 We’re just about at the end here. What I’m going to ask everybody to do, what we always do with these, is to summarize where you think this space is going. I’ll start with Carey.

 I think one of the themes at ASCO [the American Society of Clinical Oncology annual meeting] this year was, again, de-escalation. We’re learning more and more about which patients need which therapy. And I think we did learn a lot about what we don’t need to do moving forward. I think the KAITLIN data told us that trastuzumab/pertuzumab in the adjuvant setting is here to stay. I think the metastatic space has really been fantastic. Leaving the San Antonio Breast Cancer Symposium this year, I think I was the most enthusiastic about a space that I’ve been in a really long time, thinking about all the new agents that we have for metastatic HER2-positive breast cancer. It makes it more challenging, but that is certainly a challenge we will all take on because it’s going to improve our patients’ outcomes. The challenge now is going to be in the metastatic setting, determining the sequence, determining the right patient for which treatment, and try to do this in the most logical manner, so that we are able to keep patients stable and living well with their breast cancer for as long as they possibly can in the HER2-positive space.

 I’m excited by the fact that it’s clear now that HER2 ADCs [antibody-drug conjugates] are here to stay. We definitely need more than 1. We need more than 2 because what we’d like to have is a tool chest of ADCs with noncross-resistant payloads so that we could use them in sequence or with different epitopes for the targeting antibody backbone. You could even use them in combination, as long as there is not too much overlapping toxicity.

The other thing that excites me is the tucatinib data from our colleague, here, Dr Murthy. It’s just spectacular data. It’s so nice to finally have a pure HER2 antagonist. That was the holy grail all the way back to the early lapatinib days, recognizing that the other HER2 TKIs [tyrosine kinase inhibitors] that are approved have off-target toxicities due to EGFR [epidermal growth factor receptor] kinase inhibition. There are huge opportunities there, especially in early stage disease, particularly in the extended adjuvant or post-neoadjuvant setting, indeed, a la ExteNET. I think there is a huge opportunity there that I would not want to see lost.

I’m very keen on further antibody engineering, in particular bispecifics. There was a very nice HER2/HER3 bispecific antibody presented at this ASCO that looks very interesting. It binds to subdomain 1 on the HER2 extracellular domains, so it doesn’t bind to pertuzumab or the trastuzumab, so a whole new epitope. On the HER3 molecule, it binds to HER3, and it is tethered confirmation so it can’t bind to ligand. You can’t get HER2/HER3 ligand activated activity at all with that molecule, so it’s very interesting. Zymeworks, Inc has a HER2/HER3 bispecific that’s very potent as a naked antibody in heavily pretreated patients in the phase 1 dose escalation. Very nice and high frequency anecdotal responders, so I think that’s really cool.

Finally, antibody fusions, where you can fuse other therapeutic moieties to the Fc [fragment, crystallizable] domain of a HER2 antibody and give it whatever attribute you want, an I-O [immune-oncology] attribute, for instance. Since we’re doing that now at Stanford Cancer Center with an investigator-initiated trial from a company called Bolt Therapeutics, Inc, it’s a new startup, that’s going to be really interesting to look at the fusions in the future, as well.

It was interesting at ASCO, there were 2 discussions. One is when to escalate, and the other was when to de-escalate treatment. Obviously we’re seeing this more and more in the neoadjuvant and adjuvant setting where we don’t want to overtreat patients. We don’t want to undertreat patients, either. What’s interesting for me in the future is the 

 low. We have, so far, an ADC that seems to be active in that space. I can’t wait to get more results. 

 mutations, again, we have a TKI that seems to be doing pretty well. I’m sure others will do pretty well, as well. HER2 becomes more than just the HER2-positive disease. It becomes a lot more inclusive, and that’s what’s exciting.

 Yes, I echo everyone else’s thoughts, but also I would say I think the most exciting parts, for me, since San Antonio Breast Cancer Symposium, has been the approval of all these agents and the expansion of our toolbox for patients in the clinic, which ultimately is going to lead to improved outcomes. It’s been very exciting to be able to think about systemic treatment options now for patients with brain metastases. And I hope that the future would allow us to even think about prevention early on, so to prevent them from having CNS [central nervous system] relapse, whichoftentimes drives their overall prognosis in the setting of metastatic disease. I’m looking forward to more studies and more work to further delve into that.

 Great. Thank all of you in this. It was great, and thanks to our viewing audience for listening to this, and we hope you found this 

 discussion to be useful and informative. Again, thank you very much.

Videos

Impact of Recent Clinical Data on Treatment for HER2+ MBC

 Let’s start with I-O [immune-oncology]. Do you think I-O is going to add anything to HER2-positive disease or not? Who wants to take that one? I see Mark smiling. I’ll give it to you first and then everybody else can go.

 I don’t know the answer but we’ll find out because the CLEOPATRA plus or minus atezolizumab trial is underway, and we’ll get a definitive answer, hopefully. I’m going to stay on the sidelines on this one. I don’t think it’s a guarantee. I bet you that there is a subset of HER2-positive patients who probably do derive a benefit, but I bet there are others who probably don’t, and so in an unselected population who knows? PD-L1, is that going to be the same in the HER2-positive case as it was in triple negative? I don’t know.

I have a patient, we had a phase 2 trial with atezolizumab, HP [trastuzumab, pertuzumab] plus chemotherapy, and this young patient who just had a baby, came in with metastatic disease, bone mostly, so ER [estrogen receptor]-positive, as well, and we put her on the trial. She was on it for a while and, of course, stopped chemotherapy, progressed, restarted chemotherapy, and now she’s, again, off of chemotherapy on atezolizumab/trastuzumab/pertuzumab for—this is her 41st cycle. She stayed pretty much no disease in the breast because she was de novo metastatic, just some bone lesions. We have not put her on endocrine therapy. She’s just cruising along. I’ve started chemotherapy once, twice, on her, and now off chemotherapy. Now, is this the atezolizumab effect? Is she really lucky? I don’t know. The data, so far, are not as impressive as the triple-negative data, which weren’t that impressive to begin with, initially.

 I agree. Before we go on to the very fascinating question of the treatment of triple-positive disease, does anybody have any more comments about I-O and where they think this is going? Didn’t K2 not do too well? Was that the trial I’m thinking of? It was I-O plus something, some regimen second line and beyond in HER2.

 There was a T-DM1 [trastuzumab emtansine]/atezolizumab trial that halted due to futility, actually.

 That’s the one I was thinking of. That was K2.

 We had the PANACEA trial a couple of years ago at the San Antonio Breast Cancer Symposium. Sherene Loi, MBBS, PhD, presented. It was trastuzumab/pembrolizumab and associated with TILs [tumor-infiltrating lymphocytes]?

 I’m curious if Virginia has sequenced the tumor for her patient who’s on cycle 41?

I have not, yet. I’m planning on doing all that around the time that she progresses so I can figure out what to do.

 The sad thing about the anecdotes is I have multiple similar anecdotes back in the single-agent trastuzumab days.

 We can learn something from them if we do biomarkers and genomics, we’ll learn something from all the single anecdotes.

 Going back to the PANACEA trial, that had a very modest response rate, only 15%, but I think of those patients who did have a response, their duration of response was quite prolonged, and this was a heavily pretreated patient population. I’m keeping my fingers crossed for the NRG atezolizumab study, though, but we’ll see.

 I’ve heard that doesn’t have a lot, accrual is poor on that. The scuttlebutt is it is not accruing very well so. We’ve had a hard time getting people on it.

 Yes, I referred a young patient to that trial before. We had it open at a different site, and I did hear back from her. She had a fantastic, near complete response, in a patient who had liver disease. I’m hopeful that immunotherapy is going to have a role, but I think we’ll have to see.

 Let’s go to the next one, what about CDK4/6 [cyclin-dependent kinases 4 and 6 inhibitors]? Any comments on CDK4/6 with anti-HER2? Carey, what do you think?

 We have the PATINA study open, which is the transition from taxane/HP at the time that you’re transitioning to antibody therapy alone, with endocrine therapy for the hormone receptor-positive patients to have a randomization to palbociclib, yes or no. It’s very interesting, like Mark said, we’ll have to sit on the sidelines to see what happens, but I’ve certainly been recommending it for my patients who have triple-positive breast cancer. It’d be wonderful to see that we could push the PFS [progression-free survival] even farther than the 18-month median with the addition of the CDK4/6 inhibitor.

I do worry because I have seen where this has been done without trial work, and I particularly would caution against adding abemaciclib, at this point, until we have safety data, due to the concurrent adverse effect profile of GI [gastrointestinal] toxicity and diarrhea with our abemaciclib compound and the HP.

 We’re doing that, anyway, because we have someone who is triple-positive and you can decide whether to go the HER2 route or the ER route, and we’ve gone the HER2 route. As Mark has told us, there’s enough trastuzumab on board for a couple of months once you stop it. You are doing the combo anyway by putting them on abemaciclib. You’re doing it anyway. It’s interesting where that’s going to go.

I think the monarcHER data are relatively interesting, and I think that approach is great. The issue is going to be that we have all of these options in these triple-positive patient populations, so what do we do? Do we continue triple therapy? Do we stop something? Do we continue something else? I don’t know that we’re ever going to know.

 No one knows. It is all going to be clinical judgment.

CDK4/6 Inhibitors for Triple-Positive Breast Cancer

 You brought up a good question about ILD [interstitial lung disease], and we should talk about it. Then we’ll talk about margetuximab. The question is ILD, has anybody seen it yet? Has anybody seen an ILD? You did, Mark, what happened?

 I just had one on Wednesday. Wednesday was my first one: asymptomatic, picked up on a restaging examination, just in the upper lobes, patchy infiltration, no fever, no white count, no cough, completely asymptomatic, but we had to hold. That’s what the package insert says, you hold even for grade 1, and then only reinstitute if it resolves. Even the package insert says consider steroids in this instance. It says consider. For grade 2, you permanently discontinue the drug and you do give steroids, according to the package insert.

 This is something our audience really has to know, that women with metastatic breast cancer— they’re tired, they’re short of breath, they have haziness on their CTs that we blow off. We can’t do that anymore. We have to be very careful because if you don’t, they can get into trouble. Would anybody treat someone with lung metastases or lymphogenic spread with this drug?

 We have. We had 2 cases, recently, with symptomatic pulmonary metastases. We presented to the tumor board, and it was decided to treat them. I have follow-up on just 1 of them. I don’t know what happened to the second one yet because it’s so recent. The first one had a dramatic response, despite high disease burden in the lung, symptomatic pulmonary metastases. We’re all very concerned, but if you didn’t treat her, she was going to die of respiratory failure from tumor. She has had a nice response. They showed the follow-up this past week at tumor board. Very impressive results, so I wouldn’t say that metastasis alone would be necessarily a contraindication to DS-8201 [trastuzumab deruxtecan].

 I have a 27-year-old with lymphogenic spread, and it has been really hard to get her to chemotherapy. She finally did, she lost her hair. Now, we’re OK with it, but she’s still getting worse. We thought it was COVID-19 [coronavirus disease 2019] because it looks like COVID-19 on her CT in some ways. The issue is that we’re thinking about DS-8201, but we’re going back and forth. It’s lung problems…but what’s left?

 At some point, the risk of mortality from the cancer will become higher than the risk of mortality from ILD and on that day, DS-8201 is a great choice.

 Anyone else have any comments about ILD before we go on to margetuximab?

It’s not just with the DS-8201. I’ve had 2 cases with T-DM1 [trastuzumab emtansine], and both patients were intubated. We have cases with docetaxel. We have cases with everolimus, so we’re not strangers to ILD.

 ILD is listed in the trastuzumab prescribing information, believe it or not.

 This teaches us something. It says the immune system is being affected by our therapies because ILD is an immune reaction in the lung, and we’re doing something, we just don’t know what it is. I’ll bring that up. I’ll throw that out there.

Speaking of immune reactions, let’s talk a little bit about margetuximab. Mark, margetuximab is it deglycosylated or glycosylated? I always forget which it is.

 It has several attributes to distinguish it from trastuzumab. Number 1, it is chimeric, not humanized, but it does have the same Fab fragments as does trastuzumab, same amino acid sequence, at least. It is relatively afucosylated compared to trastuzumab, which is, to your point, but more importantly, it has 5 deliberate point mutations that have been introduced into the Fc[fragment, crystallizable] domain to increase binding to activating Fc gamma receptors on NK [natural killer] cells, specifically CD16A, and they also have a lower interaction with some of the decoy receptors. It should enhance ADCC [antibody-dependent cellular cytotoxicity], at least, theoretically.

 Let me ask you a question. Just from a scientific point, before you go on to the therapy, there are 3 Fc gamma receptors, right? There’s CD16A, CD32A, and CD64A. Have people thought of the interaction of this with those receptors because they’re going to bind to it, too, aren’t they?

 Yes, they’ve all been measured, and as far as the decoy receptors go, there is lower, and certainly no worse finding, as compared to trastuzumab.

 The SOPHIA trial, as I understand it, can someone describe it? Carey, want to take a crack at SOPHIA? Are you familiar with the design?

 SOPHIA was essentially comparing margetuximab with chemotherapy versus trastuzumab and chemotherapy for patients with HER2-positive metastatic breast cancer. Essentially, they found about a 3-month difference in overall survival favoring the margetuximab compound, about 19 months versus 21 months. PFS [progression-free survival] was around 4 months versus around 6 months, and there did appear for there to be preferential activity, translated improvement in PFS even further for the patients who had the CD16A high affinity genotype.

 Actually it what was the low affinity F allele carriers who did better.

 Everybody says that the high affinity was worse. The VV allele, if you are homozygous with a VV, you did worse, but was it really? It was small numbers.

 A little bit. A little, but not statistically significant, I don’t think.

 Was that really true with small numbers with really wide confidence intervals? I’m comfortable saying it was no worse. I don’t think I’m comfortable saying it was worse. I don’t know what other people think about that. That was just my take on this.

 I think it is probably going to be an F allele drug. It’s very easy to measure these polymorphisms, and there’s already a companion diagnostic in development that could complement further clinical use of this drug, especially the FF allele carriers, the lowest affinity CD16A binders. They had the biggest benefit from margetuximab in the randomized SOPHIA trial, so clinicians could easily make use of that information. For the F allele carriers, and especially for the FFs, it could one day, if it can get approved in the first place….

 One day it could replace trastuzumab wherever we use trastuzumab because it probably is a smarter and better drug.

 The trial had a coprimary end point, right? You had to meet PFS and OS [overall survival]. It met PFS but didn’t meet OS, so will the FDA approve it?

 We don’t know. We’ll find out. The date is at the end of the year.

 Oh, is it really? OK. I think it would be a really cool place to use this in the neoadjuvant setting. They had this trial, MCHP [margetuximab, carboplatin, trastuzumab, pertuzumab] against TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab]. Is anybody ever going to do that? I think it’s like a TBCRC [Translational Breast Cancer Research Consortium] trial or something like that. Is anyone going to participate in that? Are you guys going to do it at Stanford Cancer Center, do you think?

 You know, we have not gotten the protocol synopsis for that yet. We are part of the TBCRC. We’ve already committed to another neoadjuvant trial, meanwhile, so we’ll have to have a group meeting and decide. It’s going to be a tough call. I’d love to do it.

SOPHIA: Margetuximab + Chemotherapy for RR HER2+ MBC

 Let’s talk about DS-8201[trastuzumab deruxtecan]. This is the decade of the ADC [antibody-drug conjugate]/ We have all the Trop2 stuff with sacituzumab, we are probably going to add SYD985, biospecific antibodies, there is going to be all sorts of cool stuff coming out. Virginia, what is your take on DS-8201, the phase 2?

Looking at the data, you see a little over 60% response rate in relatively heavily pretreated patients, but when you look at the waterfall plot, I think there were 3 patients that had a little bit of an increase in their tumor volume and everybody else had a decrease in their tumor volume. Pretty impressive data, but it comes at a price. There’s over 10% rate of pneumonitis and several deaths. Definitely not a benign drug, a little more toxic, as far as I’ve seen, than T-DM1 [trastuzumab emtansine] and just people not feeling as well. T-DM1, most people, besides a little bit of neuropathy, barely know that they’re taking something. DS-8201 is a little bit worse than that.

 Comments on DS-8201. Mark, what do you think?

 The nausea we’ve seen within our group tends to be delayed nausea. You have to warn patients to be prepared for that and make sure they have scripts at home to accommodate it. You have to warn them about alopecia, as well. It’s got toxicities very much like a TOPO-1 [topoisomerases type 1] inhibitor chemotherapy drug. It’s not as bad as irinotecan or topotecan, but the same types of toxicities, albeit a little bit lower level. You have to be prepared to co-medicate, dose adjust, et cetera. Fatigue is another feature you have to worry about, as well as cytopenias. It’s real chemotherapy. It just happens to be linked to an antibody.

 I’m very impressed by this. The trials clearly are going to come out. They had the trial and I gave Daichi a real hard time about this because it still is a trial of DS-8201 versus capecitabine/trastuzumab. I said, “Everybody has already had capecitabine/trastuzumab. Why are you doing this?” I understand, now, why they did it because it’s a control arm of HER2CLIMB. I don’t think they knew that when they did it, but it will be very nice comparison. Do you think we can get that done anymore in the United States? I don’t think we can get that done anymore. It is all going to be ex-United States.

 Not with the advent of the HER2CLIMB data.

 We’re just not going to get that trial done, and not only that, but on the DS-8201 side, as well. This is a question everyone wants to know: Do you have a patient in mind for DS-8201 versus tucatinib? Is there a particular person that you would treat one way or the other? Carey, we will start with you and go around the table.

 I do think the status of the CNS [central nervous system] disease matters because, as Virginia said, the evidence that we have in progressive brain metastasis is much higher level with randomized data for HER2CLIMB. If I have a patient who presents with metastatic disease, extracranial, yes or no, but progressive CNS disease, I’m going to reach for HER2CLIMB regimen. In a setting of stable brain metastasis, I think it would be a discussion with the patient, looking at what their prior toxicities have been and their compliance with the oral therapies. I completely agree giving trastuzumab/deruxtecan is not like giving T-DM1. It’s really important for us to warn our patients about that because I have also seen the fatigue and the nausea in my patients who’ve had trastuzumab/deruxtecan. The response rate matters, as well. The 60% response rate in the DESTINY-01 study was quite impressive. All of those patients had received T-DM1, so if I had someone who was near visceral crisis, maybe with liver disease, I might favor the DS-8201 over the HER2CLIMB regimen that had about a 40% response rate. Those would be some of the things that would be going through my mind in making that decision.

 Before we go to someone else, being the brain metastasis expert, what do you think of the data that was presented from Carsten? It was Carsten Denkert, MD, or someone, about the brain metastasis in DESTINY-01.

 For DESTINY-01, I think it’s really interesting. We just need more data. There were 180-some patients in DESTINY-01, of which 24 had brain metastasis, and their progression-free survival was very similar to what we saw on the nonbrain metastasis population. All of the patients in DESTINY-01 were deemed stable at the time of entry, nonprogressive. When you look at the subset analysis for the CNS disease, there were very few CNS events at the site of progressive disease. Of the 48 patients who progressed on the study globally, only 4 had CNS events and there were documented responses in the brain. We just need more data there. We need a study that is dedicated to CNS response rate, intracranial PFS, and such before we know more. I think it has great potential.

 For the nonbrain metastases patients. I’m very impressed by DS-8201 and, albeit, it has some toxicities these are very manageable. We’re all oncologists. We’re used to dealing with all these side effects that are very routine. They all can be mitigated with dose modification or co-medications, so I have no hesitation to give the drug in those patients. Given its extraordinary efficacy and duration of response in DESTINY-01, it’s unbelievable. It’s just very impressive. If it were me, I wouldn’t use DS-8201. That said, I’ll give a balanced discussion of both possibilities with the patients because you know the tucatinib HER2CLIMB regimen is not without toxicity, either. Adverse events include diarrhea, PPE [palmar–plantar erythrodysesthesia], nausea, vomiting, fatigue, hepatotoxicity, stomatitis, headache, anemia, and rash. I mean, all those are mitigating factors for that regimen, as well. A balanced discussion is appropriate but if the patient says, “Well, what would you do, Doctor?” I would take DS-8201.

I agree and the good news with the tucatinib is that it works in progressive brain metastasis, which we don’t have data from any of the other agents. I feel very comfortable giving DS-8201 for the patients that have stable brain metastasis. Now, when they progress, I have a great option to give them.

 Rashmi, I know your answer because you’re the PI [primary investigator] of the trial, but I have to ask you anyway, what would you do?

 I think that the DESTINY-01 data is very striking. That was probably one of the most impressive plots that many of us have seen across oncology trials. Certainly, for our patients without brain metastases, I would give strong consideration for the use of DS-8201. I saw some of the toxicities in patients, as well as the nausea, hair loss, and fatigue. As Mark pointed out, they are manageable and that that wouldn’t make me shy away from use of the drug.

Now, the one toxicity that I think is of concern is the ILD [interstitial lung disease] and pneumonitis and we definitely need to keep caution and consider it carefully in patients who have any kind of underlying pulmonary issues. Outside of that, this presents a really great option for our patients, especially those who have a high systemic burden of disease. For those in whom we need to achieve a quick, rapid response, I would certainly be pushed to use the DS-8201. For patients with brain metastases, my go-to choice would probably be tucatinib, just given the response rates that we’ve seen in the brain and the survival benefits in those patients.

DS-8201 and Tucatinib in HER2+ Metastatic Breast Cancer

 Let’s say you have a woman who gets THP [paclitaxel, trastuzumab, pertuzumab] and she relapses in the brain, plus systemically. She has a new liver metastasis but 1 or 2 brain metastases. Let’s assume for the time being that she has 1 or 2 asymptomatic 1-cm brain metastases because you scanned her brain. How would you treat it? Would you give her tucatinib in that setting or not?

I would because that’s the only data that we have beside addressing the brain with local therapy, giving some radiosurgery, and all that. I don’t think it would be a bad idea, either. But the data that we have on DS-8201 [trastuzumab deruxtecan] is it’s a phase 2 trial and it’s not that many patients, whereas, tucatinib is a large phase 3 randomized trial, with way more sturdy data.

 Agreed. Carey, what do you make of this whole brain business? How many progressive metastases that are asymptomatic would you be comfortable not giving radiotherapy to and just giving tucatinib to? That’s the question everybody who is watching this is going to be asking themselves. A woman comes in the door, she’s asymptomatic, and she also has a couple brain metastases. What do I do with her?

 That would be a decision I’d certainly want to make with my local therapist. I would also want the radiation oncologist to also evaluate the patient, making certain the lesion is not in the pons because a brain stem lesion is going to be very different than a frontal lobe lesion. The location really matters as to whether or not you’re going to lead with systemic therapy in these smaller asymptomatic lesions as opposed to radiosurgery. For lesions that are in the millimeter sizes and not in eloquent areas, I would be very comfortable with the HER2CLIMB regimen as a lead in. Radiosurgery certainly comes with consequences of radiation therapy necrosis, 9, 12 months out from treatment. The good news is that many of our patients are living 2, 3, 4 years after their diagnosis of brain metastasis. We’re being very thoughtful about when we position radiosurgery for when it’s absolutely needed. It just highlights that multi-disciplinary evaluation of the patient, to make certain, as the medical oncologist, I’m not missing an area in the brain that needs immediate local therapy.

 You don’t have a number in mind? Say a woman comes in with three 1-cm lesions, all noneloquent areas. Who knows eloquent?

 I think you’re right. I don’t know that I have an absolute number in my head of number of lesions. I think any more than 4 or 5 and I’m going to start to get nervous. I do think the 1-cm cutoff is a reasonable cutoff. If you follow a 6-mm-or 7- mm lesion 3 months later, I would definitely adhere to at least 12 week, or maybe even earlier, 9 week re-imaging brain MRI, in the setting of an untreated lesion. Hopefully, you would not see doubling during that timeframe and if you did, that would be a time where you’d want to go ahead and initiate local therapy. I think subcentimeter, about 3 or less, is very reasonable for systemic therapy first.

 Rashmi, was there a cutoff in the trial of the size? Erica Hamilton was telling us this story. You were there at that ad board when she said it. I treated an asymptomatic woman with a 4-cm brain metastasis and it went away. Was there really a limit, a size cutoff?

 There wasn’t a size cutoff but with discussion with the medical monitor, if the treating team felt like they wanted to defer local therapy because the patient was asymptomatic and didn’t require it for any urgent reason, they could actually get a pass on the size cutoff. I believe the size cutoff was 2 cm.

 There is no number cutoff, right? You could have as many as you wanted.

 Mark, what would you do? Would you do that, too. Would you just treat anybody?

 If there was a large lesion or multiple large lesions, I would feel uncomfortable relying on systemic treatment. However, with post-clinical follow-up, and frequent re-imaging, I’m not completely opposed to it, but I would do it under the auspices of our neuro-oncology group. We basically have a tumor board equivalent with the neurosurgeon, with radiation therapists, and ourselves, and so it would be discussed, and we could adjudicate it that way with buying in from the patients.

Treatment Choice for Patient Relapsing With Brain Metastases

 Virginia, what are your first- and second-line standards of care right now for metastatic 

 [human epidermal growth hormone receptor 2]–breast cancer?

Assuming somebody has not just finished TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin]?

 Assume it’s 12 months after these or de novo.

The de novo is it would be the CLEOPATRA regimen. A taxane plus HP [trastuzumab, pertuzumab] then second-line would be T-DM1 [trastuzumab emtansine]. We have the T-DM1 versus DS-8201 [fam-trastuzumab deruxtecan-nxki] trial, so I try to put all those patients on that trial. Those are my first 2 lines of therapy in the metastatic setting.

 Basically, it’s THP [paclitaxel, pertuzumab, trastuzumab] followed by T-DM1?

 Is that the consensus? Anybody have any other nuances that you would do here? Probably not. All right, very good. So we’re all fine with that. All of us who have traveled around the world realize that T-DM1 is not available everywhere. That’s the 1 thing we don’t realize in the United States. You go to the Philippines or somewhere else, they can’t get it. It’s really interesting how people are doing their treatment, at least in my experience. I’m curious about what you guys have heard. You’ve heard they use a lot of capecitabine, trastuzumab. There’s a lot of vinorelbine, trastuzumab—the stuff we used to use 10 years ago. Is that your experience outside the United States, Europe, and the wealthier Asian countries?

 gene amplification story can be useful in those jurisdictions. For instance, if you can’t get another 

-targeted agent and those patients are still anthracycline naïve, which many are in this era, then 35% of those patients will be 

 amplified, and those patients do benefit from single-agent anthracycline.

 Meaning not with trastuzumab, just by itself?

 Just by itself. I remember when it was hard to get trastuzumab in the United States, and it still is in some areas of the world such as in sub-Saharan Africa. At any rate, in those jurisdictions or even now, patients who have already had antibody-based and chemotherapy-based treatments in the neoadjuvant or adjuvant setting or first-line metastatic, even if they’re still anthracycline naïve, that’s still a therapeutic opportunity. Of course, they won’t be able to pay for the FISH [fluorescence in situ hybridization] test. That’s the problem with this jurisdiction.

 There are cheap FISH tests if they really want to do them, but that’s another issue. Now we get to the big mystery of our business. Not so mysterious anymore, but third-line therapy. Carey, I’ll put this to you first. What are we really trying to do in third line and beyond? Is it the brain, is it systemic? We all know how many percentages of people relapse in the brain by third line. Is this 50%? Some high number.

 Upward of 50% at that point in time. We will be managing both intracranial and extracranial disease. In our patients who have extracranial disease, we also are hopeful to prevent intracranial recurrence. In that setting the brain metastasis consequences are either on our mind because we’re actively treating disease in the brain or we’re trying to prevent that patient from developing CNS [central nervous system] recurrence.

 We’re really getting to this dilemma. It’s a brain-nonbrain relapse, right? The brain dominant versus the nonbrain dominant. Some interesting stuff has come out of ASCO [American Society of Clinical Oncology Annual Meeting] that’s going to really speak to this. Do you agree that it’s the brain? Is that how you’re thinking of the third line and beyond, as a brain-nonbrain-dominant thing? Mark, what do you think?

 The most impressive brain metastasis data at this ASCO was the data presented by Dr Nancy Lin. In the CNS subset analysis of the HER2CLIMB study, there was a 68% reduction in risk of CNS PFS [progression-free survival] in the tucatinib arm with statistical confidence. Median CNS PFS was 9.9 months in tucatinib versus 4 months in the control. Risk of death overall was reduced by 42% in the tucatinib arm with statistical confidence. Median OS was 18 months versus 12. Overall response rate intracranially was higher in the tucatinib arm. Median duration of response intracranially was higher. Every attribute you look at with any metric of CNS disease activity, tucatinib clearly is superior.

 That’s really dramatic, and the cool thing about the trial is that in the patients with stable brain metastasis, what would you define as stable? They didn’t have all those benefits. That’s the weird thing. It was really only in the progressive patients. In other words, what people were thinking is that the people with stable brain metastasis were dominated by their systemic disease. The people with the progressive brain metastasis were dominated by their CNS disease. Rashmi, can you comment on that? Because we waited for this data. This was our question at San Antonio Breast Cancer Symposium, and you gave it to us finally. You want to comment on that?

 The study enrolled patients, stable as well as progressive or new brain metastases, and about 50% of the study actually had some history of brain metastases. Of that, about 40% actually had what we would consider to be active brain metastases. That’s either new disease that was found on the baseline MRI [magnetic resonance imaging] or progressing disease in a patient who had prior history and treatment of their brain metastases. In looking at the results, it is very important to note that these were not patients who just had a history of brain metastases with stable disease. Of that patient population, 40% had what we would consider to be very high-risk brain disease, new disease, or progressing disease. That also brings up the question with the labeling—the FDA approval and the labeling of tucatinib. Technically, we would be allowed to use this after just 1 line in a metastatic setting. Certainly, we also have the T-DM1, the DS-8201 trials, so a lot of our patients do go on that study. But in a patient who has CNS relapse, it may be important to give some thought for actual use of this tucatinib regimen, especially after the results we saw at ASCO, using it in the second-line setting after the CLEOPATRA regimen, before T-DM1. Although in the HER2CLIMB study, 100% of the patients had received prior T-DM1.

HER2CLIMB: Brain Metastases Data

 Virginia, did you see the stuff from Carsten Denkert? He was the PI [primary investigator], and it was the KATHERINE investigators.

The bottom line was that they didn’t come up with anything that significant. 

 mutation status did not seem to influence the outcome. The benefit from T-DM1 [trastuzumab emtansine] appeared to be independent of all the other biomarkers. We still don’t have a biomarker that tells us whom to use the T-DM1 on and whom not to.

 I like to look at the parts that are trends. They’re not quite there yet. You see the CD8, PD-1, and those little things, and you’re going, “Maybe you if you had more power in their trial we would have seen something.” Do you think there could be an immune signature that could mean something here eventually?

If you look at the PD-L1 that was potentially important in the trastuzumab arm but not in the T-DM1 arm, moving toward the fact that T-DM1 might be doing the work regardless of the immune system, that’s good.

 There was really nothing. Let me look back here, there’s a cytokine gene signature. It looks a little different but not a lot, and the hazard ratio between the 2 aren’t significant because the confidence intervals overlap but they clearly are a little different. Is it enough to make something of or just blow off?

 My take-home was very similar to Virginia’s. Was the T-DM1 superior to the trastuzumab? It seems to overcome many of the differences that were seen in the trastuzumab arm by either CD8 or PD-L1, and there was no differentiation between PIK3CA. It told me to continue choosing T-DM1 in that setting until I know more.

 I’m thinking more of the mechanism of what’s going on behind all this. There is no marker that can tell if T-DM1 or trastuzumab is better. That’s the clear bottom line to this. From a teaching standpoint, what is it going to teach us?

Most of the time we test the primary tumor and give neoadjuvant therapy. Then we find the results—and I guess a lot of institutes look at ER [estrogen receptor]/PR [progesterone receptor] and HER2 at the time of surgery, as well—the more you do it, you get discordant results. You have a patient who is ER negative and 

-positive. You give them neoadjuvant TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin]. They have some residual disease, but now the residual disease is triple negative. What do you do in that setting? It happens more and more; the more we check, the more we get these results.

 I thought someone did an analysis on that a couple of years ago and found they had a worse prognosis. Is that correct? Someone presented it at ASCO [American Society of Clinical Oncology Annual Meeting] or San Antonio Breast Cancer Symposium a number of years ago. I just remember it saying that if you are discordant at surgery, you do worse. Maybe there’s something there. What do you do? What are we going to do? The answer to it, and this is where we’re probably going to see it, is going to be when we start using DS-8201 [fam-trastuzumab deruxtecan-nxki]. DS-8201 has activity in lower HER2 than T-DM1, right? Is that what we all believe, or no?

 It has a bystander effect. It can kill the tumor cells that aren’t even bound by the antibody backbone. They can still be killed.

 Rashmi, what do you think? Is that a reasonable thing? Is this COMPASS or the other 1? This is B60, right? COMPASS is 1 where we use tucatinib. In B60 we are comparing DS-8201 to T-DM1, right? What do you think, Rashmi, will this help us out at all?

 Yes, definitely. There seems to be significant clinical activity of DS-8201 in the low 

-expressing tumors. We actually had several of the trials open at our institution, and we definitely saw clinical benefit in our patients. It will really be interesting to see what type of role that has in the future in terms of bringing it to the earlier-stage settings.

 Is anybody using T-DM1 instead of TH [paclitaxel, trastuzumab] right now, based on the ATEMPT trial that was presented? Didn’t they publish that? I didn’t see it published. I’m assuming it is going to be out sometime. Does anyone use T-DM1 now, or not?

 Our group decided that during the COVID-19 [coronavirus disease 2019] pandemic, we would consider it, especially for elderly patients and patients who have high-risk factors for COVID-19 mortality. It keeps them away from a high-risk area, which is a medical center. By definition, a medical center is high risk for the virus transmission. As a group, we decided that we would at least consider the ATEMPT approach during the pandemic.

 If there weren’t a pandemic, would you have done it?

 No, probably not. Even the authors who presented the paper in San Antonio, in their conclusion did not endorse it.

 Any other comments before we move on to something else?

 It is interesting. I know it was a non—

 I think in select patients, elderly patients, or those who have—

 Obviously, you don’t lose your hair. That’s a biggie with women. They don’t want to lose their hair, and they still want therapy. It’s reasonable. Carey, you were going to say something. I’m sorry.

 It’s interesting that the trial design was clearly noncomparator. It’s hard not to do that by human nature when you’ve got 2 arms in the same study. The results were not that much different, but the discontinuation rate of the T-DM1 was not insubstantial. Even though we think of it as a gentler, kinder regimen, many of the women did transition over to complete their year with trastuzumab. I do agree, if I had a woman who said to me, “I will not take anything for a small node negative, 

-positive breast cancer that would cause me to lose my hair,” I would strongly consider, based on the ATEMPT data, offering her T-DM1 over nothing. That would be a very reasonable option based on the data we have.

 If she’s got tumor heterogeneity, I’m not going to do that.

 That’s 1 thing I will not do it because I understand those are the people who are not going to do well with this. That’s a very good point.

In this COVID-19 era, what do you think about the FeDeriCa data that was presented at San Antonio? I don’t know if it’s been approved, the combo subcutaneous trastuzumab and pertuzumab? Has that been approved?

 No, not yet. There is a capacity-use trial that’s open, and it allows home administration of a fixed-dose combination of pertuzumab, trastuzumab, and recombinant hyaluronidase by a home-visiting nurse. We have a trial open at our center, and that trial was developed mainly for the COVID-19 issue.

 I haven’t, personally. I have to ping my colleagues at the next tumor board. I don’t recall.

 I’m really curious because the preference trials from Europe—the HannaH, PrefHER—where they have half trastuzumab subcutaneous and half regular trastuzumab, the women loved it. Patients loved this. Approximately 90% of the people wanted the subcutaneous instead of the IV [intravenous].

 For the subcutaneous, if somebody’s getting the APT [adjuvant paclitaxel and trastuzumab] regimen during the COVID-19 era, subcutaneous is a faster amount of time in your infusion area. Therefore, it will be a lower risk of virus transmission because that’s also time dependent. Acute trastuzumab is already available, and I would use it in a heartbeat during the COVID-19 era.

 Let’s look ahead to 2027. Tesetaxel gets approved as an oral taxane. Can you imagine treating women with an oral taxane and subcutaneous pertuzumab-trastuzumab as their therapy for 4 months? No hair loss, and it’s equally as good. That’s the future we’re probably looking at, at some point.

Biomarker Data After Neoadjuvant Therapy for HER2+ Breast Cancer

 Let’s go to the post-neoadjuvant setting. Rashmi, does everybody get T-DM1 [trastuzumab emtansine] post-neoadjuvantly right now at The University of Texas MD Anderson Cancer Center who has residual disease after TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] or whatever you give them?

 Anybody with residual disease we offer T-DM1 to. One piece of the striking data from the KATHERINE study that hit home for me is the impact of T-DM1 versus Herceptin on the patients who develop CNS [central nervous system] metastasis, there really wasn’t a huge difference. There was about 5% in both arms who still ended up with CNS relapse. Thinking about the role for a drug such as neratinib, a HER2 tyrosine kinase inhibitor, in the extended adjuvant setting, after T-DM1, even though we don’t have data for that, we don’t have data for the role of neratinib, pertuzumab, or T-DM1, given that patient population that is not receiving much benefit or impact from T-DM1. There should be some thought for use of neratinib. I certainly discuss it with my patients who are extremely motivated, who are younger, and who have very high-risk residual disease. If they have a large amount of residual disease after neoadjuvant therapy, I do talk about both T-DM1 as well as extended therapy with neratinib.

 Before we get into the lower limit of what people would treat with here, let me ask a question. Are you involved in the COMPASS trial now? I know you were involved in HER2CLIMB? Are you involved in COMPASS at all?

 I am involved in COMPASS, so that’s another trial that’s coming up that patients will be able to enroll onto. It is going through the regulatory process.

 Can you explain that design to our viewers because it’s a really cool trial that is going to be very important?

 This is a randomized study that is looking at patients with residual disease after neoadjuvant treatment with a taxane plus dual HER2-targeting with trastuzumab and pertuzumab. It randomizes patients in the postoperative setting to receive either T-DM1 or T-DM1 plus tucatinib. The thought is to further escalate adjuvant therapy for those with residual disease.

 That’s cool. We’re going to trials because it was a 12% relapse rate despite the T-DM1, 11%, 12%, and half of that was brain metastases. The brain metastases, as you pointed out, are going to become the most important thing. Obviously, resistance is important, but clearly, we have a wide-open field to be able to treat that 5% or 6% of people who develop brain metastases as a first sign of relapse. Let me ask Carey. What’s the minimum amount of disease you would treat in the post-neoadjuvant with this therapy?

 I remember right after KATHERINE was presented, I got an email from a colleague, I’d just gone home after the San Antonio Breast Cancer Symposium conference, and said, “I had a patient who just came in after her TCHP. She has 8 mm residual disease, lymph node negative, would you give T-DM1?” I went back to the paper in 

, and if you look at the forest plots, pretty much every stage of residual disease benefited from the T-DM1 over trastuzumab. I really haven’t had a lower limit cutoff. I’d be curious to hear if others have taken a different approach, but I’ve routinely recommended T-DM1 and I’m happy to have the COMPASS study on the horizon with the addition of the tyrosine kinase inhibitor to see if that might help, as well.

The other thing I think is perplexing, and I see this a lot in my practice taking care of patients with brain metastasis, is I also see patients with pathologic complete response [path CR] recur in the brain as the only site of disease. It’s something for us to think about for our patients who have a path CR. It would be nice to have some predictor, even in those patients we relax our shoulders about, to know if they are at higher risk for CNS recurrence.

I think as much as we congratulate the path CR, I am struck by the number of women I see in my CNS metastasis clinic who had a path CR to HER2-directed therapy. I just want us to think about that further.

 I agree. Mark, do you think the prevention of brain metastases in this setting is going to be an advance if we can do it?

 It would be huge, there’s no doubt about it. I do like the idea of integrating tucatinib into the extended adjuvant setting because as a single agent, and certainly in combination with endocrine therapy, it would be very manageable in terms of safety signals. In addition to combining it with T-DM1, one wonders, could you do it following T-DM1 and perhaps even as a primary end point of onset to brain metastasis? I think that would be a very clever strategy moving forward.

 The problem is that the power of this is going to be huge. What is COMPASS going to be, a couple thousand patients? We are getting to the point now where we’re above 90%, and to get each little increment above that is going to take thousands of people. Like the cardiologists, I don’t know what we’re going to do. I don’t know where we are going to find all these people. It’s going to be really tough.

HER2+ Early Stage Breast Cancer With Residual Invasive Disease

 Before we get into the post-neoadjuvant setting, we’ll talk about the other big thing in this: what are we doing about the KAITLIN study? Does somebody want to talk about KAITLIN and those results? Mark, do you have that?

 Yes, I’ve got it. It was a substitution of T-DM1 [trastuzumab emtansine] for paclitaxel and 2 antibodies; it was T-DM1 plus pertuzumab. The trial did not meet its primary end point, so chemotherapy HP [trastuzumab, pertuzumab] remains the standard of care. Moreover, there were more dropouts in the T-DM1 arm, although the quality of life was a little bit better during the T-DM1 sequence in the trial. The bottom line is, it’s a negative study. It would be a consideration only for selected patients who can’t tolerate paclitaxel and 2 antibodies. For the vast majority of patients, it’s an interesting trial but didn’t meet its primary end point. It’s not superior, but it looks to be highly similar to the 2-antibody chemotherapy control. There would be no barrier to using it, in terms of efficacy, but really no advantage.

 They made a big deal about how it was not noninferior, so they’re trying to tell you don’t use it. On the other hand, you’re going to have a woman who comes in who doesn’t want to lose her hair. What about then? That’s probably the only time I’d think about using this regimen. Virginia, what do you think?

 You’re still using AC [doxorubicin, cyclophosphamide]….

 I forgot, it’s true, you’re going to lose your hair. That doesn’t count.

 This is not the only trial that has shown similar results with T-DM1 in the neoadjuvant setting compared to a taxane-based regimen. Then you look at the cost, and you realize it’s probably not worth it.

 Especially now, we have biosimilars, so that’s a good point. Can anyone explain why that would be? I think it’s a really interesting scientific question. Shouldn’t it be better? It works as salvage therapy in the metastatic setting, but it’s not better in the first-line or frontline setting.

 That was shown last year by multiple trials that T-DM1 cannot accommodate HER2 heterogeneity. In the Dana-Farber Cancer Institute study, about 10% of their patients were heterogeneous and they had a lower PCR [pathologic complete response] rate to T-DM1. The same was true in the neoadjuvant trial, also about the same frequency. About 10% or so didn’t respond from the get-go during the T-DM1 neoadjuvant treatment. I-SPY 2 also showed similar results that T-DM1, as a single agent since it lacks a bystander effect, T-DM1 is not soluble, it can’t diffuse into adjacent tumor cells after dead cells are lysed. That’s a big handicap of T-DM1.

 That point is an excellent one. The fact that you need functional HER2 expression to have it, and if you don’t, or there’s not enough amplification, it’s not going to work. That’s an important clinical pearl. As you know from San Antonio Breast Cancer Symposium, the whole ATEMPT trial, comparing T-DM1 to TH [paclitaxel, trastuzumab], you’re ready to reach for the T-DM1, but the woman has heterogeneous disease. I never would have thought of that. Does anyone want to comment on that?

 The other issue is a dose. T-DM1 maintains all of the attributes of trastuzumab, the naked antibody, insofar as it has signal perturbation, in terms of HER2/HER3 association, it engages activating Fc gamma receptors in NK [natural killer] cells. If any of those are also important to the mechanism of trastuzumab with chemotherapy, you probably lose some of that with T-DM1 because of the much lower dose, almost half, and the half-life is far shorter with T-DM1 compared to free antibody. That’s another mechanism of potential failure.

 The dose is 3.6mg per kg? And every 3 weeks?

 The half-life is less than a week. The trastuzumab half-life is 3 to 4 weeks.

 I never thought of that, either. These are very good points.

 When you look at the presentation that they did, it seems that they presented data at ESMO Breast, about the patients who, post-neoadjuvantly, were HER2 negative, and these patients did get benefit from T-DM1. How is that explained?

 Let’s answer it. I don’t know the answer. Mark, what do you think?

 I don’t think that in the case of T-DM1 the question of HER2-low has been critically addressed. There’s been a small study but in that study, HER2-low included 1-plus and 2-plus. The current IHC [immunohistochemistry] antibodies that are commercially available for HER2 testing were not designed to discriminate the nuances below 3-plus. I can envision, especially in the case of micrometastasis, there may be some cells that have just enough HER2. All you need to get is internalization and then DM1 can nicely kill the tumor cells. You have to have enough, though, and these heterogeneous cases seem to be admixtures of truly HER2 negative cells mixed with HER2 positives. Those are the ones in which T-DM1 seems to fail, in the neoadjuvant setting.

KAITLIN: T-DM1/Pertuzumab After Anthracycline-Based Adjuvant Therapy

 Before we get into KATHERINE in the postneoadjuvant setting, let’s talk about one of the big adjuvant things that happened at ASCO [American Society of Clinical Oncology Annual Meeting] this year, and that’s TRAIN-2. Anyone want to take TRAIN-2? Who is the TRAIN-2 person today? Virginia, what do you think of TRAIN-2?

 I don’t remember the last time I used an anthracycline for 

 [human epidermal growth factor receptor 2]–positive disease. This is our way of using it in the metastatic setting when we have to, after we’ve given all the other agents. When you look at all the data, and you can talk about the BCIRG 006 study and how it was not powered to look at the 2 arms and the AC [doxorubicin, cyclophosphamide] arm was numerically superior and all that, but when you look at the neoadjuvant pertuzumab studies, it is pretty clear that the TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] arm has very good benefit. That’s why I’ve been doing that for a long time.

 Does someone familiar with the design want to talk about that? Just so we can tell our viewers what it looked like? Carey?

TRAIN-2 was a randomized study that enrolled patients with HER2-positive breast cancer, stage II and III. One group got 3 cycles of FEC [fluorouracil, epirubicin, cyclophosphamide] followed by 6 cycles of TCHP. The other group got 9 cycles of TCHP, and then they completed 

-directed therapy for the full year. About two-thirds of the patients were node positive, and path CR [pathologic complete response] was no different between the 2 groups, about 67% and 68%. There was no difference in the invasive disease-free survival or overall survival with the addition or subtraction of the anthracycline. They did report that febrile neutropenia was 10% in the anthracycline arm and 1% in the nonanthracycline arm. So pretty compelling data with path CR as well as longer-term outcomes.

The one question that comes to my mind is, would anybody start giving 9 cycles of TCHP? In my own practice, by the time we get to the sixth cycle of TCHP, most of my patients are pretty ready to move away from the chemotherapy portion. It answers a fantastic question, in terms of the anthracycline benefit, but it was a little different from how I traditionally give TCHP in my practice.

 In this trial it is very important to point out that the key was paclitaxel, not docetaxel.

 That’s why they get so many cycles. You’re right, nobody can tolerate 9 cycles of TCHP with docetaxel.

 They were doing 9 cycles of the weekly T, paclitaxel, of THP [paclitaxel, trastuzumab, pertuzumab]. Is that correct?

 Let me talk to Rashmi at MD Anderson. You are like the dream of anthracyclines. How are you handling this?

Since pertuzumab was approved back in 2012, the use of anthracyclines in the neoadjuvant setting for 

-positive breast cancer has probably declined a bit. The time I use anthracyclines generally tends to be in the case of tumor heterogeneity. If we have a focus that was, for example, triple negative, plus the focus that was 

-positive that we know about, then sometimes in that type of patient I might opt to use the AC followed by THP regimen. But most predominantly, I have been using TCHP, and I think the TRAIN data certainly support continued use of dual 

 targeting, as opposed to use of anthracyclines.

 I stand corrected. It was weekly paclitaxel at 80 mg/m2 in TRAIN.

 For how long? For what, for 9 months or 9 cycles?

No, in 9 doses of the paclitaxel. The carboplatin was given 6 mg every 3 weeks.

 That’s reasonable. Again, I guess the issue is we’re all settling on the fact that—a reasonable thing would be if you think there’s a lot of tumor heterogeneity, do the AC followed by THP. That is probably the last place I would go with it, but short of that anthracyclines and this disease may be forever on the way out. Remember the topoisomerase II amplification 10 years ago, Mark? We used to go around: That is anthracycline; you’re topoisomerase II amplified. How far we’ve come.

TRAIN-2: Anthracyclines in HER2+ Breast Cancer

 Let’s talk about APHINITY. Rashmi, what do you think of APHINITY and the stuff that Martine Piccart presented at San Antonio Breast Cancer Symposium 6 months ago?

 That was a really nice update on the previously presented study, and my biggest takeaway is that the benefit of pertuzumab was seen more in the node-positive patients. Currently, I’m strongly advocating for my node-positive patients to continue pertuzumab for a duration of 1 year. In the node-negative patients, it opens up a real question as to whether we should advocate for them to get HP [trastuzumab, pertuzumab] maintenance or just H [trastuzumab] alone. That becomes a point of discussion with the patient. But I strongly encourage my node-positive patients to continue it for a whole year.

The other interesting piece that came up in APHINITY is that in the updated analysis, there’s really no difference seen between the hormone receptor–positive and hormone receptor–negative.

, there is absolutely no difference for benefit of pertuzumab in APHINITY based on steroid receptor status. The confidence limits are completely overlapping. The point estimates are very similar, so that was incorrect.

 Some random stuff that has been presented every so often shows that somehow, if you’re a specific luminal subtype, you get more benefit from pertuzumab. That was like wandering around in neoadjuvant circles for a while.

 It hasn’t been shown in the APHINITY data.

Mark D. Pegram, MD, Stanford Cancer Center

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