Introduction: Journal Club with Mark D Pegram, MD

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research to Practice, and welcome to Meet The Professor, as today we start a new series on the management of HER2-positive breast cancer with Dr Mark Pegram from the Stanford University School of Medicine in Stanford, California. We have a great faculty for this series, and later on we’re going to show you a survey we did of the faculty of their usual treatment practices.

As always, if you have any cases for Dr Pegram just type them into the chat room, and we’ll bring up as many of these as we have time. If you could please take the brief 10-question pre-meeting survey, and then afterwards we would really appreciate that. We can learn a lot about your needs and interests and really contribute to what we’re trying to do here.

If you’re into audio programs, we know a lot of people end up listening to our webinars, check out our Oncology Today podcast series, including a recent program with Dr Modi on HER2-low breast cancer.

Next week we’re doing a webinar that’s a spinoff from the SOHO Meeting on MDS. Lots going on there. And then the following Tuesday we’ll be doing a similar program, again coming out of SOHO, this looking at diffuse large B-cell lymphoma, so much going on there, first-line therapy, CAR T as second-line therapy, et cetera.

But today we’re here to talk about another area of very rapid change, particularly in the last year, HER2-positive disease. As always, we have a bunch of great cases we’re going to be presenting today, mainly from general medical oncologists in community-based practice.

Here’s where we’re heading. We’re going to start out and review a few papers that Dr Pegram’s done, then we’ll go through the cases, then we’ll show you the faculty survey, and then we’ll do a few more papers. We have an appendix with a lot of interesting papers for you to check out as well.

So Mark, first I want to welcome you. I’m so excited today, finally after 6 months football’s starting tonight, college football. You were here. A lot of people don’t know that between UCLA and Stanford you actually were here in Miami with us, and you were a part of the U. I don’t remember who was quarterback at that time, but we’re all excited about football today, and the Dolphins in pro football. Any thoughts, Mark?

DR PEGRAM: I don’t follow football because I went to a basketball school. My undergraduate college was University of North Carolina, and when I was a senior in college the dorm was across the street from the basketball arena, and the starting 5 players were James Worthy, Sam Perkins, Michael Jordan, Matt Doherty, and Jimmy Black, and they won the championship that year.

DR LOVE: Wow.

DR PEGRAM: So when I was in Miami I will mention that the Miami Heat won 2 championships while I was in Miami for the 5 years I was there. And then as soon as I came to San Francisco the Golden State Warriors have been on a streak, so they won again this past year.

DR LOVE: Right.

DR PEGRAM: So good basketball follows me. Yeah.

DR LOVE: It seems like it. All right. Let’s talk about HER2-positive breast cancer. I wanted to ask you about this paper. When you were particularly at UCLA, and I noticed, I was talking to Dr Modi, in the HER2-low paper your former colleague, Sara Hurvitz from UCLA, who actually was an author on this paper as well.

DR PEGRAM: Yeah. She’s still my colleague. Not former colleague. She’s still my colleague.

DR LOVE: Yeah. You’re right. She’s still your colleague, just in another place. But in any event, she brought up the issue in the editorial of cardiac disease in T-DXd, and I asked Dr Modi about it. But I was curious about this paper, a broad look at the issue of anthracyclines. Of course with Dr Slamon at UCLA, when you were there, that was a big issue. You all developed the TCH regimen. I thought this comment was very interesting in the paper, “The following statements are true: as of this writing, there has been no prospective randomized trial that demonstrates a survival benefit of anthracyclines to taxane chemo in the curative setting, no randomized study showing the addition of anthracycline to taxane/trastuzumab for HER2-amplified disease. The conclusion being rather than asking which patients can be safely given an anthracycline we should be asking does the data exist to even warrant the use of anthracyclines.” Any thoughts?

DR PEGRAM: That’s provocative isn’t it? I mean the data that everyone points to in the modern era is the ABC trial, also known finally as the TIC TAC trial, which was basically TC versus TAC initially and then TC versus AC-T in various permutations as the trial unfolded. That study showed that eliminating anthracyclines was not noninferior. In other words, the doxorubicin group actually did a little bit better than the nonanthracycline group, and they could not prove noninferiority statistically.

But the primary endpoint of those studies is typically iDFS in the early-stage setting not overall survival. So the statement is true that in terms of overall survival it’s been difficult to prove that the anthracyclines contribute anything. Moreover, in the case of HER2-positive disease it’s been demonstrated I think convincingly that you gain literally nothing either in the adjuvant setting based on the BCIRG 006 data now with 10 years of follow up showing only a few events separating the anthracycline versus the nonanthracycline curves in the adjuvant setting with chemotherapy plus trastuzumab.

And the TRAIN-2 study, which is a neoadjuvant study comparing various regimens, including anthracyclines versus not, in the pertuzumab modern era, and it showed no difference in pCR rates whether you added anthracyclines or not in the neoadjuvant setting. So I like to say that the TRAIN-2 trial finally has derailed the use of anthracyclines, at least for HER2-positive early breast cancer.

And then the paper that Dr Hurvitz has written and published recently, on which she graciously asked me to be a coauthor and write some small sections, we draw kind of a similar conclusion for all breast cancer.

But it is provocative. It remains controversial. And no one’s going to be penalized if they choose to use anthracyclines, especially for high-risk patients perhaps. But it’s hard to find data to prove with an OS endpoint that it makes any difference.

DR LOVE: So I really enjoyed looking through your CV and picking some of these papers out because some of these ideas are really cool. This is another one I want to ask you. Actually one of the faculty members, Dr Lin, was on this paper as well. “Pertuzumab and High-Dose Trastuzumab in Brain Mets.” Any comments?

DR PEGRAM: Yeah. I mean this is based on the observation made years ago that if you PET label trastuzumab with zirconium-89, which is a positron emitter, so it’s fairly straightforward to label trastuzumab, and then infuse that intravenously into human subjects with metastatic breast cancer and HER2-positive brain metastasis, you get very nice PET imaging of their brain metastasis in vivo, in human subjects. It’s very real. So that means that the trastuzumab antibody can and does diffuse into tumor deposits probably through fenestrations in the endothelium because the endothelium is disrupted, and the blood-brain barrier is disrupted in the tumor microenvironment of brain metastasis. That’s well known and published and described in detail.

And so we thought well, if that’s true, maybe by giving a high dose of trastuzumab by mass action we can get even more trastuzumab into the tumor microenvironment in HER2-positive breast cancer brain metastasis. So we gave a triple dose of trastuzumab, which is 6 mg/kg IV, every week. There were no new safety signals whatsoever. We gave pertuzumab along with it just for those patients that may have extracranial disease that also need to be kept kind of like in remission. So we gave a standard dose of pertuzumab in the same regimen.

And we observed about an 11% objective response rate, which doesn’t sound like much, but the clinical benefit rate, which were the responders plus the prolonged stable disease for about 6 months, that was more like 30% or so. It was actually pretty interesting. And there were some anecdotes with patients with very long follow up now out to a couple years who did well on that trial and haven’t progressed in the brain yet. So very provocative. I think this gets a shout by the NCCN in their latest version of the guidelines, but it’s still considered an experimental method. I wouldn’t say it’s standard of care by any stretch, but just interesting biology and hopefully it demonstrates that with mass action you might actually be able to achieve therapeutic concentrations of trastuzumab in the brain.

DR LOVE: I don’t know if I’m remembering this correctly, but I think there was a trial of intrathecal trastuzumab. Do you remember?

DR PEGRAM: There’s been more than 1. Yeah. None of them were big trials. Most were anecdotal case reports or small case series, but there are objective responses described in the literature for intrathecal trastuzumab, believe it or not. Back in the day you had to use the preservative-free version of trastuzumab, but now I think the modern vials don’t have preservatives in them, if I remember right.

But double-check with your local representative before you try that and read the literature to make sure you use the right trastuzumab. I haven’t used it for many years. Dennis Slamon and I tried it, we were the first to try it as far as we know, back in the day at UCLA. But we didn’t have any responders in the handful of patients where we tried that, and we had 1 patient who actually lost consciousness for a while after the intrathecal injection, so that scared us quite a lot. It was a man with breast cancer, as a matter of fact, and HER2-positive brain mets. He fully recovered but it gave us pause about using that approach.

DR LOVE: I’ll bet it gave you serious pause. That sounds seriously scary.

DR PEGRAM: Yes.

DR LOVE: So kind of fast-forwarding to more commonly-utilized strategies, any comments about this update presented at San Antonio? You were telling me this is about to be published, as well, from the HERCLIMB study.

One of the things — I mean we’ve known this for a while, but when I was looking at this paper one of the things I noticed, everybody gets all excited, justifiably, at the waterfall plots and the activity of T-DXd, but here you have a hazard rate of 0.38, which is really a pretty significant hazard rate. Any comments about the HERCLIMB strategy? We’re going to talk about it later in some of these cases.

DR PEGRAM: I mean the remarkable robust nature of the HER2CLIMB randomized Phase III trial showed that at the time of the first planned interim analysis it achieved its endpoint of overall PFS, overall OS, both with statistical confidence, and CNS PFS with statistical confidence at the time of the first planned interim.

Subsequently Dr Lin has presented data on overall survival in patients with CNS metastasis, and that is also significant, with the 1 caveat the subset of patients with stable brain metastasis did not have a statistically significant improvement in overall survival. But that’s the only subset that didn’t have an OS signal with statistical confidence of all the brain mets patients in that trial, which is about half of the patients mind you. And moreover, the CNS PFS endpoint was significant even for the stable brain mets subgroup in that final analysis as well. And so this will be published soon. I just saw the last version of that manuscript across my desk recently, so it should be out in journals soon.

DR LOVE: So a couple cool comments from our chat room, one from Danny. “How comfortable are you using T-DXd in a patient with pulmonary lymphangitic spread of disease?” I would think from an efficacy point of view it’d be exciting to think about, but I get the issue of the ILD. Any thoughts?

DR PEGRAM: We had a couple of cases like this at my institution that were presented at our tumor board early on when T-DXd became available. And it is scary, and that’s why these cases got presented at our entire group’s tumor board because it is controversial, perhaps. In both cases the patients had symptomatic pulmonary metastasis and were in trouble as a result. They were approaching impending respiratory failure. So we said if you don’t give them something, and if they don’t have a response quick, they’re going to get into really big trouble. So both of them were treated with T-DXd, and both of them had clinically meaningful responses and improvement if not resolution of their pulmonary symptoms.

So I think if this patient with lymphangitic metastasis, if they’re symptomatic and starting to get into trouble, and you don’t have other good therapeutic options, you may have to absorb the fact that you won’t be able to screen for ILD, as well, unless their lymphangitic pattern gets worse on therapy. That would be a cause for alarm, or if they develop worsening symptoms compared to baseline that would actually be a cause to stop the drug permanently and give steroids.

So it all depends on whether the risk of mortality from ILD exceeds the risk of mortality from respiratory failure from metastatic breast cancer, and on the day that balance tips towards the therapeutic option I think it’s reasonable to do as long as you advise the patient and their families that it is perhaps quite risky. But the response rates are so extraordinary with T-DXd. The DB03 response data was 79.7% objective response rate.

DR LOVE: Right.

DR PEGRAM: I mean you can’t beat that with any other HER2-targeting agent. So if you’re in trouble, I think it would be ill advised to withhold that from the patient simply for that reason.

DR LOVE: So I think sparked by your comments about anthracyclines Dr Kumar wants to know did we abandon CMF or CMF-T prematurely? I don’t even know whether people new to oncology know what CMF actually is.

DR PEGRAM: It hasn’t been abandoned. Every once in a while you get an octogenarian. When I was at UCLA there were little old ladies from Pasadena, now there are little old ladies from Los Altos Hills or wherever, and sometimes they’re not good candidates for anthracyclines, and they may not have other meaningful go-to regimens. They might not be able to tolerate let’s say docetaxel plus cyclophosphamide.

Docetaxel is tough, particularly for elderly patients with multiple medical comorbidities in their past medical history. So for those patients we have used, even to this day, CMF. And my colleagues at Memorial I know for a fact do the same thing. Judicious experienced oncologists of a certain age haven’t abandoned it entirely, but it’s used only rarely, to be honest. But many of us have and still use it to this day.

DR LOVE: I just had a weird flashback to Dr Bonadonna, which again I’m sure none of the newbies to oncology know, from Milan, who really developed that program, who used to say “CMF-a” with an Italian accent.

DR PEGRAM: Yes. Exactly.

DR LOVE: Anyhow, we may spend the whole time just dealing with the chat room. They’re just like popping every 2 seconds here.

DR PEGRAM: Sure.

DR LOVE: But let’s just do 1 more, and then we’ll go back to the papers. And Hassan wants to know what you think about trials combining T-DXd and tucatinib.

DR PEGRAM: It’s interesting. We’ll get the first impression of that strategy of combining a HER2-targeting ADC plus tucatinib in the DESTINY-Breast02 trial, which is actually T-DM1 plus tucatinib. That trial’s ongoing. So that’ll be the first.

DR LOVE: That’s the KATHERINE.

DR PEGRAM: No, no.

DR LOVE: KATHERINE scenario.

DR PEGRAM: I’m talking about the metastatic trial.

DR LOVE: Oh, metastatic. Okay.

DR PEGRAM: T-DM1 with or without tucatinib.

DR LOVE: Wow. Interesting.

DR PEGRAM: That’s already accruing, so I think that will probably report first before any of the others. So then it begs the question of what to do with T-DXd since T-DXd is better than T-DM1 in a randomized Phase III trial head-to-head. Could you add to that with tucatinib? And the issue I think really is that of toxicity. T-DXd is not without some toxicities. It’s a moderately emetogenic regimen so you have to use antinausea drugs with it. It causes some degree of fatigue, so does tucatinib in some cases.

Tucatinib can cause transaminase elevations, et cetera, et cetera. So I predicted that that may not be the easiest regimen to give, but it’ll be very interesting in a nonrandomized Phase II trial to see whether it’s active and feasible. But first we have to demonstrate feasibility with that combination before we can determine whether it’s going to be superior in terms of efficacy, or therapeutic index, more importantly, which is efficacy divided by toxicity. Because there will be some significant toxicities with that combination you would predict, even if it has additive toxicities of the 2 component agents. For some patients that might be a little bit challenging.

DR LOVE: So this is another paper I wanted to ask you about. In the HER2-low plenary presentation Dr LoRusso, who did the discussion, brought up the issue of HER2 mutations, and we’ve been talking about that for quite a while now in lung cancer. Matter of fact, the lung cancer docs want to give T-DXd, a lot of them, first line. But then the question is what about HER2 mutations in breast cancer. And this is a paper that you did, a study looking at neratinib and fulvestrant.

First, can you just comment on how often you see HER2 mutations, and then again what you did in this study?

DR PEGRAM: Well, Cynthia Ma invited us to participate in this trial soon after I arrived to Stanford back in I think about 2012, and we opened it at our center along with many other coauthors, as you can see. And the reason we had so many sites for this study was that HER2 mutations in breast cancer are uncommon, to say the least. In our screening program for the first paper that was on this topic that Cynthia published back in 2017, and I’m a coauthor on that paper, as well, our mutation frequency in our hands, in our little consortium, was 1.6% of the patients screened. So you have to screen a ton of patients to find them.

That said, by the time we finished the cohort or 2 of that trial we didn’t have to screen many patients anymore at all because that’s when the likes of Foundation Medicine and Caris and Tempus and other diagnostic companies started finding these for us on the commercial level, and suddenly these patients just appeared in our clinics out of the woodwork. We didn’t have to go through the toil of screening them anymore inhouse, we just got the results from the commercial reference lab, and they appeared out of the woodwork.

Now the frequency of HER2 kinase domain mutation is highest in lobular breast cancer, so that’s kind of a clinical pearl. If you really want to find a case check out your lobulars. It’s between — in our hands it was 7% in the first paper in 2017 in this trial, and I think other papers show around 10% of lobulars can have these HER2 kinase domain mutations. But they do appear to be pathogenic. The cause constitutive activation of the kinase domain and aberrant HER2 signaling, kind of akin to gene amplification caused by HER2 overexpression even when it's not mutated. That aberrantly induces a HER2 signaling cascade, and the mutations probably do a similar pathophysiologic thing. It’s a driver mutation.

These mutations are found, as you rightly mentioned, well outside of breast cancer. They’re found in multiple tumor types. The SUMMIT trial, which was done by Puma, which has recently completed its accrual by the way, that study also showed multiple varied mutations in the kinase domain and in some other domains of the HER2 receptor, interesting. They appeared to be activating mutations, and there were responders to neratinib in multiple disease types and in multiple types of mutations.

There were some patients in Cynthia’s paper, the recent paper, that showed there was some mutations that had a lower clinical benefit rate, like the L755S and L755 insertion or deletion mutations had lower clinical benefit on neratinib. She also got the impression over time that neratinib plus fulvestrant, since most of these patients are also ER positive, that combination in general seemed to be superior to just neratinib as a single agent. So we actually closed the neratinib arm of this trial as it was underway.

There were second site mutations after selection pressure from neratinib. We found these second site mutations analogous to the EGFR second site mutation in non-small cell lung cancer, and we found that in the circulating tumor DNA it came up during disease progression in a few of our neratinib-treated patients, even after they responded. One of them was the gatekeeper mut T798I, and also the L755S mutation. At the time of progression those mutants would go up, indicating resistance mechanisms to neratinib in this case. And there is some literature, at least ex vivo, that there may be other HER family kinase inhibitors that can target some of these other acquired mutations under selection pressure for neratinib.

So it’s a fascinating story with remarkable parallels, as you rightly point out, to the EGFR mutation story in non-small cell lung cancer, where there are multiple therapeutic tools now available for clinicians. We need to get that same kind of tool chest for these uncommon mutations in breast cancer.

DR LOVE: So Nicholas in the chat room has the same question I was thinking about as you were talking about that, which is how would you compare neratinib to tucatinib, both for HER2 mutant and HER2 overexpression.

DR PEGRAM: So there is new data now on tucatinib against some of these HER2 kinase domain mutations, and it does block some of the mutations, as does neratinib. So that might be another therapeutic opportunity that needs to be studied more rigorously in the clinic. The data I’m talking about is preclinical data so far, but in theory tucatinib may bind to some of these important mutants, as well, and that needs to be tested in the clinic, in my opinion.

Case: A woman in her mid 60s with ER/PR-negative, HER2-positive metastatic breast cancer after multiple lines of HER2-directed therapy with no evidence of disease after 8 years of pertuzumab/trastuzumab — Raman Sood, MD

DR LOVE: All right. Well let’s make some rounds here with our cases that we have here. And this first case from Dr Sood really presents a question I remember asking you many times in the past, I’m curious if your answer has changed, which is how do you explain these super responders that you sometimes see with HER2-positive disease. I can remember cases from Dr. Slamon, I think it was back in the early 90s, of people who were alive 10 years or so.

DR PEGRAM: That’s correct.

DR LOVE: Here’s another case. And also of course what seems like the age-old question of would you ever stop anti-HER therapy in a patient like that. Here’s the case from Dr Sood.

DR SOOD: She presented almost 14 years ago with inflammatory breast cancer, ER/PR-negative, HER2/neu 3+.

She had neoadjuvant TCH back then and did not have a very good response. Pretty significant residual disease by the time she went to surgery.

Soon after she developed pulmonary metastases, which were confirmed on a biopsy that they were the same disease.

So she did receive some trastuzumab combinations with different chemos. Kind of stable disease. We gave her a trial of lapatinib for about 6 months in 2010, which resulted in stable disease, but she had transaminitis, pretty severe.

So a year later pertuzumab was approved and available, so we added that to her trastuzumab and she has since then stayed on a combination of trastuzumab and pertuzumab 8 years now. She gets scans every 6 months and there’s no active disease on the PET scan.

So again, that brings up the question, is she cured now?

Would you ever consider stopping treatment and give her a break, although she’s tolerating it pretty well? Not having any issues.

DR LOVE: So of course, again, the question that comes up a lot, and this one’s a little different than the patient who starts out on trastuzumab and goes 10 years. She didn’t seem like she did that well with pertuzumab and chemotherapy, but it was when he brought in the pertuzumab that things changed. It seems a little bit unusual.

DR PEGRAM: Interesting.

DR LOVE: But anyhow, what are your thoughts about that?

DR PEGRAM: Yeah. I mean for patients in particular who have clinical CRs from metastatic breast cancer that’s HER2 positive on HER2-targeting therapy I have enthusiasm to start talking about cessation of treatment after about 5 years or so. But that number’s made up. There’s no data whatsoever on this topic to this day, so we don’t know what to do with these patients. Most patients are fearful to stop treatment.

In the case of pertuzumab and trastuzumab you can actually give that subcutaneously now in the clinic, so it’s little burden to the patient at all in terms of coming into the clinic for their treatment. In fact, we had a clinical trial during the COVID era where — there was a study where trained infusion nurses would give this combination subcutaneously at home for patients so they wouldn’t even have to come to the clinic, where there might be a risk of COVID transmission. So that was a very successful study, but you have to do it with a nurse who has treatment ready for anaphylaxis or infusion reactions, et cetera.

That said, in this case, since she’s well more than 5 years with at least stable disease if not response to pertuzumab, I would try to start talking her into a drug holiday. And the way to do this probably, realistically, since when you tell people that they can think about it straight up, they’re usually very insecure and a little superstitious. They have a routine already in your infusion centers, they often know so many friends that they get in the waiting rooms for the infusion center and for your clinics. It’s hard for them to lose that social contact, as well.

So one way to initiate the conversation is if they take a long vacation tell them that they can take a long break from treatment, especially in the case of these antibodies which have 21- to 28-day half-life anyway. They should be able to say yes to that, and if they agree to that you can say well do you want to do a holiday where we check you scan in a few months and see if you do just as well off therapy for a while and kind of work your way into it. Going all in I find usually is successful. I’m rarely able to talk my patients to talk my patients out of continued treatment.

DR LOVE: So Rosanna, actually one of the does brings up this question that I’m going to ask you now. Rosanna from the chat room wants to know, you mentioned the subq trastuzumab — trastuzumab/pertuzumab, Rosanna wants to know would you utilize that in the neoadjuvant setting? Would you use it in a curative setting?

DR PEGRAM: I believe you can because the clinical trials, as I recall, were any patient who was on that regimen for any clinical indication was part of the eligibility criteria, as I recall. And so yeah, I mean the infusion is shorter, much shorter, for a subq infusion compared to the long IV infusions of 2 different antibodies so I don’t think that’s a problem.

Case: A woman in her early 60s with a 1.8-cm triple-positive invasive ductal carcinoma after partial mastectomy/axillary lymph node dissection (9 N+) receives adjuvant TCHP x 6 — Shaachi Gupta, MD, MPH

DR LOVE: All right. Well here’s the first case that you’re going to hear. I just put it out here just for you to think about this scenario. I’m also curious how often this happens. So this is a patient who presented with a 1.8 cm tumor, even though it was HER2 positive the feeling was it was small, and the patient could go to surgery, which the patient wanted to do, and then they found the patient had 9 positive nodes. And the question is what do you do. We actually asked this in our pretest, and I’ll tell you that those first 4 choices were about equal choices, so that tells me that may it’s not that clear what to do in this situation. And actually a quarter of the people said they weren’t sure, so they were maybe more honest. Anyhow, here’s the case.

DR PEGRAM: Wow.

DR GUPTA: She’s a nurse. She’s 63 years old. Former smoker.

We discussed her case in the Tumor Board and fora tumor that’s less than 1.5 cm, we decided to proceed with surgery.

And lo and behold she had T1c disease with 9 total positive lymph nodes. And totally took me by surprise because now I’m wondering, oh, gosh I could have given her neoadjuvant chemotherapy. I could have gone to see some response or lack of response and then change therapy to T-DM1.

And the patient was a little disappointed too. So we started her adjuvant treatment with TCHP.

So for her, I thought that I’d treat her with 6 cycles of TCHP and empirically change her treatment to T-DM1, just assuming that she never had a response, for a total duration of a year. So that’s 1 question. Would that be a reasonable decision

And then number 2 is, she’s likely to benefit from a yearlong therapy of neratinib. Versus I was also thinking of enrolling her on a clinical trial to see if she could benefit from abemaciclib in the HER2-positive setting. So what would be more important? Continued HER2 blockade or HR pathway blockade?

DR LOVE: So we didn’t have room even on this question to put in about abemaciclib, which is maybe another issue. But any thoughts? I never even thought about this idea. It kind of makes sense to me. I don’t even know how likely it is that you could even access it, but what are your thoughts? What do you think? Have you been in this situation, Mark, and what do you do?

DR PEGRAM: Yeah. It does occur. It’s not even rare. I would just say it’s uncommon, but it occurs with regular frequency that you don’t understand the nodal status pathologically until you sample the nodes, obviously. And if they’re clinically node negative we know that that’s not a perfect surrogate for pathologic node negative by any stretch. That’s why the sentinel lymph node biopsy was invented, to detect true pathologic spread because the best examiner can be fooled by a normal clinical exam.

So this is not surprising. This fortunately does not happen all that commonly, but it can and does happen, as it has in this case, and then you have to wrestle with what do to at tumor board. There is no data on adjuvant chemotherapy/trastuzumab/pertuzumab followed empirically by T-DM1. As you know, the KATHERINE trial was only in patients who did not achieve a pathologic complete response after neoadjuvant HER2-targeted therapy, then they were randomized onto KATHERINE to T-DM1 versus standard trastuzumab adjuvant therapy.

So there’s no basis, there’s no data I can point to for safety or efficacy regarding T-DM1 as a quasi-adjuvant regimen after 6 cycles of TCH. So for that reason my enthusiasm for T-DM1 is diminished, simply because there’s no data. Absence of evidence doesn’t mean there’s evidence of absence of a treatment effect here. Maybe it would work, but maybe she would have had a path CR on TCHP. You don’t know. There’s a good chance she would have.

So the best answer, in my opinion, would be chemo/trastuzumab/pertuzumab a la the APHINITY trial, which by the way now has 8-year follow up data that was just recently presented and shows continuous — continues to show benefit, particularly in node-positive patients and not in node-negative patients, but also in ER-positive patients in this case. So APHINITY is definitely in the cards for this patient, followed by neratinib. I mean this is a case where ER-positive disease, high risk due to the multiple positive nodes, that would be a bread and butter instance where neratinib would be a very appealing operation. So I would vote for that sequence personally, and it’s data driven, evidence based. It’s in the guidelines, no questions, Level 1 evidence across the board.

DR LOVE: So just to be complete what about abemaciclib? And Vershal in the chat room says what about anthracyclines here.

DR PEGRAM: There’s no — there’s no basis for anthracyclines. In the TRAIN-2 study even the highest-risk subset patients that had the highest tumor burden, highest stage, et cetera, even in that randomized trial they did not have any increased likelihood of achieving a path CR by the addition of anthracyclines. And in the BCIRG 006 retrospective subset analysis the highest-risk subgroup in that trial, with 10-year follow up, and the high risk was defined as 4 or more positive lymph nodes, that subset had absolutely no benefit in the anthracycline/trastuzumab arm compared to taxane/trastuzumab arm, or TCH arm I should say.

And then the question about clinical trial, if the clinical trial allows you to introduce the abemaciclib along with continued endocrine therapy after she completes all of her HER2-targeted, so she’s completed the APHINITY regimen, has completed neratinib, because I’m sure you can give neratinib with abemaciclib on that study, but if it allows you to give it after the completion of all the HER2-targeted therapy I would absolutely be a proponent of any clinical trial that she’s eligible for, but I’m not sure this case would be eligible for that study. I’m not sure. I’d have to look into that. Or you may have to talk to the medical monitor to see if you can get an exception.

DR LOVE: Wow. Really amazing when you think about it. Okay, let’s try to help somebody out. George in the chat room has a case, and I’d love to have you just weigh in briefly on it. 30-year-old black female with Stage IV, bone mets, inflammatory breast cancer, ER/PR negative, HER2 3+.

DR PEGRAM: So this is just de novo metastatic disease? Bone only?

DR LOVE: Yeah. Well no. This is — yeah, yeah, yeah. Bone only, right.

DR PEGRAM: Bone mets. She should get a bone-acting agent.

DR LOVE: Inflammatory.

DR PEGRAM: Yeah. She should get a bone-acting agent for her metastasis, and she should get the CLEOPATRA regimen. To this day nothing has ever surpassed the CLEOPATRA regimen in first-line HER2-positive metastatic disease. Now there are many trials that are going to threaten the CLEOPATRA regimen in the not-too-distant future. For example, the PATINA trial will test the hypothesis that you can add CDK4/6 inhibition for metastatic breast cancers that are ER positive after the taxane portion of the CLEOPATRA regimen along with maintenance with dual antibodies.

But this case is ER negative, so PATINA won’t apply to this case, but that trial has finished its accrual, and it’s a Phase III study, so we should have answers within the next year for that study.

Another study is looking at integrating alpelisib for PIK3CA-mutant HER2-positive breast cancer patients, also following the taxane treatment sequence in a CLEOPATRA-like regimen in the maintenance phase along with the dual antibodies.

And then finally I’ll mention DESTINY-Breast09 will pit T-DXd head-to-head against the CLEOPATRA regimen. It’s a 3-arm study; T-DXd, T-DXd plus pertuzumab, or the CLEOPATRA regimen of a taxane, pertuzumab plus trastuzumab. So that’ll be very interesting, as well, and we’ll see if T-DXd can beat CLEOPATRA in that trial in the future. But for now, CLEOPATRA regimen. I would use weekly paclitaxel at 80 per m2 in this case because it’s less toxic than docetaxel. And based on a nonrandomized Phase II study by Dang and colleagues, published by the Memorial group a few years ago, it looks to have a similar point estimate on PFS as did the original CLEOPATRA trial with docetaxel. And docetaxel’s much more toxic, a lot more GI toxicity in particular, compared to weekly paclitaxel with pertuzumab plus trastuzumab for metastatic breast cancer.

Case: A woman in her early 70s with de novo ER-positive, HER2-positive breast cancer develops asymptomatic, bilateral brain metastases on TCHP — Chris Prakash, MD

DR LOVE: So we’re leading into another case of a 70-year-old woman who gets TCHP for metastatic disease and then has disease progression that includes asymptomatic bilateral brain mets. So my questions about this case, I’m going to show you the video in a second, is first of all would you give radiation therapy or would you go ahead with systemic treatment, the lung cancer non-small cell paradigm. Do you want to apply that here and hold off and just use systemic? And then the second question is what kind of systemic therapy would you likely be using for this patient? We’ve already had a couple questions in the chat room about the CNS activity of T-DXd, so here’s the case from Dr Prakash.

DR PRAKASH: The brain metastases were asymptomatic. So tucatinib cross the blood brain barrier so that’s what I did and she’s responding.

DR LOVE: So you gave her tucatinib second line instead of T-DM1.

DR PRAKASH: That’s right.

DR LOVE: What happened with the diarrhea and what led you to dose reduce the capecitabine as, for example, as opposed to the tucatinib as well?

DR PRAKASH: Yeah. So tucatinib is the main agent that I was wanting to continue for the brain metastases, so I thought I’ll just dose reduce capecitabine first and get the diarrhea under control.

And my next step would have been to dose reduce tucatinib as well.

DR LOVE: And what’s her current situation?

DR PRAKASH: She’s doing good. Brain metastases responding, asymptomatic. Diarrhea’s pretty much gone.

DR LOVE: Any questions for the faculty?

DR PRAKASH: In choosing therapy for women with metastatic breast cancer, HER2 positive, how do you decide tucatinib triplet versus trastuzumab deruxtecan?

DR LOVE: Any questions about T-DXd?

DR PRAKASH: In the community setting, if we do decide to treat a woman with trastuzumab deruxtecan, how worried should we be about interstitial lung disease, and how often in the real-world setting would you recommend doing pulmonary function test or CT scan imaging for such women.

DR LOVE: So about 30 issues to talk about there. I’ll just let you pick out whichever ones you want to talk about.

DR PEGRAM: Great questions.

DR LOVE: Yeah. Go for it.

DR PEGRAM: So this case, it sounds like, had brain-only new metastatic disease. All the other case discussion prior to that was all the adjuvant setting for her primary HER2-positive breast cancer. So this is really first-line new CNS mets, so just for the record I want to get that straightened out with the audience.

So in this case we don’t know the number of lesions, the size of the lesions. I would still run this case past our neuro-oncology team, which consists of both neurosurgeons and radiation therapists, because oftentimes if the lesions are sizable but still within the number of lesions that can be easily dispatched with the stereotactic radiotherapy approaches, for example, that might still be in the cards as another option for primary treatment.

Now in this case the treating physician decided to go purely with systemic therapy, which leads me to believe that these lesions were probably small and not so numerous, for example, in which case systemic therapy could be — could be entertained.

There is an overall survival benefit in the all-comers population with CNS mets in the HER2CLIMB study. It was mostly in the patients with active brain metastases, and you would consider these active because they’re untreated. So you could make a strong argument to use the tucatinib-based HER2CLIMB regimen with capecitabine/trastuzumab for this case, and there’s Level 1 evidence to support it. Moreover, in that trial there was an interesting metric that was looked at in subset analysis, that is time to — the length of time until the need for local intervention for brain metastases, either with radiation or neurosurgery or both, and that was prolonged also, significantly so, in the patients randomized to tucatinib. So again, for that reason, tucatinib would be a good choice, and it would be evidence based, in my opinion.

Now could you use T-DXd? I suppose you could. There’s just a lot less data, and there’s no randomized data to show superiority, and this is active brain mets, which were excluded from the DESTINY-Breast03 trial. That only included about 20% of patients or so that had stable brain metastases as eligibility for that particular protocol.

So I think I would choose tucatinib over T-DXd in this case, but I couldn’t fault anybody if you had some enthusiasm to consider T-DXd, and you certainly might in the future. If this patient has disease progression in the future then that would be certainly in the cards if the disease progression is in the CNS space.

But you’ll have to ask me the other couple of questions that he related because in all the excitement I’ve forgotten them.

DR LOVE: Well, one of the issues was the diarrhea that the patient had, and the way he approached dose reduction. He was trying to protect the tucatinib so he decreased the capecitabine.

DR PEGRAM: I do the same. I do exactly the same. Yup. I totally agree with that. Oftentimes you can mitigate the diarrhea simply with capecitabine dose modification and reserve tucatinib dose modification for later in case it doesn’t resolve in the face of dose modification of capecitabine. So I agree with that maneuver, and I would have done the same thing initially.

He had a couple of other questions, which I forgot what they were though.

DR LOVE: Yeah. This is like a memory test. I think you actually covered most of them.

DR PEGRAM: Maybe I got them all.

DR LOVE: The other thing — no, the one thing that you didn’t talk about that he brought up was the issue of T-DXd and interstitial lung disease.

DR PEGRAM: Oh yeah. Let’s talk about that.

DR LOVE: Yeah. And we’re going to get into that with the faculty survey, but any comments, particularly in terms of screening. That’s the question everybody asks.

DR PEGRAM: Yes.

DR LOVE: That’s one of the things he asked.

DR PEGRAM: I think it’s really important. His question was should you be concerned about that. The answer is yes, you absolutely must be obsessive about ILD when you’re treating with T-DXd. And in the trials don’t forget that the restaging interval was every 6 weeks, and it was done deliberately to identify ILD changes radiographically even on the thoracic CT imaging done for restaging purposes.

Now will insurance cover q6wk repeat staging off study? In the real world probably not, but I probably wouldn’t wait for 12 weeks on neratinib-treated patients. I’d probably do it at week 9 as a compromise if you will.

He mentioned PFTs. There’s no evidence that pulmonary function testing serially is a biomarker for prediction of ILD versus not. Moreover, you would expect that the forced expiratory volume in the first liter, as well as in forced vital capacity, those would change late in the face of ILD. You wouldn’t wait for that to happen as a screening tool. That would not be successful, nor would PO2, in my view, because of the relationship between oxygen and hemoglobin dissociation curve being a sigmoidal-shaped curve you have to pretty profound hypoxic levels before the oxygen saturation is going to change. So that would not be a sensitive method to look for changes of ILD either.

The only method that might be in a panel of PFTs would be the DLCO, the diffusion capacity of carbon monoxide might be a marker, but that needs to be proven in a clinical trial, and that has yet to occur. We don’t have data yet for that marker in the case of ILD with trastuzumab deruxtecan.

So we’re left with taking a careful review of the pulmonary review of systems. That more than ever is critical for T-DXd-treated patients. And remember, for symptomatic ILD permanent discontinuation of the drug is recommended, along with steroids at 1 mg/kg prednisolone equivalent daily until resolution, then a taper for a month thereafter.

And then for asymptomatic ILD it’s recommended, again, drug cessation, a high-res CT of the thorax as a baseline to follow the ILD changes, early intervention with pulmonary medicine consultation in case they want to do bronchoscopy, especially if there may be infectious diseases in the modern era in the differential diagnosis or if they’re on other drugs that can cause ILD, that could be a real issue, or if they have lymphangitic spread bronchiolar lavage not only for infectious info but also for cytology might be in the cards for that kind of a case. So early contact with pulmonary medicine would be of interest.

And then for the asymptomatic ILDs that are caught only radiographically, that is Grade 1, a drug interruption is still recommended. Steroids are said to be a consideration at 1/2 mg/kg prednisolone equivalent daily until resolution, and then a 1-month taper. But I would argue that I think everybody should probably get steroids unless they have some contraindication to 1/2 mg/kg per day prednisone equivalent because if there’s resolution within the first 28 days you don’t even have to change the dose when you resume the T-DXd. If it takes longer than 28 days then you have to lower the T-DXd by 1 dose level, which if they’re responding well and otherwise tolerating the drug might not be in the patient’s best interest.

So I would argue that steroids are my preference for both Grade 1 and Grade 2 ILD with this drug. And remember, if Grade 1 doesn’t resolve by day 49 then permanent drug cessation is recommended according to the FDA package information/prescribing information.

DR LOVE: Although the flipside of that is if does resolve, and we have this — one of the questions in the survey was can you retreat, and everybody said yes.

DR PEGRAM: For Grade 1, yes. According to the prescribing information, for Grade 2, no.

DR LOVE: Right.

DR PEGRAM: It says permanent cessation is recommended.

DR LOVE: Right, Grade 1.

DR PEGRAM: Yeah.

DR LOVE: Right. So any symptoms that’s it. Right.

DR PEGRAM: For Grade 1, yes.

Case: A woman in her early 30s with ER/PR-positive, HER2-negative breast cancer after neoadjuvant dose-dense doxorubicin and cyclophosphamide → paclitaxel and bilateral mastectomy, now with HER2-positive disease on repeat testing — Zanetta S Lamar, MD

DR LOVE: So your other colleague, Hal Burstein, always accuses me of coming up with these situations that he says never occur. So now I started doing these with real cases so he’ll believe it. Here’s our next case. 31-year-old patient who presented with what appeared to be locally advanced or pretty large with a node-positive tumor that was ER positive, HER2 negative. The patient got neoadjuvant chemotherapy, AC-T, very minimal response, at surgery still had a lot of disease, but at surgery was found to now flipped to HER2 positive, and along the way the germline testing came back, and she’s BRCA2 mutant.

DR PEGRAM: Wow.

DR LOVE: So the question is, and this is for real — and the question is what to do. Here’s Dr Lamar.

DR LAMAR: We completed therapy and she had an MRI which showed a partial response to therapy. She ultimately underwent a bilateral mastectomy with sentinel left node biopsy, and pathology only showed a mild response.

T2N2a disease.

Repeat biomarkers showed that she was still ER and PR-positive but now, she was found to be HER2-positive.

Since I have given her neoadjuvant chemotherapy with dose-dense AC followed by T, what would you do in this situation?

Would you consider adding trastuzumab and pertuzumab? What about paclitaxel?

Pertuzumab and trastuzumab is now available in an injection with hyaluronidase and are you routinely switching patients to injections where pertuzumab and trastuzumab is otherwise indicated?

DR LOVE: So I was thinking on our menu I didn’t even put abemaciclib. I guess theoretically you could consider that. It was ER positive. Anyhow, olaparib, neratinib, all the other things. Any thoughts?

DR PEGRAM: I agree with Dr Burstein. Hopefully these cases never happen. This is a tough one. I don’t know of any data of trastuzumab/pertuzumab and olaparib. I have not seen any Phase IB or Phase II data of that combination, so I simply can’t comment on it. I kind of like the idea, but boy there’s not even any safety data that I’m aware of.

I might be inclined to do one or the other instead of — instead of both, to be honest with you, but which one? I think it’s a balanced discussion with the patient. You have to present the pros and cons of each approach and maybe the patient will help to weigh in. I don’t know any other way to integrate both olaparib and trastuzumab/pertuzumab unless you did it in sequence, in which case there’s a long delay between the 2 regimens. Whichever one you start with first would still cause a long delay, which I have no idea if that would be of any therapeutic efficacy at that point.

So I think of HER2 as a major driver of relapse risk, so I think I would — I’m biased I’m sure in that regard, but I would be concerned about the nature of the HER2-positive disease. I’d probably look at what the definition of HER2 positive in this case is. Is it really truly HER2 gene amplification or was it one of those cases that’s HER2 equivocal, where the pathologist has to repeat the assay and make the call. Those are less certain. I probably wouldn’t be as enthusiastic about HER2-targeted therapy in those cases, and I’d be very content to move on straight to olaparib. So I would need more information about the true definition of HER2 positivity in this case, and then I would present it at tumor board because this is not an easy one. I don’t have the answer based on data.

DR LOVE: How often do you see BRCA mutations, for example, or other HRD issues in HER2-positive disease, and do we know that PARP — I mean I don’t see any reason why they wouldn’t work, but do we know — do we know that they do work?

DR PEGRAM: BRCA mutations do occur in the case of HER2-positive disease, that’s well described in the literature, and those patients should be considered for BRCA mutation targeted therapy as well. There’s no reason to consider that they wouldn’t be responsive to PARP inhibition as well. But how to integrate a PARP inhibitor along with HER2-targeted therapy has not been worked out because the frequency of both HER2 alteration and BRCA mutation is low, it's a very low-frequency event, so there have not been any trials, to my knowledge, testing integration of both together. I just haven’t seen it.

DR LOVE: So Nirmala in the chat room has a case that sounds very challenging, a 50-year-old woman with extensive chest wall disease progressing after all HER2-directed therapy, radiation therapy. However, it’s ER positive also, as well as HER2 positive, PI3-kinase positive, PD-L1 positive. So checkpoint inhibitors, alpelisib, in HER2-positive disease.

DR PEGRAM: Again, the PATINA trial will be the first randomized trial to test that approach of integrating CDK inhibition along with HER2-targeted therapy in metastatic breast cancer that’s ER positive and HER2 positive.

So if she is eligible for a clinical trial that’d be by far my first choice. Off study, again I think it’s a balanced discussion with the patient about the various possible options, and they may have some deciding factor that they focus on between the various options that will pique their interest if you’re lucky. So another tough case.

DR LOVE: So I want to go to another case that in a way is a little bit like the case we talked about earlier, the patient with the 1.5 cm tumor who ended up having 9 positive nodes, really the issue of people who don’t get neoadjuvant therapy, so they don’t have the KATHERINE trial strategy available. And incidentally, we had a question in the chat room about do you use neoadjuvant therapy in HER2-positive tumors less than 2 centimeters.

DR PEGRAM: Usually not, but they have to be clinically node negative, including imaging modalities, in my opinion, in order to meet that truly low risk group like the APT trial or the ATEMPT trial enrolled. Most of those patients were tumors of less than 3 cm that were all clinically node negative. So for very small tumors that are clinically node negative I would say a surgery-first approach is fine. For larger tumors or clinically node-positive disease I would for sure use neoadjuvant therapy first as the preferred modality.

Case: A woman in her mid 40s with triple-negative breast cancer at biopsy declines neoadjuvant therapy and at surgery has a 3.2-cm node-negative, HER2-positive tumor — Alan B Astrow, MD

DR LOVE: So here’s another case. Actually this was a patient that a former fellow with Dr Astrow called him about to get another opinion. This is kind of the flipside. This patient had a 3.2 cm HER2-positive tumor, ER positive also, but the patient wanted to go directly to surgery, that was the patient’s preference, and the patient was found to be node negative. And the question is now you have a 3.2 cm tumor that’s node negative, what kind of adjuvant strategy. I’m curious about whether or not, in a second you can — after you see the case, would you use pertuzumab in this situation? We have the recent follow up data from the adjuvant setting with pertuzumab. And then again, neratinib in this lower risk but ER-positive situation. Here’s Dr Astrow.

What about this case your former fellow called you about?

DR ASTROW: Forty-five years old. Didn’t want neoadjuvant. Wanted to go right to surgery.

The biopsy was triple-negative. But at surgery, turned out to be HER2-positive.

So one question is how often does that happen? And how many HER2-positives are we missing by treating people just based on a core biopsy and going them right to neoadjuvant? How often are we missing HER2-positive?

So at surgery, she ends up having a 3.2 cm cancer. Nodes are negative. So the question was, she wants to give her adjuvant chemo now, and she’s going to give her trastuzumab, but she’s asking me, based upon the APHINITY trial does she need to add pertuzumab as well? That's her question.

DR LOVE: Yeah. I should have mentioned this patient initially refused neoadjuvant therapy. Thinking that she was triple negative she refused it and was found to be HER2 positive at surgery.

DR PEGRAM: Yes.

DR LOVE: But anyhow, getting back to the main question. Now that we know she’s 3.2, node negative, what about pertuzumab? What about neratinib? How would you manage it?

DR PEGRAM: So the adjuvant APHINITY data was recently updated with 8-year follow up, that’s about 100-month follow up now, and in the node-negative subset there is still no benefit for the addition of pertuzumab. So my enthusiasm in this case for pertuzumab is low because the subset analysis — remember that was a huge study so the subset is a big subset. And so I think instead of doing pertuzumab I would probably do the APT regimen of TH or weekly low-dose paclitaxel plus trastuzumab with no pertuzumab, then endocrine therapy with or without neratinib.

You could discuss neratinib in this case because she’s a little bit higher risk based on her T stage compared to a T1N0 case, arguably, so you could talk to her about neratinib. And the good news about neratinib in the extended adjuvant HER2 regimen is that when you do the dose escalation like they did in the CONTROL trial that has a much lower incidence of diarrhea compared to comedication with high-dose loperamide or colestipol or other maneuvers. So you really can get by with neratinib in most cases with dose escalation of the neratinib backbone with only PRN loperamide if needed. In some cases they may not even need it. So that’s what I would do for that ER-positive, 3.2 centimeters —

DR LOVE: So Vish in the chat room — Vish in the chat room has a seemingly similar case, 45-year-old woman, 1.5, hormone receptor negative, HER2 positive, 1 node with micromets. So she wants to know APT? and pertuzumab, and I think you just discussed it. It sounds like the same scenario.

DR PEGRAM: Yeah, micromets has the same prognosis as node-negative disease. And so I would treat micromets the same as I would a node-negative case because their prognosis is the same, therefore their risk of recurrence would be judged to be highly similar if not identical to node-negative disease and therefore any theoretical proportional reduction in risk afforded by the addition of pertuzumab would probably be along the same lines as the intent-to-treat population in APHINITY, which is none for the node-negative subgroup.

Let me just address this 1 issue of the node negative — I’m sorry, the HER2-negative case changing into a HER2-positive case —

DR LOVE: Right.

DR PEGRAM: — because Nehmat Houssami and I published a meta-analysis on this topic years ago on 2,520 cases, and in our pooled meta-analysis we found a HER2 discordance rate between the primary and metastatic disease in the entire population, all 26 studies included, was 5.5%, so it can and does happen.

The primary versus distant metastasis discordant rate was higher though. It was about 11 1/2% when you compare the primary to distant metastasis versus primary versus nodal metastasis discordance rate was only about 4% in this meta-analysis. But the difference between 11 1/2% and 4.1% was statistically significant, so there’s something about distant metastasis. And there was evidence, some evidence, marginal evidence indeed, of directionality. In that series we were more likely to observe HER2-negative cases in the primary converting to HER2 positive at the time of metastasis compared to the reverse, but the p-value on that was a marginal 0.07, so I can’t say that with statistical confidence, but it can and does happen. We observed that in this huge data set, and it was very interesting.

So the bottom line is if you find a HER2-positive component, whenever you find it, you probably are going to err on the side of treating it. So I think they’re doing the right thing by treating this case that was originally alleged to be HER2 negative but now appears to be positive on repeat biopsy. I would err on the side of treatment.

Case: A woman in her early 60s with ER/PR-negative, HER2-positive breast cancer develops paralysis but recovers functioning after paclitaxel/trastuzumab, now with bone metastases responding to T-DXd — Joanna Metzner-Sadurski, MD

DR LOVE: So one final case, a really inspiring case I think, a patient who had persistent back pain and actually presented with hemiplegia, turned out to have metastatic HER2-positive disease, ended up on T-DXd and did amazingly well. Here’s the case.

DR PEGRAM: Wow.

DR METZNER-SADURSKI: Three years ago presented with back pain, did not come to see me, went to ER several times, until she became paralyzed, but never lost bowel or bladder function. But she couldn’t walk.

I treated her actually with paclitaxel/trastuzumab at that time. And the reason I didn’t add pertuzumab is because of the diarrhea risk, and couldn’t imagine her husband carrying her to the bathroom all the time.

She actually recovered beautifully, and I remember 3 months into therapy she stood up for me in the office, and we both cried. With physical therapy she was able to regain function of her limbs, and she’s doing really well.

Progressed in the bone about 3 months ago, and I put her on trastuzumab deruxtecan, and she has done well. Her scans show that she has been improving.

DR LOVE: So she’s having an objective response?

DR METZNER-SADURSKI: There is an objective response by scans on trastuzumab deruxtecan.

DR LOVE: Any tolerability issues?

DR METZNER-SADURSKI: She hasn’t had any problems at all really.

She is very happy on the treatment considering where she started. She’s not a complainer. She’s a very tough lady. She works.

She had to work very hard all her life.

DR LOVE: Any questions about T-DXd?

DR METZNER-SADURSKI: Yes. How do we follow? Is it enough to just follow patients’ symptoms and listen to them or do I have to scan them every 6 weeks? I haven’t with this patient. She has done well. She hasn’t complained of any shortness of breath, so I had no reason. But sometimes you might have a patient who has been a smoker, they have underlying shortness of breath. So what’s shortness of breath from their COPD versus — exacerbation or their shortness of breath related to interstitial lung disease — to interstitial lung disease? How often to follow those patients? Would it be every 6 weeks? Every 3 months is enough? Do I do pulmonary function tests and how often?

DR LOVE: So yeah, just another issue in terms of T-DXd and ILD. What about the patient, the smoker with COPD?

DR PEGRAM: Patients with significant underlying pulmonary disease were actually excluded from the DESTINY series of trials for T-DXd, so you do have to be mindful. For example, anybody with a prior history of ILD treated with steroids was an exclusion criteria in all of the DESTINY-Breast trials, for example. So you have to kind of watch it. It depends on how bad the COPD is.

It's no surprise that this patient has had a robust response given the data from DESTINY-Breast03, which had a PFS hazard ratio of 0.28, which is unprecedented in the history of metastatic breast cancer Phase III trials. I’ve never heard of a hazard ratio that low, and the p-value was something like 10^-22. That’s just unbelievable. And when you have that kind of robust efficacy data, response rates approaching 80%, then you should consider using it for selected cases, even if they have a little bit of pulmonary history background, as long as they’re not oxygen dependent or steroid dependent or dependent on bronchodilators, et cetera, it could be reasonable.

Let me just mention the kinetics of the onset of ILD because I failed to mention that previously. Most of the drug-related ILDs on the DESTINY trials occurred in the first 12 months of treatment, so you should particularly be on the lookout for the first 12 months.

We already talked about the issue of q6wk restaging versus 9 or 12-week restaging. I would try to get away with as often as their insurance is willing to cover it, and you could even do a peer-to-peer contest with the payor and say that for the clinical trials they’re using q6wks, at least early on in those trials, to look specifically for ILD upon the restaging intervals. But I’d probably be satisfied with about 9 weeks off protocol. That would be a fair compromise, I think, to address that question once again.

DR LOVE: So one more question, and I should say too we never got to the faculty survey, but we always like to push people into the slide set to read what’s in there and even to look up some of the papers. One of the papers you’ll see in there relates to our next webinar next week, Mark, is — because we’re doing this webinar next week on myelodysplastic syndromes, and we’ve got a great faculty for that. One of the things we’re going to ask them about is the anti-CD47 antibody magrolimab, which I find totally fascinating. And here I find a paper in your CV looking at magrolimab in solid tumors and breast cancer, specifically HER2. So magrolimab in solid tumors, Mark, is that where we’re heading? And here’s the symposium if you want to hear more about that and venetoclax/HMA in MDS. But what about anti-CD47, Mark?

DR PEGRAM: CD47 is the checkpoint for macrophage phagocytosis. Just like PD-1/PD-L1 is the checkpoint for cytotoxic T-cell lytic activity against tumor targets, CD47 is the checkpoint for macrophage phagocytosis killing mechanisms of tumor targets. The native ligand for CD47 is called SIPRα.

So at Stanford Irv Weissman and Ravi Majeti invented an anti-CD47 antibody, and they humanized the antibody. The first-in-human Phase I studies in solid tumors was completed here at Stanford. There were anecdotal responders even published in JCO a couple of years ago. The first-in-human Phase I study in acute myelogenous leukemia, or refractory leukemia, was done at Oxford in the UK. I was the medical director of that project at the time because there was nobody else at Stanford that didn’t have a conflict of interest with the molecule it seemed. And so I got to the medical director while it was on campus.

So now we just published a paper in the Proceedings of the National Academy showing that trastuzumab and CD47 antibody magrolimab are actually synergistic both in cell-based assays against ADCC-resistant cell lines that were developed in my laboratory, and also in xenograph models of those same ADCC-resistant xenografts, the combination of CD47 antibody plus trastuzumab was synergistic. So now we would like to propose an investigator-initiated trial to our colleagues at Gilead to see if they would entertain a Phase IB study of that combination in metastatic breast cancers or maybe in HER2-positive metastatic solid tumors. It wouldn’t have to be restricted to breast cancers necessarily. We’re going to have to have discussions to decide on final study designs soon, and then go from there.

Thanks for bringing that up.

DR LOVE: So great to work with you again, Mark. Thanks to the audience for attending. Come on back next Thursday and we’ll hear about magrolimab in MDS. Be safe, stay well, have a great Labor Day Weekend. Thanks so much, Mark.

DR PEGRAM: Special thanks to you for inviting me, Neil. It’s always a pleasure to work with you. And a special thanks to our viewers for taking time out of their very busy schedules on weeknight to consider this presentation. I’m very grateful to your participation.

DR LOVE: All right. Have a good one.

DR PEGRAM: Have a good one.