A panel of experts discusses factors to consider when selecting treatment for patients with HER2+ mBC including brain metastases, quality of life, and treatment resistance.
Erika Hamilton, MD: Tiffany, I'm going to ask you a question that there's probably no great answer to. What do you think about the idea of delaying or preventing brain metastases? Are we at the point that we feel like we can do that? How are we thinking about that?
Tiffany Traina, MD: I think it's certainly hypothesis-generating that we have some tools that might get us there because the development of brain metastases over the lifetime of a woman with HER2-positive [HER2+] breast cancer is unfortunately quite high. Beginning to see a signal of our drugs having great activity in the CNS (central nervous system) has us hopeful that we can find a prevention benefit from moving those drugs sooner, perhaps. This is hypothesis-generating [and] needs support from a clinical trial, but you can imagine tools like tucatinib combined with other agents or as a single agent—perhaps moved up earlier—might help to prevent the onset of brain metastases. I think having good systemic control helps to minimize the development of brain metastases down the line as well.
Erika Hamilton, MD: Absolutely. I recently had an unfortunate case with somebody that had a pathologic complete response to surgery and then relapsed in the brain, only while on adjuvant [trastuzumab/pertuzumab], which was kind of devastating. I feel like HER2+ disease is really one where we tend to see more brain metastases. Do you feel like the patients that you see from a breast cancer perspective, with brain metastases—that we are certainly more likely to see a patient that's HER2+ than maybe hormone receptor-positive? How do you feel like the radiation oncologist contributes here? And how often are you seeing these patients?
Ryan Jones, MD: I think our role is still central for brain metastases. We're encouraged by improved, newer drug regimens that have more activity inside the CNS. I’m certainly biased being a radiation oncologist, but I think our role is still central. A lot more HER2+ or triple-negative than say ER (estrogen receptor)-positive HER2-negative.
Erika Hamilton, MD: Absolutely. Rita, we're branching out with tucatinib beyond just capecitabine and trastuzumab. Can you outline for us some of the other places that we're looking to put tucatinib and trials that are ongoing?
Rita Nanda, MD: There are a few trials that are ongoing looking at adding tucatinib to our antibody-drug conjugates (ADCs) that we're using. Obviously, there's the HER2CLIMB-02 trial (NCT03975647), which is looking at T-DM1 (trastuzumab emtansine) with or without tucatinib, and then the HER2CLIMB-04 trial (NCT04539938) is looking at trastuzumab deruxtecan with or without tucatinib. As Tiffany's already alluded to, we're looking earlier now, even in post-neoadjuvant therapy. In the CompassHER2 RD trial (NCT04457596), in the early-stage setting for those patients who have not achieved a pathologic complete response to their standard neoadjuvant therapy, there's the option to be randomized to T-DM1 with or without tucatinib. [It’s] really exciting looking for [whether] we can prevent brain metastasis for these patients with early-stage breast cancer.
Erika Hamilton, MD: Absolutely. I think we all agree that brain metastases are really devastating for our patients. Instead of just trying to treat them, if we could prevent them, we'd be definitely winning.
Tiffany, what about new agents? We certainly have had a lot of new agents recently over the past several years for HER2+ disease, but what's coming down the pipe?
Tiffany Traina, MD: Great question. I think what we have to keep in mind is [that] many of these trials were designed in parallel before we had the data from the other trials. As we're trying to interpret optimal sequencing of agents, a lot of this is unclear. I think that as we're incorporating antibody-drug conjugates, a big question is trying to understand what is the mechanism of resistance when it does develop. Is it a matter of the target being downregulated? Does it have something to do with the resistance to the payload? I think some of the novel agents that we're seeing are other antibody-drug conjugates facing HER2 but with different payloads. [It’s] really important to again emphasize [that] we have to understand mechanisms of resistance. We've seen data…yet another ADC that showed benefit against HER2 with a differing payload and a lot of work being done in trying to unpack these mechanisms of resistance.
Erika Hamilton, MD: Absolutely. It always strikes me that no matter how much we have, we really need more. Inevitably resistance develops and we need more options for these patients
Transcript has been edited for clarity.