Dr. Virginia Kaklamani:
Hello and welcome to The ASCO Post Roundtable Series on Next-Generation Therapies for Meta-static Hormone Receptor–Positive Breast Cancer. I'm Dr. Virginia Kaklamani from UT Health in San Antonio. And joining me today are two of my colleagues, Dr. William Gradishar and Dr. Komal Jha-veri. Bill, would you like to introduce yourself?
Dr. William Gradishar:
Sure. Bill Gradishar, Professor of Medicine at the Lurie Cancer Center of Northwestern. Happy to be here with both of you.
Dr. Kaklamani:
And Komal?
Dr. Komal Jhaveri:
Hi, I am Komal Jhaveri, breast medical oncologist from Memorial Sloan Kettering Cancer Center in New York, and really delighted to be here with both of you.
Dr. Kaklamani:
So, today we'll be discussing the treatment and management of metastatic breast cancer with three patient cases. Our final installment will focus on a patient with endocrine-resistant metastat-ic breast cancer. So, let's move on to our case.
This is A.L, she is 66 years old. She's postmenopausal, diagnosed with right ER 30%, PR 20% HER2 2+ breast cancer. She undergoes partial mastectomy showing a 2.1-cm tumor, one positive lymph node. She has a genomic score that is 35, and because of that, she receives adjuvant chemotherapy with docetaxel cyclophosphamide followed by radiation. She started on an aromatase inhibitor and abemaciclib, but while on abemaciclib she presents with shortness of breath. She has imaging done showing a pleural effusion and lung nodules. The lung biopsy shows metastatic breast cancer, ER 20% PR 0%, and HER2 1+. So, the question here is would we be starting out by doing any other testing and what kind of therapy would we be recommending? Bill, what would you do next?
Dr. Gradishar:
Well, I just want to make a couple comments just on the characteristics of the patient, because this is one that wasn't strongly ER positive to begin with. And then even when she's progressing, the expression of ER is diminishing with time. So, this is probably a patient that was not likely or as likely to benefit from endocrine strategies. I would do NGS testing. Again, that may be informative for some interventions down the line. She is seemingly symptomatic at this point too, which is go-ing to influence what I do as well, because again, you'd have to see her, but this notion that she's short of breath and that makes me a little bit more worried about what's going on. So, I would do NGS testing, see what that tells us. It may not change my first maneuver, but again, I would want to know that information.
Dr. Kaklamani:
And Komal, what would you do as far as your first maneuver? The NGS testing really doesn't come up with anything very specific.
Dr. Jhaveri:
Yeah, no, I think this is the kind of patient that you really worry about, endocrine-based regimens, as Bill pointed out for the right reasons. The ER is low, the disease burden is high, the Oncotype was high despite adequate therapy that we think could have made a difference. It did not, and she's progressing and very symptomatic from it. These are the kind of patients that we think are this primary endocrine-resistant tumors, right? When we define them, where the tumors are really growing within the first 2 years of their adjuvant endocrine therapy or we can also look at them in the metastatic setting and say they are really growing or progressing within the first 6 months of their metastatic therapy.
And this is when we're thinking about chemotherapy and trying to get a faster response in a patient with symptomatic disease who's really not doing well with endocrine-based manipulations, and the ER is low as well. That goes with that finding. So, I would be thinking about initiating a systemic reg-imen, an intravenous regimen perhaps, to be able to control this disease better at this point.
Dr. Kaklamani:
So, you mentioned intravenous regimen. We now have data from DESTINY-Breast06, suggesting that maybe giving an antibody-drug conjugate in that first-line setting may be beneficial for these pa-tients. So, what would you do based on that data?
Dr. Jhaveri:
Yeah, no, so I think my first distinction when I think about DESTINY-Breast06, obviously we don't have approval yet from that data, but impressive data and an option hopefully available for patients down the line very soon. We have data from DESTINY-Breast04, which did allow patients to get trastuzumab deruxtecan if they've had one or two lines of systemic chemotherapy already. And so there's no wrong or right as to what, but I think it's the patient population that we think about.
So, if I am worried about a disease where I think I want to think about an intravenous-based regi-men for symptomatic disease, for disease burden or rapidly growing disease, if I'm thinking intrave-nous, I'd be happy when we have the DESTINY-Breast06 data approved to apply that data, because that's a systemic IV-based regimen that has this infusional commitment that the patient has to make, does have this alopecia, does have an adverse event of special interest we also want to keep in mind.
And in that study in DESTINY-Breast06, 9% of the patients were included when they had progressed on their adjuvant CDK4/6 inhibitor as well, which is what fits here as well. In my mind... So, once that becomes approved and available, I would be tempted. I have, to be honest, I tried to do trastuzumab deruxtecan in scenarios like this where somebody had progression rapidly and has very symptomatic disease within the first 6 months of their metastatic setting, where if I did not have a trial with T-DXd open, I've tried to obtain and sometimes gotten it. But yes, our official label cur-rently is based on the DESTINY-Breast04 data, which allows you to give you one line of therapy. And I would apply that for somebody who does not have exploding disease and would be okay with capecitabine at that point. Here, I could have gone either way. I would've done weekly paclitaxel as a choice, and because I'm doing weekly paclitaxel as a choice, I think T-DXd would be equally appropriate, should that be available for our patients.
Dr. Kaklamani:
Bill, what would you do in this case?
Dr. Gradishar:
No, I agree entirely with what Komal said. Again, I may try to get T-DXd for this patient. I think we all sort of feel that the data is pretty compelling, even though we don't have an approval. If we couldn't sneak it by and get it, then I would give chemotherapy of course, and the chemotherapy agent may be decided upon based on what the patient looks like. So, I think if it's more of a trajec-tory not going in the right direction fairly rapidly, I'd certainly use IV chemotherapy. If not, I'd feel comfortable with capecitabine.
Dr. Kaklamani:
And I'm somewhere there as well. This patient concerns me a tiny little bit because of her lung comorbidity in a sense. Obviously this is disease mediated, but we know that there's a rate of ILD with T-DXd. This is somebody that we need to get some sort of cytotoxic therapy in. So, I'd proba-bly be more likely to give my first-line chemotherapy either with capecitabine or weekly paclitax-el. I think that's a great option, or nab-paclitaxel. Bill, I know that you generated that data a while back showing some good efficacy there as well.
So, let's say, so she was started on capecitabine, she had a response lasting for 8 months, but at this time she now has disease progression, new liver lesion progression in her lungs. What would we do next? We have two antibody drug conjugates approved. Bill?
Dr. Gradishar:
You're right, we have two: sacituzumab govitecan and trastuzumab deruxtecan. We have data from clinical trials that have looked at the use of these drugs in so-called “endocrine-refractory” pa-tients. The sacituzumab govitecan trial, the TROPiCS-02 study was a little bit more heavily pretreat-ed patients than this one. And for all the points that we made earlier about trastuzumab deruxtec-an, I would still probably be more inclined to use that first in this patient just because I perhaps have a bias that it's a more effective drug. So, that's how I would proceed with this patient.
Dr. Kaklamani:
And Komal, how would you sequence these agents? This has become a hot topic in breast medical oncology, but how do you feel about sequencing these ADCs?
Dr. Jhaveri:
Yeah, no, I think the sequencing question is a little more challenging than not, because if we think about systemic chemotherapies, it's not like we think about using docetaxel after paclitaxel in some ways, right? We don't necessarily do that. We just change the mechanisms of action of these chemotherapy drugs without knowing what the resistance mechanisms were. But with antibody-drug conjugates, their potency has been very good.
There's just some data that we have at the San Antonio meeting that we learned about was a fan-tastic session on antibody-drug conjugate sequencing, really a poster discussion session, which was very helpful in some ways—just some small data sets from single institutions from real-world data—where we learned that regardless of whichever antibody-drug conjugate we used, the PFS that we achieved on the first antibody-drug conjugate was definitely longer than the second. Having said that, there were some patients who had a very short PFS on their first antibody-drug conjugate, but a longer on the second one. We had a scenario where there was a known mechanism of resistance to the payload, and yet the patient stayed on that ADC with that same payload for a very, very long time.
So, this really highlights the issue that we have a lot more work to do here. We have two ongoing studies right now that might potentially help a little bit. One is the TRADE-DXd trial, which is going to sequence trastuzumab deruxtecan and datopotamab deruxtecan, another TROP2 ADC that is cur-rently in late-phase development with similar payloads, the deruxtecan payloads. So, will it matter if we use one before the other? That's the answer that the TRADE-DXd trial hopefully can enlighten in a couple of years.
And then we have the registry that we're trying to do from real world, where we're trying to see when we use trastuzumab deruxtecan and sacituzumab govitecan in either sequence, does that make a difference? I think we need a little bit more to answer that definitively.
Currently, what do I do? What do I feel like doing that day for that patient, given that patient in front of me? I usually try and use what I call as a sandwich chemotherapy for no good reason that I can explain, but I give them eribulin. So, if I have a patient who had T-DXd and had progression in-stead of jumping onto sacituzumab, which I think I could, and I don't know if it's any better if I give eribulin in between, but eribulin has a different mechanism of action and I try and justify that first and then bring in hopefully sacituzumab after. I don't think I can tell you with that approach what I have been able to see in my cohort of patients, but that's what I currently do.
Dr. Kaklamani:
And obviously the toxicities are a little different between sacituzumab and T-DXd. Bill, how do you feel about these toxicities and does that make you change what agent you use first or second?
Dr. Gradishar:
Well, I think I would still choose the one that I view as most effective. This particular patient, just to make the point that she's got lung disease, and we often hear these questions when we do dis-cussions with practitioners. Is there some concern about using T-DXd in people who have lung dis-ease? Well, the answer is no. You want the most effective drug that's going to eradicate metastatic breast cancer. Now, if the patient has an ILD or a pneumonitis for some other reason, yeah that would be a reason they have some concern and perhaps some reservations about using it. So, ILD is the big one, obviously with sacituzumab govitecan above and beyond the hematologic toxicity of more of the GI symptoms that we don't necessarily see with trastuzumab deruxtecan. So, again, it's a trade-off. You have to take into account what the patient's baseline functional status and symp-tomatology is, but I think you're still driven by what you think is the most effective drug for that patient at that time.
Dr. Jhaveri:
If all the biopsies were consistently IHC 0, then there would be making a case for utilizing saci-tuzumab and even though the TROPiCS-02 data set is for heavily pretreated patients, we have NCCN guideline endorsement to try and utilize even sacituzumab slightly early on in the treatment course for a patient if they are not candidates for T-DXd and who are not candidates for T-DXd. I think the two scenarios that are really important to think about are IHC 0.
So, consistently primary or metastatic, every biopsy we have is IHC0, we don't have HER2-low to offer T-DXd or baseline ILD pneumonitis, which would not make them a candidate for T-DXd. That's when I think about sacituzumab first. This particular patient with lung metastasis, at least in the pooled risk analysis for ILD, lung metastasis, did not shout out to be a risk factor. So, I feel like I will do my PFTs just to be extra cautious. I would do a scan and make sure there are no ongoing ground glass opacities that might muddy my interpretation—and if that's not the case, I would go ahead and give her T-DXd.
Dr. Kaklamani:
And as Komal you mentioned, we have Dato-DXd coming up next as well and interestingly, this agent has very little cytopenias. It may have some stomatitis, it may have a little bit of ILD. It doesn't seem that the ILD is as much as what we see with T-DXd, but definitely an exciting agent to look forward to in the future.
So, as our clinical takeaways in this endocrine-resistant tumor, I think cytotoxic therapy can be giv-en in the first-line setting. Again, we're not going to see a lot of these cases. Most of these endo-crine-positive tumors will have enough ER that we can use endocrine therapy. But for some of these endocrine-resistant tumors, we're probably going to be relying on cytotoxic therapy. Novel antibody-drug conjugates such as sacituzumab govitecan and trastuzumab deruxtecan really have shown improved outcomes compared to chemotherapy. And of course, we have the side effect profiles that are going to include diarrhea, interstitial lung disease, neutropenia, depending on which ADC we use, that we need to be looking out for. So, this brings us to the end of this case. Please see other segments for further discussion about the latest research in metastatic breast can-cer or visit ascopost.com.
