaning that the payload is able to leak outside the cell that’s being targeted and hit neighboring cells, which may help with this idea of heterogeneity that we talked about earlier.

The basic, same idea as T-DM1, but perhaps more potent because there’s more chemotherapy attached, and it’s a very potent chemotherapy and a different class.

Results of a Phase I trial of trastuzumab deruxtecan for patients with advanced HER2-positive breast cancer previously treated with T-DM1

DR KROP: The data we have so far for this, which is from that Phase I trial this patient of mine was treated on, is that this is a very active drug. In the Phase I trial, which was recently published in Lancet Oncology, the response rate in heavily pretreated patients, patients all of whom had had prior T-DM1, most of them whom had had prior pertuzumab, the response rate was approaching 60%. Objective response rate was 60%, progression-free survival was over 20 months, which is really quite astounding in this population.

And my patient has had a good response as well. And she’s been on it now for quite a few months and doing quite well.

DR LOVE: It says here she started end of 2017. I mean like a year and a half.

DR KROP: And so again, the median progression-free survival in this trial has been over 20 months.

DR LOVE: Wow!

DR KROP: It’s really kind of unprecedented. If you think of, like, the EMILIA trial, which was in a pretreated population with T-DM1, again, not that we should be comparing cross trial, but the median PFS with T-DM1 was only 6 or 7 months.

Benefits and risks of trastuzumab deruxtecan for advanced HER2-positive breast cancer

DR KROP: This really looks like an active drug. Now the trade-off is that it has more toxicity. And whether that’s because it’s a more potent chemotherapy or because of this bystander effect, it’s not clear. But it definitely has more toxicity. There is about a third of the patients have hair loss. Nausea is definitely more prevalent with this than with T-DM1.

This patient, perhaps partly because she’s so young and so those are more disposed to nausea, had a substantial amount of nausea when she first started. We’ve been able to control it by increasing her antiemetic regimen with each dose. And now that she’s been on it for a while the nausea is really largely gone. It’s definitely manageable, but it’s definitely something to pay attention to. And it’s different than T-DM1.

We’ve seen alopecia. We’ve seen GI toxicity. And then the one other thing that’s been noticeable with this drug is that there is more pneumonitis. About, overall, roughly 10% of patients have been getting some degree of pneumonitis. And there have been some fatal cases.

DR LOVE: Hmm.

DR KROP: Hopefully, now that we’ve gotten more familiar with this potential toxicity and we’re able to manage it better, we will get rid of the more high-grade toxicities of pneumonitis, but it’s definitely something that we need to pay attention to when using this drug.

DR LOVE: What happened to this woman’s hair?

DR KROP: She actually has kept her hair. She started out with a lot. I can’t remember whether she’s had any thinning. But looking at her, her hair’s been fine. And I said, it’s only about a third of patients who’ve lost their hair or have had a substantial degree of alopecia.

DR LOVE: What do you see in terms of counts, cytopenias?

DR KROP: There’s been some cytopenias, so in addition to the thrombocytopenia that seems to be somewhat of a class effect, the thrombocytopenia is no worse than T-DM1. But there has been some more neutropenia and anemia seen, although it hasn’t really been dose limiting for this drug. It’s the other things that we’ve been more paying attention to.

DR LOVE: What about activity in the CNS?

DR KROP: We don’t really have much data on that. Like most early trials of novel therapies, we’ve been excluding patients who have progressive brain metastases. We don’t really know. Again, this is a big molecule, so I wouldn’t expect it to be much different than T-DM1. But we don’t really have data to speak to that.

Response to trastuzumab deruxtecan in patients with breast cancer and low HER2 expression

DR LOVE: I’m not sure if I’ve seen data on this, but has it been looked at with HER2-negative disease?

DR KROP: Yes. And that’s kind of an interesting finding was that in this Phase I trial there was a cohort of patients with HER2-low disease, and what we mean by HER2-low are nonamplified but either 1+ or 2+ HER2 expression by IHC. And somewhat surprisingly, there was quite a bit of activity in that population as well with a response rate of over 40%. And that’s been now the motivation for a large randomized trial in HER2-low patients comparing this drug versus chemotherapy of physician’s choice in pretreated, largely ER-positive/HER2-low patients.

If that’s borne out in that registrational trial, it really is a true game changer because right now we don’t think of those patients as anything other than HER2-negative. Because, from a practical standpoint, whether you’re at 0 or 1+ or 2+ doesn’t matter, we don’t treat them with HER2-directed therapy.

If this Phase III trial shows benefit of trastuzumab deruxtecan in that HER2-low population, it really creates a whole new breast cancer subtype.

And there’s another HER2 conjugate that’s also seen some activity in HER2-low patients as well. It may not be unique to this drug.

DR LOVE: I’m curious how many patients have been treated who previously progressed on T-DM1. Actually, this woman progressed on T-DM1. And —

DR KROP: Yes.

DR LOVE: It looks like she didn’t have much of a response either.

DR KROP: No. She didn’t. And, I mean, she did respond earlier to other HER2 therapies, but she had virtually no response to T-DM1. And that Phase I trial I told you about with the 60% response rate that was all patients who had had prior T-DM1.

DR LOVE: Wow.

DR KROP: And 60% also had prior pertuzumab, and that didn’t seem to affect the response rate at all. That also was 60%.

This drug does seem to have activity regardless of prior therapy. It’s really impressive in that way.

DR LOVE: Where was this woman’s disease when she got treated? And what exactly happened?

DR KROP: This particular patient had mostly lung disease. Which is a little unusual for HER2-positive cancers, which typically goes to the liver as well. Her disease was mostly in the lung. And her burden of disease wasn’t that great, but she was having some pulmonary symptoms. And now her lesions have shrunk and her pulmonary symptoms have largely gone away. Her cough is gone. She’s got no dyspnea. And in fact, she’s a runner, and it’s funny. Sometimes she complains about fatigue, and she said she’s only been able to run 5 miles 3 or 4 times a week, which makes me look like a weakling.

But no. Now that the nausea has been controlled, her quality of life is pretty good. And she’s really not limited by her cancer or by the drug, which, of course, is what we want to see.

DR LOVE: You don’t have to hear about too many cases like this to be thinking about using it because now you’re talking about just using a treatment by itself. You’re not adding something on. It’s just this drug. And you don’t have to hear too many cases like this to maybe be thinking about it for your patient. Is there a compassionate use protocol right now?

DR KROP: As far as I know, there’s not a compassionate use study. But the company has announced that they’re accelerating their BLA submission to the FDA. There’s a Phase II trial that’s completed enrollment that they’re going to use for submission for accelerated approval, and they’re hoping to get that submitted before the end of the year. I think the hope is that this drug will become available in the relatively near future and will not have to wait for the several Phase III trials that are going on right now.

DR LOVE: Yes. I always think about the ibrutinib versus chlorambucil trial. Did we really need to do that in CLL? And, like I said, how many cases do you need to hear like this? But I guess that’s just the issues in terms of the regulatory system.

Other novel agents and approaches under evaluation for HER2-positive breast cancer

DR LOVE: Anything else going on in terms of HER2 disease that you want to comment on that you think is important?

DR KROP: I mean, I think what we’ve seen, and what we continue to see, is that if you come out with a new HER2-directed therapy that works via different mechanism, it’s still quite a valid target. And even though, as we talked about a little bit earlier in this conversation, there is this concern that tumors can lose HER2 expression over time, and then you see the data with drugs like this new conjugate where you’re seeing 60% response rates in heavily pretreated patients and that would seem to suggest that HER2 still remains something that we can go after, even after multiple lines of therapy.

In terms of the next set of drugs, again this isn’t the only antibody conjugate that looks promising. There are others in development as well. We talked a little bit about immune therapies, and while there, we don’t have yet much activity that’s been demonstrated, it’s still something that we’re very hopeful about, and we just need to figure out new ways to do it.

There are other tyrosine kinase inhibitors that are being evaluated. And I think there’s still plenty to be hopeful about in the future in the pipeline.

Again, I think this is an area where fortunately there’s been a lot of progress made. We’re now starting to talk about dose de-escalation, as you mentioned earlier. Can we start cutting back because patients in the early disease setting are doing so well?

Again, I think it’s a pretty hopeful time in the HER2 space.

Optimal duration of adjuvant trastuzumab; analysis of the results from the Phase III PERSEPHONE and PHARE studies

DR LOVE: I next met with Dr Sara Hurvitz. To begin, we discussed a recent editorial she authored in the Lancet on the duration of adjuvant trastuzumab therapy for patients with HER2+ localized breast cancer.

DR HURVITZ: In that issue of the Lancet, 2 clinical trials were both published at the same time looking at whether a shorter duration of adjuvant trastuzumab, 6 months, was noninferior to 12 months of adjuvant trastuzumab. And they’re both very large studies, academically-funded studies, the PHARE study out of Europe, primarily the French group, and then a large study based in the UK.

And what was interesting to me, if you look at all of the studies, I think there have been about 5 now, looking at whether fewer than 12 months is noninferior to doing 12 months of adjuvant trastuzumab. The thought being if you do fewer than 12 months of trastuzumab, it’s less cost financially and potentially safer for patients. And of those 5 studies, 4 failed to meet their noninferiority statistical endpoint, but 1 did. And in this journal article, the 2 that had differing results were published.

And my editorial was comparing and contrasting these 2 studies and trying to figure out, how do we sort out these discordant results. And actually when you look at it, noninferiority designs are actually pretty tricky. You have to, like, say what level of noninferiority? What are you going to be comfortable with as an investigator in terms of a chance that 1 arm is actually better than the other? And so they each set their level of noninferiority a little bit differently. They both came up with the same hazard ratio, or very close hazard ratio, but one’s conclusion was the PHARE’s conclusion, was noninferiority was not demonstrated, 12 months remains the standard. And the other study’s conclusion was that boundary and noninferiority was demonstrated.

Now when you look at those 2 studies, the PHARE study had longer data, had been looking at it longer term. There were some subgroups that were analyzed early on in their initial publication that seemed to indicate subgroups that might benefit from doing 12 months, higher-risk subgroups, compared to 6 months. But with longer follow-up, all of that subgroup differential washed away, and you really couldn’t define clearly a patient who is going to benefit just as well from 6 months as 12 months.

The other point I’d like to make about these 2 studies is that 90% of the patients in these studies received anthracycline-based therapy. My point was, if we’re really trying to de-escalate risk for patients, we have a couple regimens that don’t utilize anthracyclines now. We have the TCH regimen from a large Phase III BCIRG 006 study. We have the more recent paclitaxel/trastuzumab regimen from Sara Tolaney’s APT trial, and we have Steve Jones’ docetaxel/cyclophosphamide/trastuzumab. Those were both Phase II trials.

But we have now evidenced-based regimens to utilize that avoid the risks that are inherent with the anthracyclines. Instead of shortening the duration of trastuzumab, why not just choose a nonanthracycline-based approach that is going to be safer and utilize the 12 months of trastuzumab, since 4 out of 5 trials indicated that 12 months and 6 months are not necessarily equivalent, and 12 months may be superior.

It was a little bit of a controversial take I had in the editorial that I wrote. I do concede the cost of trastuzumab is something to consider in many parts of the world. Using a nonanthracycline-based regimen doesn’t get around the cost of 12 versus 6 months. However, with the advent of biosimilars and cheaper forms of trastuzumab, perhaps this debate is becoming moot, if we can de-escalate our therapy in a different way.

Perspective on the role of trastuzumab biosimilar agents in the management of HER2-positive breast cancer

DR LOVE: I was thinking about biosimilars as you were talking. I was kind of curious where you stand on using biosimilar trastuzumab.

DR HURVITZ: I have absolutely no problem with using biosimilar trastuzumab if it’s met its noninferiority endpoint, which these studies are well designed, that have been performed. And I think that it’s important on a global perspective that we have these agents available to patients to make trastuzumab available globally. The cost benefit may be substantial. We’re already utilizing biosimilar growth factors in our clinic. There are a number of biosimilars that are being utilized in the oncology setting. And I think cost of medications, especially in our own health care system, or costs, really does need to be taken into consideration, is an important factor.

But I think there is a lot of misunderstanding about biosimilars when you’re talking to community oncologists and oncologists, perhaps, who aren’t as familiar with the terminology and the level of FDA regulation surrounding the development pathway of biosimilars. I think it’s quite stringent. And it’s not as though patients were going to be swapped without the physicians not knowing. There is a high amount of regulations that go into the use of biosimilars. I’m greatly in favor of these.

And I would point out that this idea that trastuzumab is not available globally is something that hit me at ASCO. I don’t know if you saw that pyrotinib PHENIX trial, where it was an Asian study looking at pyrotinib, the tyrosine kinase inhibitor plus capecitabine in metastatic HER2-positive breast cancer. It’s a HER2-targeted TKI. And they designed this Phase III trial with a placebo-based arm. One third of the patients just got capecitabine. And they have HER2-positive metastatic breast cancer. And that was okay ethically because in many countries you do not use HER2-targeted therapy after the second or third line in the metastatic setting, even though we know continuing to hold the brakes on HER2 in that setting is beneficial.

That trial never would’ve been okay in the western world. Nobody would have enrolled on it. Ethics committees wouldn’t have approved it, but here it was done, and this was a way for patients to access a HER2-targeted therapy.

DR LOVE: That is really interesting. What biosimilar trastuzumab products are available? And are you using them?

DR HURVITZ: We haven’t yet. I’m not sure, Neil, the status of which ones are actually available in the clinic and funded. It hasn’t hit our clinic yet. And I’m not as well versed on that. I mean, I know a number have reached regulatory approval. I know there’s also a lot of litigation ongoing from the makers of the originator trastuzumab. That may be holding up patients actually getting access to it at this point.

Benefits and risks of anthracycline-containing and anthracycline-free neoadjuvant regimens for patients with HER2-positive disease

DR LOVE: Getting back to this issue of de-escalating therapy. It was interesting, Ian Krop, who I interviewed for this same series, presented a patient with HER2 positive, with locally advanced disease, big palpable nodes. And he used a neoadjuvant regimen with AC followed by taxane/pertuzumab/trastuzumab. I’m curious, do you use that approach yourself? In the home of anti-anthracyclines. We started getting back into BCIRG 006 again and all that.

DR HURVITZ: Right. No. I actually don’t see the utility of an anthracycline-based approach in HER2-positive breast cancer. I think there’s really good evidence now that it doesn’t add substantial efficacy outcomes. The therapeutic index is not in favor of the use of them. I understand why colleagues do use that. It’s not as though their approach is wrong and mine is right, but I do think that the risk associated with anthracycline use in a HER2-positive setting is not outweighed by the benefit.

If you look at the TRAIN-2 study, the pathologic complete response rates were equivalent with an anthracycline-based approach compared to nonanthracycline TCHP approach.

If you look at TRYPHAENA, which was a smaller Phase II study, the PCR rates with TCHP were better numerically than FEC-THP, so I feel confident that it’s okay to proceed without an anthracycline. And now with the KATHERINE data and the availability of T-DM1 post neoadjuvant for those with residual disease, I think we have a very evidence-based pathway to treat these patients who are high risk.

DR LOVE: Yes. He was talking about the fact that maybe he would be rethinking this now that you have this other tool in the closet on the other end. But it’s interesting, too, and I was trying to think of data comparing taxane to anthracycline, and I was asking him well, is this all indirect or direct? And when I said, “What’s direct?” that’s when he brought up BCIRG 006, but that was like 15 years ago. And it was pretty soft. It wasn’t even statistically different, right?

DR HURVITZ: Exactly, yes. No, the study wasn’t designed to compare —

DR LOVE: Sure.

DR HURVITZ: — ACTH to TCH, but numerically they were similar. And I don’t know if you remember when Dennis Slamon presented the data, and he said, “Okay, let’s say that anthracyclines are going to be better for those with multiple nodes involved.”

DR LOVE: Right.

DR HURVITZ: He looked at 1 to 3 and greater than 4, and the delta between the 2 arms began to shrink at that high-risk level, so it doesn’t make sense that the anthracycline is going to work better for higher-risk patients, based on what we know.

DR LOVE: And it’s interesting, that survey that you and Hope Rugo worked with us on this project of 30 investigators, and we compared it to general medical oncologists. One of the things that was interesting, the investigators used more anthracyclines, which you may find — not you, but other people.

Comparison of paclitaxel/trastuzumab/pertuzumab to TCHP in the neoadjuvant setting

DR LOVE: One other thing about this issue of de-escalating therapy, and I didn’t realize, Ian was telling me now there’s actually a trial that’s looking at it. But I’ve been hearing people, particularly from Dana-Farber, talking about neoadjuvant paclitaxel/trastuzumab/pertuzumab. Substituting paclitaxel for TC as part of the TCH, which, of course, they had done as an adjuvant therapy. But what do you think about that as a strategy right now in the neoadjuvant setting?

DR HURVITZ: I would love to see it comparative trial of that THP, or PHP, if you will, versus TCHP. The APT trial was elegant and the data compelling for our lower-risk patients. I think it’s an important regimen that we should be utilizing in our lower-risk patients. But we have to keep in mind it was single-arm Phase II trial. It was noncomparative. If you have any question about a patient’s risk, I think we need to be using a regimen based on Phase III, Level 1 evidence.

I would love to see a comparison of paclitaxel/trastuzumab/pertuzumab to TCHP. I think that would be really great for patients. I think paclitaxel’s probably better tolerated. There’s going to be definitely less diarrhea and probably less cytopenias and febrile neutropenia than TCHP. But the synergy and clinical benefits associated with TCHP are more supported by larger clinical trials. I would love to see a trial of that.

DR LOVE: It sounds like you’re not too enthusiastic right now about doing it outside a trial setting.

DR HURVITZ: Yes, perhaps in a lower-risk patient or an older patient, somebody with comorbidities, I would feel comfortable utilizing that. But I wouldn’t use that for somebody’s who node positive, or a larger HER2-positive breast cancer in the neoadjuvant setting. I want to give them the best chance of having a path CR prior to surgery.

Activity of pertuzumab in combination with T-DM1 in the (neo)adjuvant and metastatic settings

DR LOVE: We were talking about the fact that obviously right now standard of care has acutely shifted to using T-DM1 postneoadjuvantly in patients with any residual disease. That’s clearly out there. But I’ve got to say, it seems a little weird to only use pertuzumab in that neoadjuvant setting and not continue it. From a theoretical point of view, does that make sense to you? And we’re going to talk about the KRISTINE study that looks at the combination, but any reason to think about T-DM1 plus pertuzumab?

DR HURVITZ: Just to back up a minute. The KRISTINE study we developed, Dennis and I developed. It started as a 5-arm clinical trial, where the S in KRISTINE was the number 5. When the sponsor took it over, it morphed into this 2-arm trial. But we actually had an arm that just looked at T-DM1 because we’re not convinced that the synergy between pertuzumab and T-DM1 is actually necessary. That you actually need the dual HER2 blockade. And the MARIANNE study calls that into question a little bit, as well. That was in the first-line T-DM1 in metastatic setting.

DR LOVE: It’s kind of like CLEOPATRA, but you’re substituting T-DM1 for the chemotherapy/trastuzumab.

DR HURVITZ: Exactly. Exactly. We don’t have the answer to that question. I’d love to know whether or not the addition of pertuzumab improves outcomes, but we just don’t know.

I’m okay utilizing pertuzumab in the neoadjuvant setting and for those patients who have residual disease, meaning it didn’t hit the homerun, switching to T-DM1. We don’t have evidence adding pertuzumab is going to help things. It may add toxicity with a little bit higher rates of diarrhea and skin toxicity. I don’t feel uncomfortable with that approach.

The question I have is, when you do reach that homerun, that PCR, and you’ve used a TCHP-type regimen, what benefit is continuing the pertuzumab if the patient’s node negative? And we don’t know. If the patient tolerated it well, I feel that probably we should continue and complete that full year.

DR LOVE: And it was interesting, that same survey of the 30 investigators, when we asked them about adding pertuzumab — of course we had to throw all that out as soon as the KATHERINE trial came in — but when we asked them about that in terms of adding pertuzumab with a path CR there was a consensus. Just kidding, it was completely split —

DR HURVITZ: Right.

DR LOVE: — like 50/50 yes and no.

DR HURVITZ: Right.

DR LOVE: Nobody knows.

DR HURVITZ: Yes.

DR LOVE: What do you do? I don’t remember what you do? I think you add, right?

DR HURVITZ: Yes, I add in the higher-risk patients. Node positive, if they have a path CR, I feel good about continuing it, yes.

Case: A woman in her mid-40s with ER-positive, HER2-positive breast cancer attains a good response to neoadjuvant T-DM1/pertuzumab on the KRISTINE study

DR LOVE: Let’s hear about this 45-year-old lady who was actually on the KRISTINE trial. I always thought that was a really neat study. And again, you presented some more data from that at ASCO, but let’s hear about her first. What happened there?

DR HURVITZ: Yes, so she was 45. She had a left-breast T2N1 cancer. It was ER-positive, very strongly positive. PR was mildly expressed. The HER2 was positive. The Ki-67 was around 30%. This is a legit HER2-driven tumor. She went on the KRISTINE study. She was assigned to the T-DM1/pertuzumab arm. She completed all 6 cycles, did really well, and she had a mastectomy in 2014.

And she did have residual invasive cancer, but she had so much chemo effects, there was so much necrotic tumor in the tumor bed, she clearly had a great response. But there was still 1.2 cm of residual tumor in the breast. There were 3 nodes that were positive, macrometastases. The Ki-67, interestingly, was down to 5%. And in the tumor specimen at the time of surgery, it remained ER strongly positive. And the HER2 was 2+ by IHC, which is interesting. But it remained positive by amplification.

In the KRISTINE study, the centrally confirmed HER2 positivity, so she did meet criteria. But it’s interesting that her HER2 expression was a little lower, and that kind of goes a long with hormone receptor expression. We see that.

In the KRISTINE study, it was advised or recommended that patients who had residual disease who were in the T-DM1 arm be recommended to receive standard adjuvant chemotherapy. I talked to the patient about doing this. We talked about her risk of recurrence, and she declined going onto adjuvant chemotherapy. And she went on, however, to receive exemestane and an LHRH agonist. She remains on that, and she completed her radiation, and she remains disease free 5 years later.

It’s an interesting case because it underscores the type of patient who fails to achieve a path CR from neoadjuvant therapy in the HER2-positive setting, and that is usually hormone-receptor-positive breast cancers. They are the ones who have more of a challenge. In KRISTINE, hormone receptor-positive patients, the path CR rate for T-DM1 was 38% versus 46% for TCHP. She didn’t have a great chance of achieving a path CR. She did choose not to receive adjuvant chemotherapy, and she is still disease free 5 years out.

KRISTINE: A Phase III study of neoadjuvant TCHP versus T-DM1/pertuzumab for HER2-positive breast cancer

DR LOVE: Can you talk a little bit more about the study itself and the key results?

DR HURVITZ: Sure, yes. KRISTINE was a 444-patient trial. It was a randomized Phase III study, 1:1 randomization of 6 cycles of T-DM1/pertuzumab versus 6 cycles of TCHP. And in this study we were hoping T-DM1/pertuzumab, a much better tolerated regimen, would yield at least the same path CR rate, if not better, than TCHP. However, 56% path CR with TCHP and only 44% in T-DM1/pertuzumab. So a statistically significant inferior result with T-DM1/pertuzumab. Study did not meet its primary endpoint.

But I’ll tell you, I had a number of patients who did achieve path CR with T-DM1/pertuzumab. Very high-risk patients who had no disease at the time of surgery, and they were spared all of the chemo toxicity. We’re very interested in understanding, can we select patients who are going to potentially have a good outcome without standard chemo?

At ASCO we presented and simultaneously published the final outcome, which is 3-year event-free survival and invasive disease-free survival. The study wasn’t powered to show differences in EFS or iDFS. What we did show was not surprisingly the 3-year event-free survival was inferior with T-DM1/pertuzumab. Event-free survival includes any progressions that occur prior to surgery. It was 85% EFS for T-DM1 arm, and it was 94% for the TCHP arm.

But if you look at the invasive disease-free survival, so how many patients had recurrences after surgery, either noninvasive or invasive recurrences or death? They’re exactly the same: 92%, 93% iDFS for both arms. If your starting point is the time of surgery. The whole difference between the 2 arms is that there were more progression events in the T-DM1 arm.

So to kind of pull this all together with the patient I told you about, we looked at the patients who had those locoregional progressions, and we looked at the level of HER2 expression in those patients. And patients who had 1+ or 2+ protein expression of HER2 or HER2 heterogeneity or low MRNA, these were the patients who tended to have locoregional progressions. But those patients with homogeneous, strong expression by IHC or high MRNA levels, those are the patients who did very well with T-DM1.

We can potentially begin thinking about doing a study, which I’d love to see, I don’t know if it’ll ever get funded, where we just take patients who are strongly expressing, by protein. We know T-DM1 requires protein expression of HER2 for its activity, so only those patients with homogeneous 3+ expression, and see if T-DM1 does just as well as standard chemo in the neoadjuvant setting.

DR LOVE: That would really be interesting. Ian was commenting on some of the immune work that’s been done. I think it was more on the APHINITY trial. But do you think that’s part of the puzzle also, in terms of escalating/de-escalating therapy? People with better immune systems maybe won’t need as much therapy, or they need more?

DR HURVITZ: Yes. It’s possible. There’s a lot of work being done to look at tumor infiltrating lymphocytes.

DR LOVE: Right.

Primary analysis of SOPHIA: A Phase III study of the novel anti-HER2 antibody margetuximab and chemotherapy versus trastuzumab and chemotherapy for pretreated HER2-positive mBC

DR HURVITZ: You saw the SOPHIA study results, which was in the metastatic setting. But it’s the first prospective study that indicates if you can increase the binding of the HER2 antibody to the immune cells, that FC receptor binding, and increase that ADCC, that immune activation, that you might have better outcome. I think there definitely is an immune story, and perhaps one of the ways we can get around using cytotoxic chemo is picking patients who do have a better immune milieu and do combination therapy of HER2-targeted therapy with immune therapy. But this is all investigational still.

DR LOVE: Can you talk a little bit more about the SOPHIA study and the agent there? It seems like really unique.

DR HURVITZ: It is an interesting, very unique study, and I have to say, my take in the beginning was actually that improving ADCC for patients, improving the binding of the FC portion of the antibody to the FC receptor on NK and dendritic cells isn’t going to give us a big homerun because ADCC isn’t the primary mechanism of action of trastuzumab. That was my hypothesis going into this work.

And it was based on a study that I did, a correlate study, that came out of the BCIRG 006, where we looked at patients’ outcome based on which allele they expressed. Were they tight binders of the FC receptor? Did they have a 158VV allelic type? Or were they loose binders FF? And you would expect the loose binders would do worse with trastuzumab. And we failed to demonstrate that in the 006 study. But other studies have suggested that there may be a correlation with outcome.

This antibody, margetuximab, is very similar to trastuzumab. It binds to HER2 the same way. But the FC portion is designed to bind the FC receptor on dendritic cells much more tightly, with a higher affinity. And preclinical studies have shown that those dendritic cells that have the FF allelic type, or the VF, those would be looser binding FC receptors. The affinity is much increased with this antibody.

And about 80% of patients have an F allele. They designed this study that head-to-head compared margetuximab plus chemo versus trastuzumab plus chemo. They allowed patients with all different genotypes, VV, VF, or FF. There were over 500 patients in this study. And it was a 1:1 randomization. And they were heavily pretreated. All of them had had trastuzumab and pertuzumab. Patients were allowed to have up to 3 lines of therapy in the metastatic setting. Over 90% of patients had received T-DM1, so very heavily pretreated patients.

And the median progression-free survival was mildly improved with margetuximab. It was like 5.8 months versus 4.9 months. Not a homerun, right? We’re seeing maybe a 0.9-month improvement in PFS. But what’s interesting is if you look at the F carriers, those patients do seem to have more of a delta. They have more of an improvement with the use of margetuximab. 6.9 months versus 5.1 months. The hazard ratio was 0.68. It was statistically significant.

It looks like it does do better for those patients whose immune system is not equipped to set up an immune response. I would like to see this antibody looked at in the earlier-phase setting, in patients whose immune system is less beat up by lines or chemo. Maybe in combination with immune therapy. I’m not super excited to utilize this in the clinic in the heavily pretreated setting based on these results. But I do think that the drug will have a future, especially if it can be looked at in these other settings.

Case: A woman in her late 40s with HER2-positive mBC receives trastuzumab deruxtecan on a clinical trial after experiencing disease progression on tucatinib

DR LOVE: Continuing along the lines of new agents in HER2-positive disease, I wanted to hear about your patient, the 49-year-old lady, actually originally diagnosed 17 years ago.

DR HURVITZ: Yes, isn’t that amazing?

DR LOVE: Amazing. But actually got neoadjuvant TCH in 2002.

DR HURVITZ: Yup.

DR LOVE: That’s interesting.

DR HURVITZ: Yup. Yup. Mark Pegram treated her.

DR LOVE: Really? This is Mark Pegram —

DR HURVITZ: He was at UCLA.

DR LOVE: Wow.

DR HURVITZ: Yes, he was at UCLA at the time. Actually, I was chief resident at UCLA when she was diagnosed, and he was treating her.

DR LOVE: Wow.

DR HURVITZ: When he left UCLA, I inherited her.

DR LOVE: Wow, interesting. What happened more recently?

DR HURVITZ: Yes, let’s see, 15 years ago was diagnosed with bone metastases, and then it progressed to the lung in different areas. She’s been heavily pretreated, but it’s ER-positive, HER2-positive, so it’s been a disease that slowly progresses, and then slowly declines. And she’s incredibly smart. She is very active in the advocacy world. And she will email the radiologist and say, “Please compare the SUV values of this lesion.” And she’ll graph it out. And so to convince her to switch therapy or that she’s progressing is quite a task. I’ve spent a lot of hours with her, but I just adore her because I learn from her. But she —

DR LOVE: Could I just ask, because one of the things I was talking about with Ian, it’s been kind of a curiosity I ask people about, this issue of hormone therapy in HER2-positive disease. He had this case, and I was curious because the patient had never gotten fulvestrant and was —

DR HURVITZ: Yes.

DR LOVE: — way far down the line. I see that happening. I see your lady was on fulvestrant/trastuzumab for 3 years.

DR HURVITZ: Yes, and isn’t that funny, because Rich Pietras was working in Dennis Slamon’s lab, or working with Dennis Slamon, and showed beautiful synergy preclinically with fulvestrant and trastuzumab. Better than other types of estrogen deprivation. And Mark Pegram, who worked closely with Rich, translated that into this patient’s story. And her disease was controlled for 3 years. He actually had a trial that just was so sluggish to enroll, it never really took off and never was reported, looking at fulvestrant/trastuzumab.

But at any rate, yes, I think we have to keep in mind that the preclinical data that many have published showing that when you have co-expression of hormone receptors, and even when not, when you block HER2 there is upregulation of the hormone receptor pathway. When you block the hormone receptor pathway, there’s upregulation of HER2. You can do well by blocking both pathways. And that approach worked well for her for 3 years.

DR LOVE: And then I see, amazingly, she went from fulvestrant/trastuzumab, and then you added lapatinib? And she got another 4 years?

DR HURVITZ: Yes, yes.

DR LOVE: Wow.

DR HURVITZ: Yes. Yes. When the data came out in support of lapatinib and trastuzumab together —

DR LOVE: But you kept the fulvestrant going?

DR HURVITZ: — there was synergy. Kept the fulvestrant going, yes, because her disease progression was very subtle, and she was very convinced she needed hormone blockade. And she had been on tamoxifen in the adjuvant setting and was not yet postmenopausal. Fulvestrant made sense in terms of the biology of how to treat a premenopausal woman.

But yes, she’s just kind of gone along the way, using vinorelbine, never actually has lost her hair in 15 years of treating metastatic disease —

DR LOVE: Wow.

DR HURVITZ: — which is amazing.

Ongoing Phase II HER2CLIMB study investigating tucatinib with capecitabine and trastuzumab for advanced HER2-positive breast cancer

DR HURVITZ: And so we enrolled her on this study with her most recent progression in 2017, the HER2CLIMB study. I’m not sure which arm she was on, but it’s a Phase II randomized registrational strategy study looking at tucatinib, which is the furthest along HER2 selective tyrosine kinase inhibitors. If you are selective for HER2 and omit that EGFR activity as much as possible, you can presumably reduce diarrhea and skin toxicity. This is a study where patients receive trastuzumab plus capecitabine and then either tucatinib or placebo.

And she did well on that. She did have a lot of diarrhea, which we think is related to the capecitabine. She had an issue that actually hospitalized her early on —

DR LOVE: Wow.

DR HURVITZ: — but with dose reduction of the capecitabine, she was fine. And she did well for over a year on this study, but then had progression of disease at that time.

DR LOVE: How many patients have you put on that study?

DR HURVITZ: At my center, as PI, I believe we put on 9 or 10 patients, so we were pretty heavy enrollers.

DR LOVE: Can you guess who’s on the treatment arm?

DR HURVITZ: I don’t know. I really don’t know. One of my subinvestigators had a patient with active progressing CNS mets. This study was unique in that it allows CNS mets that are progressing because it penetrates the CNS so well, and in their Phase IB study, they showed about a 40% objective response rate in the brain in like 12 patients out of 12 patients who had progressing CNS mets. They have orphan drug status for HER2-positive CNS mets. And it will be interesting to see how the HER2CLIMB sorts out.

At any rate, my subinvestigator put a patient on with active progressing CNS mets, and she had a regression in the CNS. Now capecitabine can penetrate the CNS. She had partial response in the CNS, a durable partial response. But I’ve not seen capecitabine do that in a patient with progressing CNS mets. I’m hopeful that she was on tucatinib and that there’re other patients like her. But I don’t know yet.

Emerging data with trastuzumab deruxtecan for patients with advanced HER2-positive breast cancer who received prior treatment with T-DM1

DR LOVE: And she then subsequently progressed?

DR HURVITZ: This patient, yes, subsequently progressed. And voilà, I had just opened this study of this new molecular known as DS-8201, now known as trastuzumab deruxtecan, which is an antibody-drug conjugate. It’s a HER2 antibody linked to what’s called DXd, which is like an irinotecan-type derivative, so it’s a topoisomerase inhibitor. The antibody drug ratio is much higher than that seen in, for example, T-DM1.

And the activity from their Phase IB study is absolutely phenomenal. And their Phase IB, which was originally primarily in Japan, but also included other sites, showed over a 40%, upward of 50%, objective response rate in patients who’d had a median of 7 prior lines of therapy in the metastatic setting.

We put her on this study, a single agent. It was a Phase II study. We knew she was getting the drug, and she’s had a terrific response in her lungs. She’s doing very well with it. Normalization of her tumor markers. And she continues on. She’s 10 months, so far, on this drug. The main toxicity we are concerned about with this drug is pneumonitis, so we have to watch patients carefully for that, and educate them and keep an eye on that so that we can take patients off if they develop that. But a pretty well-tolerated agent, and very exciting activity.

DR LOVE: How did this woman tolerate treatment?

DR HURVITZ: Really well. There is nausea associated with this drug, so we have to treat it. It’s interesting, they talk about the activity perhaps being related to the antibody-drug conjugate dissociating and the chemotherapy can go through the tumor cell and into the tumor microenvironment and kill nearby tumor cells that are perhaps not as high in overexpression of HER2. But with that comes a little bit more toxicity.

But she’s not lost her hair. She doesn’t have problems with vomiting or diarrhea. It’s definitely better than standard chemotherapy.

DR LOVE: What about in HER2-negative disease? My understanding is there have been some responses, and there’s some kind of bystander effect? How would you explain what’s going on there?

DR HURVITZ: Yes, so that’s what I was talking about a little bit, the bystander effect. The company explained, and there are some theories that what’s happening is when the tumor cell dies, it activates the immune system and the surrounding area, and cells are killed that are nearby that may not be as high HER2 overexpressing. But we know that the drug itself, the chemo, can seep into the tumor microenvironment and kill cells that are not necessarily HER2 overexpressing. So unlike T-DM1, the activity of this drug does not rely heavily on overexpression of HER2. T-DM1, we know, you really need to have high levels of protein expression of HER2 for it to work.

They’ve shown over, I think, 40% objective response rate in HER2 1+, 2+ breast cancer, so truly, HER2-negative breast cancer. And they have a large Phase III trial ongoing for hormone-receptor-positive, HER2 1+, 2+ breast cancer, looking at this drug compared to standard chemotherapy.

DR LOVE: That’s really fascinating.

Potential clinical role of trastuzumab deruxtecan

DR LOVE: Ian presented a case, and his patient I think didn’t have any hair loss, but did have nausea and vomiting. Again, your patient?

DR HURVITZ: Nausea. Yes.

DR LOVE: Some nausea?

DR HURVITZ: A fair amount of nausea.

DR LOVE: What about hair loss?

DR HURVITZ: No. No hair loss.

DR LOVE: I was telling him that it’s 1 thing when you see a big strategy where a drug’s added to something else you need a big Phase III trial to dissect it out. But here you have a single agent. It kind of brings up the issue of how much data do you have to see in order to have something come into practice, when, again, it’s a monotherapy and you’re looking at metastatic disease? Is this something that you think should be in practice right now?

DR HURVITZ: I think it should be in practice very soon. The data from the single-arm Phase II trial that I told you about that my patient was enrolled in should be presented and published soon. Can’t say more than that, but I think that’s probably what the FDA is waiting for. They do have a breakthrough status, so their data on the Phase II setting will be looked at closely. And they have at least 3 ongoing Phase III clinical trials to support an accelerated approval.

The 1 issue that needs to be contended with is this risk of pneumonitis, which did lead to 5 deaths in the Phase I study. I think it’s important to make sure there’s a lot of education relating to who should go on this drug and how to monitor patients and educate patients so that this can be picked up quickly and deaths can be avoided.

Preemptive measures to mitigate nausea and the risk of pneumonitis associated with trastuzumab deruxtecan

DR LOVE: That certainly is a major concern, and I mean monitoring, et cetera, and I’m not sure how effective that could be. I mean, I think I’ve heard about pneumonitis with other antibody-drug conjugates, not T-DM1, but maybe some in development. Any granularity to add to what’s going on there?

DR HURVITZ: I was talking to Dennis Slamon about this, and he said early on with trastuzumab there was some pneumonitis. It’s rare. It’s very rare.

DR LOVE: With T-DM1?

DR HURVITZ: No, with trastuzumab.

DR LOVE: Trastuzumab. Wow.

DR HURVITZ: Yes, and he said that the lung does express, the bronchioles express HER2 —

DR LOVE: Huh.

DR HURVITZ: — and so this may be an on-target effect, and it’s such a potent drug that perhaps —

DR LOVE: Hmm.

DR HURVITZ: — that’s what’s going on. I have talked with the makers of the drug because I have some ongoing and upcoming studies with this drug, about whether or not the use of steroid premedication might help (A) the nausea, and (B) prevent pneumonitis.

DR LOVE: Hmm.

DR HURVITZ: We’re thinking of doing a study where we give pulse-dosed steroids kind of like we do when we’re using a taxane.

DR LOVE: Hmm.

DR HURVITZ: Either IV the day of treatment or oral the day before and the day after treatment, the way that we do with taxanes to avoid an infusion reaction or severe edema. Because it would be nice if we could do something that would address both the nausea associated with the drug and this risk of pneumonitis.

But in terms of how do you pick it up? Should we be doing pulmonary function tests? Should we be monitoring chest CTs more closely? This is an area that’s being heavily looked into and is certainly very important, but there’s no true clarity at this point.

DR LOVE: I mean pneumonitis sounds kind of not too good, although these people have far advanced metastatic disease. But actually I was thinking about it, you actually see pneumonitis with everolimus —

DR HURVITZ: You absolutely do.

DR LOVE: — and it seems like we kind of navigate our way through that.

DR HURVITZ: Yes. Absolutely. Absolutely. And you keep an eye on the chest CT. Usually, when you’re doing your repeat looks with your scans, you pick up these ground-glass opacities, which is Grade 1 pneumonitis. That’s when you get pulmonology involved. That’s when you start telling your patient let me know if you’re short of breath, if you’re coughing. And you really begin to look at it closely and hold therapy and use steroids when needed.

DR LOVE: It will be interesting to see when that data’s presented.

Case: A woman in her early 40s with HER2-positive mBC experiences a prolonged remission with trastuzumab and lapatinib in combination with chemotherapy

DR LOVE: Let’s hear about another 1 of your cases. You have this 41-year-old lady who initially, again, presented in 2003. What happened with her?

DR HURVITZ: Yes, she came to me just devastated. She had kids who were not even yet in middle school. She was with her husband and sister. And she came in. She was diagnosed in 2003. It was ER-positive, HER2-positive. She received FEC by somebody in the community, followed by radiation, and then they were early adopters of trastuzumab and actually gave her a year of trastuzumab, thinking outside the box, which I think was great because this was in the community. It wasn’t on a clinical trial, and it was only 2004.

She got endocrine therapy, and then this particular oncologist was following tumor markers and found that they were rising 4 years later. And they found pulmonary nodules and liver lesions. She had a liver biopsy. It was ER-negative, HER2-positive metastatic disease.

She came into my clinic. She had to lay on the bed she was so devastated. She couldn’t really talk to me. Her husband and sister spoke to me. She was just sure she was dying. And we started her on TCH, and after the third cycle her scan showed no evidence of disease. She had a brisk and perfect response to therapy.

We kept her on maintenance trastuzumab and zoledronic acid, and then in 2009, based on Kim Blackwell and Joyce O’Shaughnessy’s data of the benefits of dual HER2 targeting and trastuzumab and lapatinib and their overall survival benefits with the dual use, we added in lapatinib. Also thinking it might protect the central nervous system.

She’s no evidence of disease for 5 years. We stopped the lapatinib because she was having a lot of skin issues with it, in 2013, and she’s going on like 10 years, no evidence of disease. She sees her 2 sons graduate high school and go to college. She never thought she would see them reach this milestone. And we began having discussions about whether or not to stop therapy. Because 1 of the patients that Dennis put on the original Phase I study of trastuzumab was cured. She got like 6 cycles, and —

DR LOVE: Right.

DR HURVITZ: — she was cured. Do we need to treat everyone long term? Is she cured? And I just never was really comfortable with it. We talked about it all the time. And then she developed lesions in the lungs and bones, in October 2018. And it was now ER-positive, but also HER2-positive. And so I’m glad I didn’t stop her off trastuzumab because I would have felt like that’s what had caused the progression. But it was a lesson to me that patients can have their disease recur after a long complete remission.

And we started her on T-DM1, which she tolerated just miserably. So much nausea and malaise, and it was a very unusual reaction. But she did not do well. She had a very good response, 50% reduction in her lesions, healing of the bones, and we decided to put her on trastuzumab/pertuzumab and fulvestrant maintenance. And that’s what she is on to date, and she’s feeling great.

DR LOVE: Wow. Wow. I was just wondering, at a personal level, what it was like to have to deal with her recurrence after all those years.

DR HURVITZ: It would have been a lot harder had I advised her to stop trastuzumab.

DR LOVE: I bet.

DR HURVITZ: Because I would have felt that I had caused this. It was really hard. I hadn’t seen her husband in many years because she was doing so well. And he reemerged in the clinic. But she had a maturity level, and she said, “Look, all the years I’ve had are a gift to me. If you can give me more years so I can see my kids get married, great.” But she’s so appreciative of not dying when she came to me originally. She has a different way of looking at life. And I see this with patients in the metastatic setting. It’s like they have different colored lenses they’re looking through. The appreciation for life, I think, has deepened in many, many ways.

DR LOVE: I wonder, and I think probably that that’s part of the attraction of being in the field, to be around people who have that kind of feeling in their head all the time.

DR HURVITZ: Yes, and if I were an oncologist 20 years ago, I think it’d be a lot more depressing. I probably would be out of clinical practice by now because we have these amazing agents now to be utilizing, not just for HER2-positive, but hormone receptor-positive. 85% of breast cancers now, we have these just innovative, amazing, effective therapies. We’ve got to do better with triple negative, but I do think we have a lot to offer our patients. It’s rewarding in that sense.

DR LOVE: Certainly, there are a lot more agents available, really challenging to be an oncologist now, but also exciting.

DR HURVITZ: Yes.

DR LOVE: People who come into the field don’t realize how crazy it is compared to — but good, but good.

DR HURVITZ: Yes. Yes.

Predictors of benefit with HER2-targeted therapy; risk of recurrence for patients with HER2-positive breast cancer

DR LOVE: I remember hearing about that patient from Dennis who had that prolonged response, about what differentiates them? Is it the host? Is it the tumor? Is it the immune system? Anything?

DR HURVITZ: It’s probably a combination. There was this case series like 5 years ago that was presented at 1 of the meetings looking at characteristics of patients who have durable remissions. And they tend to be patients with hormone-receptor-negative disease, liver mets, de novo metastatic breast cancer. And my concern is, look, these patients — we’re not following them long enough. We haven’t seen them long enough to know if it’s truly going to come back. We need like 20-year follow-up.

I feel like this disease has turned into a disease like hormone-receptor-positive, HER2-negative. And so it looks like everyone’s doing great for 5 years, but maybe what we’ve done is put the tumors down quietly, and they’ve gone into dormancy, and then later on you’re going to see recurrences. And that’s why I think in the early-stage setting it’s so important for us to do these long-term, 10-year, 15-year follow-ups on our patients.

I don’t think we would have appreciated that a quarter of our patients treated with adjuvant trastuzumab will recur. 15% of node negative will recur at the 8- to 10-year mark. Those curves on the Kaplan-Meier have not — have not leveled out completely. And I think in the metastatic setting too, I’m very cautious about stopping HER2-targeted therapy. There are some patients who are probably cured, but I am not smart enough to pick them out.

DR LOVE: Yes, when you were talking about the dilemma of stopping in this lady, it did remind me of all these discussions you hear about endocrine therapy, and you stop it, and part of it is almost psychologic. That you —

DR HURVITZ: Yes.

DR LOVE: — know there’s a chance, and you hate to think that it could be correlated with stopping therapy. I’ve always been curious, too, do you see more delayed recurrences with ER-positive, HER2-positive? As opposed to ER-negative, HER2-positive?

DR HURVITZ: That’s my sense. We don’t have long enough follow up. But if you look at the long-term follow up, we are seeing more recurrences. And there was some data presented at ASCO on long-term follow-up from the joint analysis, it’s very similar to the data from the Pan et al New England Journal of Medicine 20-year follow up, and the EBCTCG Oxford Overview looking at long-term outcomes for ER-positive breast cancer. Very similar for ER-positive, HER2-positive breast cancer, where the recurrences happen later on and steady. They never go to zero. They continue on.

And that’s why I do think it’s important that we offer our patients the best in endocrine therapy. We don’t ignore endocrine therapy in HER2-positive, including ovarian suppression in the highest risk, and give them the systemic therapy that’s going to give them the best chance of outcome. And I really feel we should be looking at CDK4/6 inhibitors in the highest-risk, ER-positive, HER2-positive breast cancers in the adjuvant setting, but that’s a long way coming, I think.

Role of CDK4/6 inhibitors for patients with ER-positive, HER2-positive mBC; activity of PI3K inhibitors in patients with PIK3CA mutations

DR LOVE: Yes, again, Ian had this patient with far-advanced disease, ER-positive. I said have you given — because he was thinking about abema. The patient has brain mets, but I hear some docs in practice say they’re using CDK in HER2-positive, ER-positive patients, do you?

DR HURVITZ: I have a patient I didn’t present to you, but similar. Ten-year metastatic breast cancer survivor. I think she has had 17 or 18 lines of therapy.

DR LOVE: Wow.

DR HURVITZ: We’re having to get creative now. It’s ER positive, HER2 positive. And it’s like lymph nodes in the neck and pleural disease and bone disease, so it’s nothing that’s crazy visceral involvement. But we utilized palbociclib for her, and she had a really nice stabilization in her disease. It lasted almost a year. So biologically it makes a lot of sense. It’s not approved there, but biologically it makes sense.

DR LOVE: Alpelisib?

DR HURVITZ: Yes. If the patient has a PIK3CA mutation in their tumor, alpelisib should work. And if you look at the CLEOPATRA outcome data, Baselga, in 2014, published CLEOPATRA outcomes based on mutation status of the tumor. And those with the PIK3CA mutation had a much worse progression-free survival.

DR LOVE: Wow.

DR HURVITZ: They still benefitted from pertuzumab, but their PFS and OS —

DR LOVE: Hmm.

DR HURVITZ: — was lower. I think APHINITY did present biomarker data at ASCO.

DR LOVE: Right.

DR HURVITZ: And I think consistently PIK3CA mutation predicts for worse outcome in HER2 positive. There is a study that’s being planned to look at alpelisib in combination with trastuzumab/pertuzumab in the maintenance setting after fist-line THP, just for patients with PIK3CA mutations. I think it’s about 40% of HER2-positive breast cancer has a PIK3CA mutation.

DR LOVE: But again, no hormone therapy in that one? And they don’t have to be ER positive?

DR HURVITZ: For hormone receptor positive, I don’t know the specifics. At this point, it would make sense to utilize it, absolutely.

Neratinib and capecitabine versus lapatinib and capecitabine for HER2-positive mBC previously treated with HER2-directed therapy: Findings from the Phase III NALA trial

DR LOVE: Anything else new in HER2-positive disease that we haven’t talked about today? New agents? New strategies?

DR HURVITZ: I mean, I think the NALA study of neratinib —

DR LOVE: Right.

DR HURVITZ: — in the metastatic setting came out at ASCO. It was, again, a study, around 600 patients, 1:1 randomization, head-to-head neratinib/capecitabine versus lapatinib/capecitabine. Something that should be appreciated is the capecitabine dose was different in the 2 arms. For neratinib it was 1,500 daily, and for lapatinib it was 2,000 daily, and that’s because the diarrhea that patients have with neratinib.

And they did show that the PFS, the mean PFS, was improved around 2 months, statistically significant with neratinib. Duration of response was better. And the time to intervention for CNS mets was significantly better for neratinib compared to lapatinib.

The problem is with this drug, which remains the problem in all the studies of this drug, is a quarter of patients have Grade 3/4 diarrhea. And while the diarrhea duration tended to be short, you have to keep in mind all patients in this arm were treated with loperamide from day 1. You just don’t feel great on this drug, so is a 2-month benefit something to cause us to change therapy? Maybe. The duration of response was better, and the clinical benefit rate looked better with neratinib, but you really have to keep a very close eye on patients and manage this diarrhea side effect, and keeping in mind that you’re using a dose reduction of the capecitabine.

DR LOVE: Do you ever see patients with HER2 mutations? You hear about that in lung cancer. And what do you do? People in lung cancer sometimes use neratinib. But do you ever see that in breast cancer?

DR HURVITZ: Yes, there’s an ongoing umbrella study looking at the use of neratinib in patients whose tumors have a HER2 mutation. It’s relatively infrequent in breast cancer. It’s less than 5%. But you know what? I think we’re going to start picking it up in more and more patients. Because of the alpelisib approval, we’re going to be doing more and more next-generation sequencing —

DR LOVE: Hmm.

DR HURVITZ: — on our patients to look —

DR LOVE: Interesting.

DR HURVITZ: — for mutations. We’re not going to just send the tumor for PIK3CA. We’re going to be looking for the whole kit and caboodle. And so if you find a patient who has a HER2 mutation, and these tend to be HER2 nonamplified, non-overexpressing tumors, we may be identifying more of these patients. And I think Joyce O’Shaughnessy’s presented some dramatic responses at conferences associated with neratinib with pictures just showing real improvement in the chest wall disease of a patient with a HER2 mutation treated with neratinib.