Evolving Approaches in the First- and Second-Line Treatment of HER2+ mBC

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Vijayakrishna Gadi, MD, PhD, discusses factors to consider in the first- and second-line management of HER2+ mBC with particular emphasis on treatment selection, safety, and sequencing.


Vijayakrishna Gadi, MD, PhD:
My name is Vijayakrishna “VK” Gadi. I’m a medical oncologist. I practice at the University of Illinois Cancer Center and the University of Illinois Health in Chicago, Illinois.

Today, we’re here to chat about metastatic breast cancer, specifically the HER2 subtype. One thing that still comes to mind is, what are we doing right when we start taking care of these patients? The general approach is tripartite. There are patients who present with de novo metastatic disease. For those patients, I’ll often [select the] primary choice, which is a taxane chemotherapy—whether that’s docetaxel or paclitaxel, more commonly in the United States—and combine it with trastuzumab and pertuzumab monoclonal antibody therapy. One change to that strategy is new formulation, so to speak, of trastuzumab and pertuzumab in a fixed dose and given as a subcutaneous injection. With those combinedwith the chemotherapy, that’s a very simplified first approach. We have very robust long-term data showing this is a very effective combination.

The other group is patients who have had prior treatment with those medicines but have then their disease recurred. One group of those patients may have had a recurrence soon after treatment with those therapies in the adjuvant setting, and depending on the exposures, they would then go on to what was essentially a second-line regimen now bumped up into the first line. We’re going to talk some about that later.

Then there’ll be patients who will have distantly seen, temporarily speaking, those therapies. It is by convention that we re-challenge with the same drugs: the taxanes and the HER2-targeting agents trastuzumab and pertuzumab as we would in the [patients with] de novo metastatic [disease].

One additional question or nuance, in particular, around this is if patients have hormone-positive cancer vs not. In the patients who don’t necessarily have hormone receptor-positive expression, we feel those cancers are more often driven by the HER2 gene itself. Targeting HER2 becomes our priority there, so we’ll go after that with the trastuzumab, pertuzumab, and so on. In the patients [who] are also hormone receptor-positive, they have a second driver: the estrogen receptor. If that estrogen receptor is not addressed, you can potentially see failure of these therapies sooner in that patient population. By convention, as we stop the chemotherapy and enter a maintenance phase with those biologics—the monoclonal antibodies—it’s common that we will then add in an antiestrogen agent, typically a drug like an aromatase inhibitor, and we can see maintenance that’s improved, potentially. This has not been terribly well studied in a formalized way, but I think by convention, it’s how a lot of us will practice.

For the time being, how we address first-line therapy is pretty fixed for most of us. That might come to be challenged in the near future, but starting with the second-line [setting], things start getting very complicated. When we look at our guidelines, they’re very liberal. They allow us as doctors to make a lot of different choices. While that’s liberating for us to be able to pick what’s right for our patient, it’s also confusing at the same time. When you look at this, there are 2 to 3 options that jump out. The first is for patients who don’t have brain metastases or urgent need of management of brain-based disease. We can really focus on below-the-neck disease, and in that case, there’s a couple of options there. These are monoclonal antibodies that are directly conjugated to chemotherapy, the so-called antibody-drug conjugates. The standard-bearer for a number of years has been a drug called T-DM1 [trastuzumab emtansine]. That molecule has been both shown to be generally safe and well tolerated. [It] beat out the prior standards handily and has been the standard for a while now.

Quite recently, the DESTINY-Breast03 trial [NCT03529110] was published to a lot of fanfare [and] a lot of press. It showed [that] a different monoclonal antibody-drug conjugate [with] deruxtecan as the chemotherapy that was attached to the trastuzumab molecule is more effective. It’s got better progression-free survival. There’s an emergence of an overall survival signal. Using some sophisticated analysis looking at toxicity, even at our 2022 ASCO [American Society of Clinical Oncology Annual] Meeting, we’re seeing data that shows that our assumption that this is the more toxic therapy can be challenged because, amortized over a long period of time, it actually could be considered to be better tolerated. The ratio of efficacy to tolerability is not as horrible as we thought it was initially. I think that’s going to rise into that second-line [setting] for these patients who don’t have CNS [central nervous system] metastases.

Then, of course, there’s the other group. For patients [for] whom we can’t easily manage the CNS disease or need to consider managing that more aggressively, more proactively, there’s a different regimen that we learned about through this trial called a HER2CLIMB study [NCT02614794]. That study that looked at trastuzumab plus capecitabine plus a novel molecule called tucatinib compared with that same combination without the tucatinib, and [it] showed that this brain-penetrating small molecule inhibitor that attacks the HER2 tyrosine kinase is very effective at not just controlling patients from developing new, additional CNS metastases, but [it] can actually address untreated disease in the brain. You can see how this can play out where being able to target that site where there’s so much more morbidity and hardship associated with it helps us prioritize this regimen over the trastuzumab deruxtecan regimen. [There is] nuanced care in that second-line [setting].

Having just discussed what’s going on in that second-line [setting], the common question of course is sequencing. It’s relatively speaking, a straightforward decision, which way you’re going to go because you can use this concept of brain metastases to help you in that second-line [setting]. Then the challenge that ensues is, what do you do when those therapies might stop working? Or if they’re not tolerated, how do you sequence these things? [On] the curves, the arrows swap places. For patients who might have been on trastuzumab deruxtecan, we will probably be reaching to tucatinib-based regimens in that next line of therapy. Even though head-to-head based comparisons don’t exist, but we know just looking at the numbers [that] the deruxtecan option seems to be a more active option. However, that’s not to say that the tucatinib-based option is a bad option. It makes a very excellent second option after trastuzumab deruxtecan. Hopefully, that’s something that can additionally add more disease control, prolongation of life, and survival. That’s certainly what we’re seeing. As patients with HER2-positive disease live with that disease, there’s always the chance that they then start seeding new metastases into the brain, so this becomes an elegant option for those patients as well. That one’s easy.

If you’ve been on trastuzumab, capecitabine, and tucatinib, what do you do after that? You could then go also to the trastuzumab deruxtecan option, but some people might want to go to T-DM1 or something that is gentler. There [are] a variety of options there as well. I think, just looking at the evidence, the trastuzumab deruxtecan probably makes the most sense because it is a very potent molecule. We know, in that Nth line context, this is a molecule that is very active even after many other therapies have been used based on a prior study, DESTINY-Breast01 [NCT03248492], so there’s still a lot of optionality there.

One thing [that] is going to drive our choices of care is what are the toxicities being experienced by the patients? How fit are they? Also, what are the emerging toxicities with these treatments? With the trastuzumab emtansine, its neuropathy, liver issues, [and] platelet issues; things that we’re pretty expert at managing. With trastuzumab deruxtecan, there’s a lot of fatigue, persistent nausea, [and] persistent vomiting [such] that we have to be very aggressive with supportive care. The scariest and most frightening one is pulmonary toxicity in the form of interstitial pneumonitis. In the early studies, people frankly died from that complication. I think we’ve all woken up. We’ve become more adept at identifying patients who are heading down that path, and we’re willing to stop. We don’t see that level of death, certainly. In fact, [there were] no deaths in the randomized control trial of DESTINY-Breast03, and patients had recovery from that toxicity once we stopped the drug.

Tucatinib is a little funny. A lot of the toxicities in the trial that we observed weren’t really tucatinib; it was the capecitabine. We know that the longer one is on capecitabine. There’s capecitabine-specific toxicities that we’ll see. Things like palmar plantar erythrodysesthesia, or in lay terms, hand-foot syndrome, [and] things like diarrhea and so forth can start setting in. We can mess with the dose of the capecitabine and help our patients be retained on the active molecule tucatinib. It takes a little of showmanship and “doctormanship” to understand how to sequence these things. You can have the disease dictate what you’re going to do next, or you can have the state of the patient [and] what’s going on with the patient in terms of toxicity, and allow that to dictate what you’re going to do next.

Transcript has been edited for clarity.

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