Expanding Treatment Options for HER2+ Breast Cancer - Episode 11

SOPHIA: Margetuximab + Chemotherapy for RR HER2+ MBC

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Adam Brufsky, MD, PhD: 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?

Mark D. Pegram, MD: 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.

Adam Brufsky, MD, PhD: 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?

Mark D. Pegram, MD: 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].

Adam Brufsky, MD, PhD: 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?

Mark D. Pegram, MD: 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.

Adam Brufsky, MD, PhD: Anyone else have any comments about ILD before we go on to margetuximab?

Virginia Kaklamani, MD: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.

Mark D. Pegram, MD: ILD is listed in the trastuzumab prescribing information, believe it or not.

Adam Brufsky, MD, PhD: 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.

Mark D. Pegram, MD: 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.

Adam Brufsky, MD, PhD: 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?

Mark D. Pegram, MD: 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.

Adam Brufsky, MD, PhD: 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?

Carey K. Anders, MD: 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.

Mark D. Pegram, MD: Actually it what was the low affinity F allele carriers who did better.

Carey K. Anders, MD: I will defer to Mark on that.

Adam Brufsky, MD, PhD: 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.

Mark D. Pegram, MD: A little bit. A little, but not statistically significant, I don’t think.

Adam Brufsky, MD, PhD: Right.

Carey K. Anders, MD: Maybe a month.

Adam Brufsky, MD, PhD: 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.

Mark D. Pegram, MD: 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….

Adam Brufsky, MD, PhD: Well, exactly, that was my point.

Mark D. Pegram, MD: One day it could replace trastuzumab wherever we use trastuzumab because it probably is a smarter and better drug.

Adam Brufsky, MD, PhD: 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?

Mark D. Pegram, MD: We don’t know. We’ll find out. The date is at the end of the year.

Adam Brufsky, MD, PhD: 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?

Mark D. Pegram, MD: 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.

Transcript Edited for Clarity