Third-Line Treatment of HER2-Positive Advanced Breast Cancer: From No Standard to A Pandora’s Box - Episode 1

Third-Line Treatment Data for HER2+ Advanced Breast Cancer

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Sara A. Hurvitz, MD, and Steven E. Vogl, MD, highlight key concepts from a recently published review of third-line therapy options for patients with HER2-positive metastatic breast cancer.

Sara Hurvitz, MD: Welcome to CancerNetwork® Between the Lines. We are going to be reviewing a Journal Club experience titled “Third-Line Treatment of HER2-Positive Advanced Breast Cancer: From No Standard to a Pandora’s Box.” My name is Dr Sara Hurvitz. I’m a breast cancer medical oncologist practicing at the University of California, Los Angeles. Here with me today is Dr Steven Vogl [of Montefiore Medical Center in the Bronx, New York]. Many of you would know him as Vogl New York. Steve?

Steven Vogl, MD: Thank you. I’m a practicing medical oncologist who sees pretty much what walks in the door in New York City.

Sara Hurvitz, MD: Steve, let’s talk about this article that explores how the field has changed in recent years with the approval of multiple new HER2 [human epidermal growth factor receptor 2]–directed therapies. At last count, we have 8 FDA-approved HER2-targeted therapies for metastatic disease. This review article nicely takes us through the history of the approvals, what the standard first- and second-line treatments are, and all the data relating to third line and beyond. Do you want to get us started?

Steven Vogl, MD: Sure. Why don’t we start with the first slide?

Sara Hurvitz, MD: We’re looking at the overall survival [OS] in the CLEOPATRA trial. Do you want to take us through that?

Steven Vogl, MD: This trial sets the tone for everything that came after it. The trial is a first-line trial of docetaxel with trastuzumab with or without the HER3-binding antibody pertuzumab. Adding the pertuzumab to chemotherapy and trastuzumab improved the progression-free survival [PFS] by about 6 months and the overall survival, I think, by 18 months, to just short of 5 years. This is a humongous achievement for a breast cancer that was the worst kind you could have before trastuzumab was available. What’s going on in this trial is, if you look at the curve, those first 2 years are the chemotherapy, which is basically given for 6 months, you can’t give it much longer because of neurotoxicity, followed by the 2 antibodies. The remaining 3 years or so are second-, third-, fourth-, and fifth-line therapies. That’s all in there in that survival curve. What happens in those 3 years is probably as important or more important than what happens in the first 2. We have to think about subsequent therapies in light of what has come before.

On the next slide, we see the 3 studies that make up where we are today. This first study is the 1 I mentioned, CLEOPATRA. The second and the third ones helped define the activity of the antibody-drug conjugate T-DM1 [trastuzumab emtansine]. This is 1 of the first antibody-drug conjugates to get to the market, and it’s a very nice drug. The 2 studies are funny. One of them, the last 1, TH3RESA, looked at the physician’s choice of the 3 different chemotherapies, none of them terrible, with trastuzumab vs T-DM1 [trastuzumab emtansine]. The second 1 compared T-DM1 [trastuzumab emtansine] with lapatinib and capecitabine given concurrently, which was the treatment regimen that got lapatinib approved. T-DM1 [trastuzumab emtansine] was better than the combination of these 2 drugs. I’ve always had a problem with the control group because probably, the control group should have been lapatinib, capecitabine, and trastuzumab, because lapatinib really doesn’t work very well without trastuzumab as well. But it doesn’t matter. The point of these 2 are that T-DM1 [trastuzumab emtansine] is an effective drug and mildly toxic, so it’s a very nice drug for our patients.

Sara Hurvitz, MD: You bring up some really important points. I agree with you, the control arm for the EMILIA study probably wasn’t the best. At the time, it was the accepted standard, but lapatinib-capecitabine was approved based on showing that patients did better than those getting capecitabine alone for HER2+ breast cancer. [There was] not much of a control arm, and the authors in this article point that out.

The authors also do a nice job talking about the pre–T-DM1 [trastuzumab emtansine] era, and how not so long ago we were just figuring out that we should continue HER2-targeted therapy after progression in the first-line setting. Data aren’t that old relating to that. They go through the data you mentioned, with trastuzumab and lapatinib showing a significantly improved overall survival compared with giving lapatinib alone in patients whose disease has progressed on trastuzumab. I agree with you, and the authors point this out, that that became a standard regimen because of the survival benefit noted. I did agree the TH3RESA data were more real-world data, showing the benefits of T-DM1 [trastuzumab emtansine] compared with whatever physicians wanted to give at the time. They were supportive of EMILIA. But asyou said, in 2021, the first line is THP [docetaxel, trastuzumab, pertuzumab], second line is T-DM1 [trastuzumab emtansine], and then it’s a big mishmash after that.

Before we go into where the trial takes us in terms of post–T-DM1 [trastuzumab emtansine], I want to look at some data that were presented at ESMO [European Society for Medical Oncology Congress] in fall 2020 by the French group. They conducted a study called ESME [Epidemiological Strategy and Medical Economics], in which they collected patients who were diagnosed at any of—I think it was 18 comprehensive cancer centers throughout France, with metastatic breast cancer of any subtype. There are over 20,000 women enrolled in this, and they included women where a subtype was known, and they followed them from 2008 to 2017. They looked at what the median overall survival was for a patient diagnosed in 2008, 2009, etc. Although triple-negative breast cancer and hormone receptor–positive HER2-negative breast cancer did not have an overall survival budge over that time period, HER2+ breast cancer started with an overall survival of 39 months in 2008. By 2013, a woman diagnosed in 2013 with metastatic HER2+ disease had a median OS of 58 months.

What you were saying is that we’re beginning to change the natural history of this disease, and these real-world data are indicating how beneficial these targeted therapies are. I want to underscore what you’re saying, that it’s really important what patients get after the first-line setting because obviously that does impact long-term outcomes. The NCCN [National Comprehensive Cancer Network] and other guidelines have been developed by ESMO and ASCO [American Society of Clinical Oncology] regarding what we should use in patients with metastatic HER2+ breast cancer. We have 2 antibodies, trastuzumab and pertuzumab, which hit HER2 but inhibit the binding of HER2 with HER3.

We now have 2 antibody-drug conjugates, T-DM1 [trastuzumab emtansine] and trastuzumab deruxtecan; 3 small-molecule tyrosine kinase inhibitors; pill-based therapy—more promiscuous and less targeted therapy. More off-target effects, except this novel 1, tucatinib, which selectively targets HER2. Now [we have] a HER2-targeted monoclonal antibody, margetuximab, which is aimed to generate more of an immune response. We have level 1 evidence of supporting the use of tucatinib, trastuzumab, and capecitabine because it was based on a randomized phase 3 clinical trial that was placebo controlled for these other agents and other regimens that are listed as ones we can use in the metastatic setting. We have variable data supporting these agents. On the next slide, Steve, if you could begin discussing, as the authors did in this article, the different trial designs and outcomes that we’re seeing with some of these agents that have newly been approved based on these studies.

Steven Vogl, MD: The most impressive result in the last 2 years in HER2+ breast cancer is on the first line. It’s an uncontrolled phase 2 trial of a antibody-drug conjugate that has a lot of drug and a little antibody. That’s probably superior to having a little drug with a lot of antibody. A little drug with a lot of antibody is T-DM1 [trastuzumab emtansine]. The drug is very toxic; they probably couldn’t give more. This drug was given only to patients who had failed T-DM1 [trastuzumab emtansine]. An eligibility requirement was the patient had to have had prior trastuzumab, pertuzumab, chemotherapy, and T-DM1 [trastuzumab emtansine]. We had a whopping 60%, 61% response rate and a median time to progression of 16.4 months. The median survival had not been reached yet when the study was presented a year and a half ago. This is a very exciting agent.

Listening to the presentation, I said, “After T-DM1 [trastuzumab emtansine], this looks better than T-DM1 [trastuzumab emtansine].” That’s the good news. The bad news is there’s a 13% incidence of interstitial pneumonitis, which is sometimes severe and occasionally fatal. We don’t have randomized studies, at least not that I’m aware of, that have reported out comparing this with something else. One is in progress comparing it with T-DM1 [trastuzumab emtansine].

This is probably a better drug in terms of killing the cancer and the balance between the enhanced apparent efficacy and the occasionally very severe toxicity that we have to wait for. I’ve struggled with which to give first. So far, I’ve fallen in the camp of giving T-DM1 [trastuzumab emtansine] because it’s generally very well tolerated. Not very toxic.

Sara Hurvitz, MD: I agree completely with you, Steve. What you said about T-DXd [trastuzumab deruxtecan] is so important. We haven’t seen data like these with objective response rates and PFS and such a heavily pretreated patient population. I can’t remember ever seeing a waterfall plot that looked like that. As the authors of the article pointed out, the patients enrolled in the DESTINY-Breast01 study had a median of 6 prior lines of therapy. They were enormously heavily pretreated patients, so we would expect or get excited by an objective response rate of 20%. That’s very impressive. I also echo what you highlighted about ILD [interstitial lung disease] and the fact that this is a life-threatening toxicity. I agree completely with you and the authors as well: the T-DXd [trastuzumab deruxtecan] at this point should be positioned after T-DM1 [trastuzumab emtansine], because we haven’t seen T-DXd [trastuzumab deruxtecan] head-to-head in any clinical trial. There are a number of head-to-head clinical trials in the phase 3 setting with this drug. As you mentioned, T-DXd [trastuzumab deruxtecan] vs TDM1 [trastuzumab emtansine] is going to be very telling.

Steven Vogl, MD: The next exciting drug was tucatinib. This specific tyrosine kinase inhibitor inhibits HER2 and crosses the blood-brain barrier. This has a response rate of about 45% given with trastuzumab and capecitabine. It’s a little better in comparable populations than both lapatinib and neratinib with less diarrhea. The grade 3 diarrhea is about 12%, compared to 24% in the NALA trial for neratinib and 12% for lapatinib. It doesn’t make more diarrhea than lapatinib and makes half the grade 3 diarrhea of neratinib.

This would be my fourth-draw treatment for someone who’s already had trastuzumab deruxtecan unless the patient has brain metastases. Because this gets into the brain, this is probably the best treatment we have systemically for brain metastases that are uncontrolled. Neratinib just got approved because it was a little more effective than lapatinib, although it didn’t improve overall survival. My feeling about neratinib is that the studies of this drug have been obsessed with giving a high dose, which I find unacceptably toxic. I have no intention of giving this drug until the people developing it come up with a schedule in which most of the patients really don’t get severe diarrhea that requires hospitalization and intravenous fluids. Margetuximab is of interest. I wish it worked better.

Sara Hurvitz, MD: I agree the data relating to margetuximab are not as exciting as the data that we’ve seen come out relating to tucatinib and T-DXd [trastuzumab deruxtecan]. Margetuximab was designed to elicit an antibody-drug mediated cellular cytotoxicity response. It appears to work only in patients who have a particular genotype that puts them at a higher risk of not being able to generate that response. Subsequently, although it’s available to us to use, we don’t have a way to test for that genotype. I’m not using it in my practice at this point, and the authors pointed out that it was only about a 5-week improvement in the median PFS associated with this drug. We’ve gotten spoiled with all these great results with other agents, and that has overshadowed these data with this molecule.

Steven Vogl, MD: There’s a recent publication in JCO [Journal of Clinical Oncology] of an international trial looking at lapatinib-trastuzumab and an aromatase inhibitor vs lapatinib alone and the aromatase inhibitor and trastuzumab with the aromatase inhibitor. It looked like adding lapatinib and trastuzumab to the aromatase inhibitor was the best arm. The study was relatively small and underpowered, but the 3-drug combination with dual-HER2 blockade and a hormonal agent is of some interest and needs to be explored further. This is especially of interest if you have patients who aren’t too symptomatic, if response isn’t as important as delay of progression, and if avoiding toxicity is important because they’re old, frail, frail from a reason of beyond being old, or very toxicity adverse. For the most toxicity-adverse patients I see, in the first line I would still try to give them dual-HER2 blockade with trastuzumab and pertuzumab. Then we can talk about which chemotherapy to give to avoid toxicity. One of the issues with HER2+ breast cancer is there’s been relatively little discussion and analysis of which chemotherapy to give, basically in favor of giving everyone a taxane and working it out from there. No one really knows what to do when you run out of taxane because of neurotoxicity. It’s by no means clear that those patients who’ve stopped docetaxel shouldn’t be given an alternative chemotherapy that isn’t neurotoxic, like capecitabine or gemcitabine, or minimally neurotoxic, like Navelbine.

Sara Hurvitz, MD: With respect to the use of hormone therapy when HER2+ breast cancer coexpresses hormone receptors, it’s notable that the CLEOPATRA study did not allow patients to receive endocrine therapy when they were on their maintenance HP [trastuzumab, pertuzumab]. Many of us in practice are adding endocrine therapy in at that point. There were data presented at the ASCO Annual Meeting looking at whether we can give trastuzumab and endocrine therapy, and if the outcome is just as good as trastuzumab plus chemotherapy. The data seem to indicate that the endocrine therapy may be the way to go. However, they didn’t use pertuzumab, and they didn’t use induction of chemotherapy. I agree with the authors and with you, Steve, that THP [docetaxel, trastuzumab, pertuzumab] is the frontline treatment, but I also agree that we need more clinical trials evaluating how we should be treating patients in that maintenance phase, especially when there’s hormone coexpression.

Transcript edited for clarity.