HER2+ Advanced Breast Cancer: Selecting Third-Line Therapy


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

Steven Vogl, MD: The only exception might be someone who’s very close to death, with liver disease, failing liver, and high bilirubin. If you can give the T-DXd [trastuzumab deruxtecan] safely, I might give that because of the extra response rate and the quality of the response. That’s something we have to think about when we get to that situation. There are times when the response rate is as important and delay of progression is important, but there are critical situations where if you don’t get a response in 3 weeks, you don’t have a patient.

Sara Hurvitz, MD: Steve, we’ve both read this paper. We’re going to take a little time to discuss our key takeaways. It’s a very nice review presenting the state of the treatment of HER2 [human epidermal growth factor receptor]–positive metastatic breast cancer. I think you and I agree that the standard of care in the frontline setting is THP [docetaxel, trastuzumab, pertuzumab] based on the CLEOPATRA trial. And based on totality of evidence, safety, and efficacy relating to trastuzumab emtansine, you and I have agreed that this is a suitable second-line agent to use for the majority of patients. Where it becomes really muddy is the third-line setting. Can you take us through how you sort out in whom to use T-DXd [trastuzumab deruxtecan] vs tucatinib? Do you ever use neratinib? What are the unanswered questions and patient selection factors you use to help you sequence these new drugs?

Steven Vogl, MD: In the real world, there are all kinds of considerations. I haven’t had to treat a lady with HER2+ metastatic breast cancer with terrible lung function. I suspect I will have to at some point if my career goes on long enough. Also, it’s a little hard in someone with chronic obstructive lung disease and frequent infections to decide what’s a drug induced interstitial pneumonitis and what’s an infection. Sometimes it’s easy; sometimes it’s hard.

I had a situation of someone who I thought had a drug-induced pneumonitis from Taxol who actually had a toxic cardiomyopathy either from 2 HER2 drugs or from some prior adjuvant doxorubicin she had gotten. The radiologist was absolutely convinced she had a drug-induced pneumonitis, and I had to go to war with cardiology. It took a cardiac MRI to prove she had a cardiomyopathy, which got much better. She’s now very happy, doing well on trastuzumab deruxtecan. Anyway, there will be some patients for whom I might think twice because the drug is very expensive, and trastuzumab is becoming cheap. There will be some circumstances where we might have to bridge with trastuzumab and chemotherapy or hormone till we get the drug approved, or somehow raise the money to pay for the drug. This is the real world, and all these things are going to happen in our chaotic system of giving drugs and paying for drugs and medical care in the United States.

Basically, I want to be sure that none of my patients dies with HER2+ metastatic breast cancer without getting a chance to get better on trastuzumab deruxtecan. That would be my third line if I think I can get away with it, and the patient can tolerate it. It may become a second line if the toxicity of interstitial pneumonitis turns out not to be too severe or too frequent, or easily managed. I’m a little nervous about this formulaic way of giving steroids when the paper was presented and is in the article in the New England Journal of Medicine, the supplement. We haven’t seen a study as to how to manage this. We haven’t had any comparators on how to manage this way or some other way, and there’s some work to be done. What do you do after that? If you have brain metastases, I really think tucatinib is the way to go because it gets into the brain. Beyond that, we have a whole panoply of available therapies. Tucatinib is probably a better drug than lapatinib and neratinib, which has been too toxic.

Sara Hurvitz, MD: I agree with you in terms of the patient selection for T-DXd [trastuzumab deruxtecan]. The article nicely points out the strengths and weaknesses of all the trials that lead to the approvals of these agents. The downside of the T-DXd [trastuzumab deruxtecan] is that it’s a single-arm phase 2 trial and while the data are very impressive, they’re not comparative. We don’t have a placebo-controlled or even an open-label comparative trial of this drug, and the safety is an issue, with 13% of patients having ILD [interstitial lung disease] in this study and almost 3% having a death from the ILD. These are serious toxicity considerations, and I agree thatwe can use this as a factor in selecting patients appropriately.

Some centers are doing pulmonary function tests before putting a patient on T-DXd [trastuzumab deruxtecan]. You’re right: we don’t know how to use steroids or whether they even work. There were some nice data presented at the AACR [American Association for Cancer Research Annual Meeting], a compilation of all patients treated with T-DXd [trastuzumab deruxtecan] and rates of pneumonitis and incidence after implementing monitoring strategies to catch it early. It appears to decrease the rates of grade 5, but it’s still a serious consideration.

As the authors point out, tucatinib is based on a phase 3 trial that actually was placebo controlled and comparative, and it showed not only an improved progression-free survival, but an improved overall survival and improved overall survival in patients with brain metastases that were active as well as improved objective response rate and improved objective responserate in the brain. Data like that don’t come along every day, so I’d be comfortable putting a patient on tucatinib-capecitabine directly after T-DM1 [trastuzumab emtansine], especially if I was concerned that T-DXd [trastuzumab deruxtecan] may be too toxic. We’re going to see more data relating to T-DXd [trastuzumab deruxtecan] compared with standard of care in the coming year.

We also have studies ongoing looking at T-DM1 [trastuzumab emtansine] plus tucatinib, which might be a real winning combination. You get the activity of T-DM1 [trastuzumab emtansine] and the brain activity of tucatinib, and they’re doing studies of T-DXd [trastuzumab deruxtecan] with tucatinib as well. I agree with the authors that margetuximab has marginal benefits—playing on words—but I put that much lower on the totem pole and may not see its use in my own clinical practice.

Concerning neratinib, I agree with you: it’s highly toxic, and you have to keep in mind that the capecitabine dose that’s approved with neratinib is lower than we give with lapatinib and tucatinib. They had to bring down the dose, the starting dose of capecitabine with neratinib because of that toxicity, so they had to use mandated loperamide. We do think that starting neratinib at a low dose and escalating up slowly may mitigate those adverse effects, but it’s still bad. You have a drug like tucatinib—of course I’m going to use that earlier, and the authors agreed as they went through the level of evidence with exactly what you and I are saying.

There are a number of ongoing studies in which the authors go through new agents. We’ve got trastuzumab duocarmazine. We have antibody-drug conjugates that are targeting HER2. We have bispecific antibodies. What’s your initial impression? I know you went over that whole section there. Also, what are your thoughts about the early data we’re seeing?

Steven Vogl, MD: We’ve been spoiled by these 2 extraordinary experiences. Both tucatinib and trastuzumab deruxtecan are much better than anything we’ve had because we got pertuzumab for first-line therapy and T-DM1 [trastuzumab emtansine]. It’s been awhile. None of these seems so impressive. If the companies developing them work very hard, maybe they’ll show they have some advantage in patients who were less previously treated. Lord knows there are some diseases where there’s a revolution coming from antibody-drug conjugates and for bispecific T-cell engagers. There’s no reason these shouldn’t work, especially in epithelial cancers that have a marker as specific as HER2. If you can use HER2 to get the patient’s T cells to attack the cancer, then there’s no reason it shouldn’t work as well here as it does in myeloma. That’s coming. It’s not there yet, and it may not be there in my lifetime. Some of these drugs take a long time to develop. There’s 1 drug you mentioned to me, Sara, before the meeting that you think shows a lot of promise. What’s that?

Sara Hurvitz, MD: Yes, there’s an antibody-drug conjugate that I’ve worked with a bit in the clinic called ARX788, and it’s similar to T-DM1 [trastuzumab emtansine]. The early data coming out of phase 1 that were presented at ASCO [American Society of Clinical Oncology Annual Meeting] are showing interesting objective response rates north of 60%. The patients in this trial weren’t uniformly pretreated with T-DM1 [trastuzumab emtansine], and the payload is similar to T-DM1 [trastuzumab emtansine]. It’s a microtubular poison, so whether those data are going to be as impressive in a post–T-DM1 [trastuzumab emtansine] setting remains unknown.

There were also some data that the authors went through in this article relating to other TKIs [tyrosine kinase inhibitors], poziotinib and pirotinib. They pointed out that these were tested in some phase 2 trials, even randomized trials. They show promise, but the control arm hasbeen, in some of these studies, a non–HER2-targeted control arm—just plain old capecitabine, which wouldn’t fly in the United States. These are Asia-based studies. Also, the diarrhea rates we’re seeing are just as bad as we see with drugs like neratinib, so I’m not superexcited about these particular TKIs. I’m much more interested in seeing novel agents that are HER2 selective, like tucatinib, maybe even more potent and HER2 selective.

Then there’s a little discussion that they bring up about using PI3 kinase inhibitors in HER2+ disease. We know somewhere around a quarter to a third of HER2+ breast cancers acquire an activating mutation in the PI3 kinase gene. These patients tend to be the ones that progress earlier in the CLEOPATRA study, and these patients do worse overall. Subsequently, the question is: can you give a PI3 kinase inhibitor like alpelisib and help the outcome for patients? There’s an ongoing trial in the maintenance phase of HP [trastuzumab, pertuzumab] for patients who have PIK3CA mutations in their tumor, looking at whether alpelisib can improve those outcomes. I’m really interested in seeing those data, but those efficacy data better be good because these drugs are toxic. They cause a lot of adverse effects. What are your thoughts about that?

Steven Vogl, MD: I’ve been disappointed by PI3 kinase inhibitors. God bless those who try PI3 kinase inhibitors, but they’re moderately toxic. Also, alpelisib was not a home run. It was barely a bunt. Maybe it can get to base, and the patient will be a little better for a little while. But it’s never been clear to me that a PI3 kinase inhibitor, which is in the same pathway, won’t work as well as an mTOR inhibitor. The mTOR inhibitor that’s been used is everolimus, and it’s going off patent. I think it’s off patent. I know why it’s called everolimus—because it was “ever all” so expensive at the time. But it should be getting cheaper. It’s a good drug, and it has never been used in HER2+ patients that I’m aware of. I’ve done it when I had nothing else to offer the patient, and it worked with hormonal therapy and trastuzumab. That’s an anecdote of 1, but that’s also worthy of exploration. In addition, there’s a problem, which relates to where the money for studies in the United States and Europe is coming from. The studies are being designed to develop markets for expensive new drugs, and they’re not necessarily being designed to develop optimal therapy for the sick patients whom we’re treating palliatively. There will always be a market for a cure, that’s easy, but palliative therapy is worth exploring.

Sara Hurvitz, MD: You’re right. I agree with you in terms of everolimus. It is a better-tolerated agent, and we’re better at managing the toxicity. The BOLERO-1 study, which looked at everolimus with paclitaxel and trastuzumab, was a negative trial unfortunately. But as you mentioned, patients with hormone receptor–positive, HER2+ disease didn’t get endocrine therapy in that trial. Dr Ruth O’Regan did the BOLERO-3 trial of vinorelbine, trastuzumab, and everolimus. This 1 was slightly beneficial, but certainly it’s not approved in the setting. And looking at everolimus with endocrine therapy and HER2-targeted therapy, just in those patients with hormone receptor–positive, HER2+ disease, is an area that hasn’t really been explored.

Also, things that generate a lot of money are the things that get investigated first. It’s going to come down to investigator-sponsored trials, etc, to do this type of exploration. I would just also mention that immune-based therapies, as the authors pointed out, are being explored in clinical trials in HER2+ disease. We had the KATE2 trial, which was negative—an interesting signal in the PD-L1–positive, HER2+ breast cancers, but a small trial. The bottom line is it was a negative study. We need more data before immunotherapy is ready for prime time in HER2+ disease. Dr Vogl, we’ve gone through the entire paper. Do you have any final comments that you’d like to make?

Steven Vogl, MD: Yes. I urge the doctors caring for these patients—I am 1—not to despair and to keep trying. Afterward, when they can’t think of anything to do, call an expert like Sara, and Sara will think of something useful to give.

Sara Hurvitz, MD: Thanks very much for the vote of confidence. Steve, it was a pleasure talking to you and going through this very interesting article. What an interesting time it is. And thank you so much to our viewers as well for listening. Hopefully this has been a valuable experience for you.

Steven Vogl, MD: Thank you to the viewers. I hope we helped in some way.

Transcript edited for clarity.

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