Selecting the Appropriate Treatment for Patients with HER2+ mBC in Frontline and Beyond


Focusing discussion on the first clinical scenario, panelists examine currently available first- and second-line treatment approaches for HER2+ mBC.

Erika Hamilton, MD: Dr Traina, will you talk a little bit about how you consider first-line therapy for a patient with HER2+ breast cancer?

Tiffany Traina, MD: Sure, happy to. I think, as Rita described, the CLEOPATRA [trial] (NCT00567190) regimen really remains our first-line standard of care. CLEOPATRA compared docetaxel-trastuzumab to docetaxel-trastuzumab-pertuzumab and was associated with about a 30% improvement in overall survival (OS), and at the time, [it was] probably the biggest incremental improvement in OS [with] an absolute difference of [over] 14 months. That has really established it as a first-line standard of care. There [have] also been studies looking at paclitaxel with trastuzumab-pertuzumab. Guidelines would support taxane-trastuzumab-pertuzumab in the first-line setting. I think our expectations are that patients will have a great benefit with that drug for a long time.

Erika Hamilton, MD: Absolutely. How many cycles of taxane do you normally consider before you drop the taxane out?

Tiffany Traina, MD: That's a great point. As you've seen, neuropathy is a potential toxicity with the taxane [agents], so I don't think that there's an arbitrary number. Sometimes you hear 6 cycles and then dropping or treating to the point of maximal benefit. Rita, as you described, when toxicity develops, we're inclined to drop the chemotherapy and keep the trastuzumab-pertuzumab as a maintenance.

Erika Hamilton, MD: Absolutely. What are you thinking in the second-line setting? [We have] a little more choice here than we used to have.

Tiffany Traina, MD: That's right. I think this is enough to fill at least another hour of conversation, but we [are now lucky to] have a fortune of multiple active agents in the second line and later. We have TKIs (tyrosine kinase inhibitors), [and] as we've heard, tucatinib-capecitabine-trastuzumab is a highly effective regimen. We have the antibody-drug conjugate T-DM1 [trastuzumab emtansine] that's been around for some time. [There are] newer data around the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). We have data around a new engineered monoclonal antibody against HER2 called margetuximab. Other TKIs like lapatinib and neratinib have been around, so [there is] plenty to talk about in the coming hour.

Erika Hamilton, MD: Absolutely. Rita, this patient received tucatinib in combination with capecitabine and trastuzumab in the third-line [setting]. What was your thought process there about picking this particular regimen for her at that time?

Rita Nanda, MD: I think that she developed pretty substantial neuropathy with the T-DM1. It was very challenging to manage and took quite some time to resolve. Fortunately, it has now [resolved], but I think we were looking for a regimen that wouldn't be associated with neuropathy that would be easy to tolerate and [was] an effective strategy. While she didn't have brain metastases at the time that I did this, I felt like she was very high-risk for them, and it was very reasonable. This was prior to the availability of T-DXd.

Erika Hamilton, MD: I think you bring up a good point though. Obviously a lot of people are excited about the brain data with tucatinib, but it's not a regimen for just people [who] have brain metastases. It improved overall survival and was great for patients [who] didn't have brain metastases too. I think that's an important point here.

Tiffany, would you have done the same thing now? In 2022, what would you be thinking about? Would you be thinking about T-DXd? Would you be considering tucatinib here?

Tiffany Traina, MD: I think that's a great point. Our algorithms are evolving so rapidly, as the data is coming out month after month. Now we have data from DESTINY-Breast03 (NCT03529110), which would suggest that T-DXd was superior to T-DM1. I think the decision-making for me would've been around T-DXd versus the tucatinib-based regimen. As you said, we're fortunate that we have now 2 regimens with improved overall survival, different adverse event profiles. I think either of these are reasonable choices.

Erika Hamilton, MD: Yeah. I completely agree with that. Ryan, I might ask you a question. This patient initially presented with a fracture. When do you think about radiating certain lesions where she also had really bulky abdominal disease? How do you make those decisions?

Ryan Jones, MD: Yeah, I was following along too. I was curious if it was a pathologic fracture or from bone metastasis, but it sounds like it wasn't. Then later, she was diagnosed off the primary [site] with other boney metastatic sites. With respect to [whether] I would radiate the right axillary disease because of the edema, you're right. We are there to help for troublesome areas, [such as] areas in the metastatic setting that are painful or bleeding or causing mass effect and bothering some tissue. We'll talk a lot about brain metastases later on in the panel. We deal with the management of lymphedema a lot in the local regional setting—after surgery, after surgery plus radiation—and our preventative treatments and our therapeutic treatments of lymphedema and extremity. In those patients, as I think you can apply to certain metastatic cases, you want to minimize the time of significant lymphedema [to] try to prevent this irreversible damage. We talk about stages, whether it's correctable by elevation and the degree of lymphedema of the extremity, but [it may] be very reasonable to deliver palliative radiation to this case to try to reduce that mass effect and improve the drainage for this patient.

Erika Hamilton, MD: I think that's helpful. I've been working with tucatinib since 2013 in our phase 1 unit. I find it to be a pretty tolerable drug. [It’s] really quite tolerable. You are certainly combining tucatinib. Right now, we typically give it with capecitabine in conjunction with trastuzumab, and some of the adverse events really come from the capecitabine backbone: the hand-foot syndrome, some of the GI (gastrointestinal) toxicity, whether that be diarrhea or nausea, that can also be common with capecitabine. The adverse events that we look for with tucatinib are some LFT (liver function test) elevation. That's typically something that's asymptomatic, but we're monitoring that on laboratory evaluation. Then certainly, [we’re] following the hand-foot syndrome for capecitabine, although tucatinib does not add to that. Then [there is also] a little bit of GI toxicity. Again, capecitabine can contribute that as well.

Rita, what factors do you take into consideration when you're choosing a treatment for a patient with HER2+ disease? Is it 1-size-fits-all, or are there characteristics about that patient that [you use to] tailor your approach?

Rita Nanda, MD: I think that's a great question. I think, for all of us who take care of patients with breast cancer, it's a back-and-forth discussion with patients. We talk to patients. As Tiffany has said, we have so many amazing therapies to offer patients. The days of just having 1 regimen or a handful of regimens are long gone. We have so many exciting new therapies that there are many options, and there isn't necessarily just 1 way forward. Obviously, we know that tucatinib has great CNS (central nervous system) activity from the HER2CLIMB trial (NCT02614794), and there's a survival advantage even in those individuals who have brain metastases. That's something that I take into account when I think about who I am going to recommend tucatinib to, but I also have a lot of patients who maybe want to not lose their hair. [They] want to have hair for some time, and maybe they like this idea of a pretty convenient oral regimen. They're only coming in once every 3 weeks for trastuzumab, and that can even be given subcutaneously now. I think there are lots of reasons to consider tucatinib-based therapy. There's the survival advantage. It's very effective in brain metastases. Sometimes for patients, it's a quality-of-life determination. While we have other very effective therapies that are more effective than what we've historically had, I think there are many reasons to consider tucatinib-based therapy.

Erika Hamilton, MD: I completely agree with that.

Transcript has been edited for clarity.

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