Dr. Kevin Kalinsky:
Welcome to The ASCO Post Roundtable Series on Targeting Endocrine Resistance in Hormone Receptor–Positive/HER2-Negative Metastatic Breast Cancer. I'm Dr. Kevin Kalinsky, breast medical oncologist, Professor of Medicine at Winship Cancer Institute in Atlanta, Georgia. Joining me today are two of my colleagues, Dr. Bhave and Dr. O'Regan. Dr. Bhave, would you mind introducing yourself?
Dr. Manali Bhave:
Sure. Hello. Hi, my name is Dr. Manali Bhave. I'm a breast medical oncologist at Emory University in Atlanta and Medical Director of the Phase I Unit.
Dr. Kalinsky:
Dr. O'Regan?
Dr. Ruth O'Regan:
Hi, Kevin. Yeah, Ruth O'Regan. I'm Professor of Medicine, breast oncologist at the University of Rochester, New York.
Dr. Kalinsky:
Great, thank you both. Today, we'll be discussing the role of endocrine resistance in hormone receptor–positive/HER2-negative breast cancer with three patient case studies.
Our final installment will focus on endocrine-resistant hormone receptor–positive/HER2-negative breast cancer with a PIK3CA mutation. So case 3, Mary is a 61-year-old postmenopausal female with a history of mild hypertension, that is well controlled with medication. She's initially stage IB, ER/PR-positive, HER2 1+. For this case, we will assume FISH-negative. So she's "HER2-low." Grade 3 invasive ductal carcinoma. She was treated with lumpectomy, radiotherapy, followed by a nonsteroidal aromatase inhibitor for 4 ½ years, and her tumor progressed while on adjuvant aromatase inhibition. Further imaging documents multiple liver lesions and one 3.4-cm liver lesion. The liver lesion is biopsied, invasive ductal carcinoma, ER/PR 50%, and HER2-low. Again, this 1+ FISH negative situation.
So she receives fulvestrant and ribociclib, but is on it for just a bit of time. She's on it for only 4 months. She experiences new shortness of breath due to lymphangitic spread. She does have ctDNA. It reveals both a PIK3CA H1074R mutation, as well as an ESR1 D538G mutation. So what would we think about next? Palbociclib plus fulvestrant? Chemotherapy? Capivasertib plus fulvestrant? Elacestrant? Switching the CDK4/6 inhibitor and giving an aromatase inhibitor? Trastuzumab deruxtecan? Or sacituzumab govitecan?
Dr. Bhave, I'll start with you. Again, this is a circumstance where the patient does have mutations that can predict benefit from targeted therapies, but the patient is symptomatic and was on the prior fulvestrant/ribociclib for a very short period of time, just 4 months. So what would you think about next for this patient?
Dr. Bhave:
Yeah, this is, unfortunately, a very challenging case. The patient developed metastatic recurrence while on adjuvant AI and then, had a very limited response to first-line CDK4/6 inhibitor and fulvestrant of 4 months. And really, this is the patient where we worry about endocrine resistance, and I think, given her symptomatic disease, the pace of her disease, lymphangitic carcinomatosis, this is a case where I would actually favor transitioning to chemotherapy. The chemotherapy that I typically recommend is capecitabine. It's a well-tolerated oral chemotherapy. There's no hair loss associated with it, and very effective in metastatic breast cancer. I also think the options of the ADCs listed are not unreasonable, although the approvals require use of a chemotherapy in the metastatic setting prior to considering an ADC. But certainly, the ADCs would be in her future as well.
Dr. Kalinsky:
Dr. O'Regan?
Dr. O'Regan:
I completely agree with Manali. I think I would lean towards chemotherapy for this patient, and I typically use capecitabine. And then, we do have the option of both of the ADCs later on. I guess one of the questions would be, and again, I don't think this is going to happen with her, but if she did great with the capecitabine, would you transition her back to endocrine therapy at some point, with either alpelisib or capivasertib? But I think that wouldn't be unreasonable to think about. Elacestrant, I don't think, is a good option, because it's just another endocrine therapy. And she's got endocrine-resistant disease.
And likewise, I think switching the CDK4/6 inhibitor with an AI also would probably not be the most effective option. Of course, this is a patient who would've been eligible for the INAVO study, so it'll be interesting to see what longer follow-up of that shows us by adding a PI3 kinase inhibitor in with a CDK4/6 inhibitor and endocrine therapy in the first line setting. But I think this really illustrates how these patients who develop disease progression went on an AI and have a PIK3CA mutation do quite poorly with endocrine therapy.
Dr. Kalinsky:
Yeah, in the second installment, we talked about the INAVO120 study very briefly, but this patient, as you mentioned, would've fit the criteria for the study. So that was a study in which patients received fulvestrant/palbociclib vs fulvestrant plus palbociclib plus inavolisib. All these patients had PIK3CA mutations, all of them are endocrine resistant, all of them had miserable disease. And what was remarkable to me about that study, and right now, at this moment, we do not have approval for inavolisib, was just how quickly patients had progressed on just fulvestrant plus palbociclib. That kind of quick drop off that we see in the Kaplan-Meier curve, we didn't see that with the triplet. And so, this would've been that kind of patient for if and when that drug is approved would be appropriate. But where this patient is now, I completely agree, I would utilize chemotherapy, and I think we're waiting to see about whether ADCs will move into that kind of front-line post–endocrine therapy space.
There should be some studies coming down the pipe, which may put it into that space. And so, Dr. Bhave, let's say you started this patient on capecitabine and she had a HER2-low breast cancer. What would you think about next? Would you think about trastuzumab deruxtecan? And let's also say, just to confound this a bit more, we've seen data with dato-DXd in this setting as well, which is another TROP2 antibody-drug conjugate, which we seen an improvement compared to physician choice chemotherapy, though, at this moment, that drug is not approved yet either. Let's say it was in that space. Do you have a preference of what agent you would use, in terms of which ADC you would select?
Dr. Bhave:
That's a great question. It's nice that we have so many of these ADCs to select from, but it does become a bit confusing on how to sequence these ADCs. And there's a lot of questions on efficacy of ADC after ADC and where the resistance actually comes from, the antigen vs the payload. In terms of, for this patient, given her HER2-low status and the very impressive results from DESTINY-Breast04, I would choose trastuzumab deruxtecan. In that study, we saw a progression-free survival of 8.5 months. There was also an overall survival benefit of about 18 months vs 8 months, and so, it is a well-tolerated ADC. Given that data, that would be my first choice in terms of ADC that I would select. The biggest toxicities that I've seen have been nausea and fatigue, and so, we do premedicate those patients with antiemetics for moderate to high risk treatments, that can cause nausea.
And then, with fatigue, I'm pretty quick to reduce dose if a patient is having really intolerable fatigue. And with the premedication and dose reductions, I've had a lot of success in maintaining these patients with durable responses to the trastuzumab deruxtecan. Now, in terms of the question about dato-DXd, I think the question comes really as dato-DXd vs sacituzumab govitecan, because they're both TROP2 ADCs. And the schedules are different. Again, going back to schedules, dato-DXd is given every 3 weeks, while sacituzumab govitecan is on day 1 and day 8 of a 3-week cycle.
So from that standpoint, dato-DXd is a little bit easier for these patients to come in every 3 weeks. There's also differences in toxicity profiles. Dato-DXd causes more of a mucositis, which seems to be preventable with the use of empiric dexamethasone mouthwash. While sacituzumab, we see more of the anemia, neutropenia, diarrhea. And so, I think, if I had to select a second ADC and both were available, I might prefer dato-DXd, assuming that it was approved, and we'll see some additional data on that. But it really comes down to what we feel a patient can tolerate and where their performance status is at.
Dr. Kalinsky:
Yeah, I think the other thing just to highlight, because I appreciate you bringing up the differences in schedule, my experience with sacituzumab govitecan, all patients lose their hair. My experience with trastuzumab deruxtecan, not all patients lose their hair. And then, the other thing is the stomatitis that we can see with dato-DXd. In one of our installments, we were just talking about everolimus and utilization of the oral dex or steroid rinse. In the global studies, that wasn't available internationally across all the studies, so not everybody could utilize it preventatively. But it's certainly been something that has been shown to help decrease the likelihood of having stomatitis.
So Dr. O'Regan, let's say this patient went on to receive capecitabine and then, got trastuzumab deruxtecan, which also we should mention that about two-thirds of patients with hormone receptor–positive disease are "HER2-low." Next, would you think about utilizing sacituzumab govitecan recognizing that all the patients in TROPiCS-02, which was the study that led to the approval of sacituzumab govitecan, did not have a prior ADC, would you sequence ADC after ADC? What's your impression on that?
Dr. O'Regan:
Yeah, I don't think we have data, but I'm sure we'll get some real world data soon. I don't see why not. You've got different targets, so I think it's not unreasonable to explore them in sequence. I would agree with Manali basically. I do think I would use T-DXd first in this patient, but I have done it where I've sequenced some.
Dr. Kalinsky:
Yeah, I think it really does highlight the remaining unmet need in endocrine-resistant disease. It's nice to have our ADCs, but we're highlighting they have similar antigens, similar payloads. And so, just having novel ADCs and other systemic approaches, I think, really remains an unmet need.
Dr. Bhave, Dr. O'Regan, anything else that you would like to mention, just in terms of toxicity? One question I had for you both was, just in terms of the pneumonitis that we can see with trastuzumab deruxtecan, how are you following this? Are you doing any baseline PFTs? How often are you following those patients? And what's your experience been? Have you had to hold for asymptomatic pneumonitis? Maybe Dr. Bhave, I'll start with you and see, Dr. O’Regan, if you have anything that you'd like to add.
Dr. Bhave:
Yeah, absolutely. So I'm not doing baseline PFTs on patients. However, when we do education before initiating these ADCs, we talk through potential symptoms that could raise suspicion for a pneumonitis. Things like a persistent cough, shortness of breath. We commonly check pulse ox on patients when they come in, just as a one time, but if someone is saying that they're more short of breath or they've had a cough, then I might do the simple walk test and see if their oxygen levels start to drop. In terms of routine and serial imaging for evaluation of pneumonitis, I'm also not doing that. However, because of the nature of their cancer, we do end up getting CTs of their chest at least every 3 months, and so, if I do find a patient that has some opacities on there concerning for drug-induced lung injury, then those would be patients that I would stop treatment. I typically have them evaluated with a pulmonologist and myself, and then, depending on severity, discuss whether or not we need something like steroids.
Dr. Kalinsky:
Dr. O'Regan?
Dr. O'Regan:
Yeah, I don't even think much about it. I think the point about we are scanning them anyway, so the CT chest can sometimes show something. It was interesting, because with everolimus, we did see a lot of subclinical changes on CT chest, but I really didn't tend to do anything with that, unless they were symptomatic. But obviously, because this grade 5 toxicity is associated with this drug, you have to be a little bit more cautious, I think.
Dr. Kalinsky:
Yeah. The other thing I just want to mention in terms of toxicities is that, with sacituzumab govitecan, we're seeing a notable rate of requiring growth factor use. Even in real-world data, it can be about 40 to 50% of patients require growth factors, especially for those who are pretreated. So a great discussion. Oh, please...
Dr. Bhave:
I was going to say, on that note, are there any patients where you might consider empirically starting GCSF support, let's say, with day 8?
Dr. Kalinsky:
Dr. O'Regan?
Dr. O'Regan:
I have not done that. I just kind of see what happens to their counts and then, add it in, but it's a good question.
Dr. Kalinsky:
Yeah, I have a similar approach. The only caveat to being that, if this is a heavily pretreated patient and I've already seen that he or she has required growth factors, so I have, once or twice, given it preventatively. But generally, I just wait to see what happens and then, add it in.
This has been a great discussion. In terms of key clinical takeaways, as I think we've highlighted, there have been advances in hormone receptor–positive/HER2-negative metastatic breast cancer. For patients who have endocrine-resistant disease, chemotherapy and/or ADCs are standard of care. And there are ongoing studies that are looking at the role of sequencing ADCs in metastatic breast cancer.
This brings us to the end of this discussion. Please see the other segments for future discussion about the latest research in breast cancer or visit ASCOPost.com. Thanks so much.
