Managing Brain Metastases in Patients with HER2+ Metastatic Breast Cancer

The panel

During an Around the Practice^® program hosted by CancerNetwork^®, the panel discussed potential ways of treating patients with HER2-positive metastatic breast cancer who also have brain metastases. The discussion expanded to cover the treatment of those with leptomeningeal disease and the complications associated with organizing trials to further investigate new therapies. The panel considered the data of the DESTINY-Breast trial series and HER2CLIMB trial series.

Vijayakrishna “VK” Gadi, MD, PhD, a professor and director of medical oncology at the University of Illinois College of Medicine Chicago and deputy director at the University of Illinois Cancer Center, led the panel. He was joined by Ruta D. Rao, MD, a professor in the Department of Internal Medicine, director of the Coleman Foundation Comprehensive Breast Cancer Clinic, and medical director of RUSH University Cancer Center; and Jane L. Meisel, MD, a professor in the Department of Hematology and Medical Oncology and Department of Gynecology & Obstetrics, and codirector of breast medical oncology at Emory University School of Medicine.

Gadi / What’s your practice around monitoring [a patient with brain metastases]? How often are you looking at MRIs or hunting for problems?

Rao / My broad answer is that I don’t screen patients who are asymptomatic for the presence of brain metastases, but I have a very low threshold for any symptom that might be related to the brain. If it’s been a number of years and they’ve been on therapy, and then they progress, that’s a very reasonable time to look at the brain because it may help [you] choose what the next therapy is going to be [and help you decide whether] you want something that has more central nervous system [CNS] activity or not.

Gadi / Ruta, that’s your intrinsic way of approaching this? This is not influenced by payers saying no to an MRI or anything like that?

Rao / Yes.

Meisel / I’m no different. For me, it’s when [patients] have progression [that] I’m going to get a brain MRI to help guide my next line of treatment. I have a low threshold to evaluate anyone’s symptoms, but I’m not typically looking every 3 months if someone’s otherwise doing well.

Gadi / There’s the clinical trial definition of stable and active brain metastases, but what’s the Ruta Rao definition of stable and active brain metastases?

Rao /Stable is straightforward to define: [it’s when] you’re seeing the lesions, and they’re not changing on the MRI. For active, [you’re seeing] new lesions, lesions that are growing a little bit, even to the point where they’re causing symptoms. Just to make it black and white between the 2. In real life, it’s not always that way. Sometimes you get a couple of millimeters [between lesions] here or there, and then you have to discuss with your multidisciplinary team, including your radiation oncologist, exactly how you want to approach [the treatment of] this patient next.

Gadi / Jane, is there a cut-off size that gets you concerned, or are there other features?

Meisel / For me, it’s the rate of growth. Any symptoms from brain metastases start to worry me. Beyond something that’s tiny, stable, and asymptomatic, I usually have a low threshold to have a conversation with my neurosurgeons and radiation oncologists, just to make sure we all feel like we are on board with whatever the plan is, and [then we] bring the patient into that conversation.

Gadi / I have this [thing about location]. You can have a small lesion in some place that matters in the brain and then a somewhat larger lesion somewhere else. There’s always [that] consideration.

Meisel / It’s a tricky organ; you want to be careful.

Gadi / In terms of pure systemic vs local [surgery], what are the characteristics that make you think somebody needs actual surgery vs stereotactic radiosurgery [SRS] or [other treatments]?

Meisel / We’re doing less surgery in general these days for patients because there are so many better radiation tools and techniques, and surgery is so much more invasive. When I have patients who have active, large, symptomatic, and rapidly growing brain lesions, that’s typically when I think about neurosurgery, admitting the patient, and starting the steroids. Fewer of my patients are requiring that now than they used to, partly because we are looking at these patients with MRI at each progression, so we’re often catching things before they would become symptomatic, but also because we can radiate those smaller things as well. Those patients are the ones [who] are usually quicker to get to surgery.

Patients who have [lesions] that are growing faster than I’m comfortable with to just start systemic therapy but that aren’t large enough for surgery yet might be the ones that I need to think about radiation for. For patients who want to be particularly proactive, we’ll go ahead and radiate and then start systemic therapy, even if they’re stable. Those are the conversations that I have.

Gadi / Just a quick summary, then, of the intracranial efficacy data. Here again, I like to start on the right with the DESTINY trial series to remind everybody [that the phase 3 DESTINY-Breast03 trial (NCT03529110)] was the trial that allowed us to compare [trastuzumab emtansine (T-DM1) with] trastuzumab deruxtecan [Enhertu; T-DXd].¹ There were 114 patients with inactive, asymptomatic brain metastases, and 2 median lines of prior therapy, and you see this big signal––15 months vs 3 months for median progression-free survival [PFS]––in the DESTINY-Breast03 trial [data]. That would have been included in that combined analysis that you mentioned.

Just to set the stage for the [phase 3 DESTINY-Breast12 trial (NCT04739761)], technically, there were 2 arms on that trial, but it was not randomized, per se.² There was an arm where you had a confirmation signal on patients who didn’t have brain metastases with HER2-positive disease. Not surprisingly, we saw the same type of result. The real, actual arm for which the study was powered was the brain metastases–harboring patient arm that had 263 patients—a big, juicy, robust number of patients—[59.7%] of those with stable brain metastases and the remaining [40.3%] with active brain metastases based on the definitions we’ve just discussed. Most of them had 1 prior line of therapy, and—this is surprising—17.3 months of PFS, and the intracranial responses in the PFS are very evocative of what we’ve seen in other trials as well. It’s an active and properly done, perspective study with a number of patients that’s meaningful.

Going to the [phase 2 HER2CLIMB trial (NCT02614794)] with the small molecule inhibitor,…the [number of] median prior lines of therapy was 1 in this patient group.³ It was the first trial that tried to enroll patients with known brain metastases in the phase 3 setting, [40.4%] with stable [brain metastases] and [59.6%] with active, because these patients were never treated with other options such as T-DXd, etc. Most of them came out on T-DM1, with 9.9 months vs 4.2 months [for median PFS]. That would have been something we would have been so happy about back then—and we were—in these patients who had brain metastases. It was a very similar signal to what was observed in the overall study; numerically, it was better than what was observed in the overall study.

The [phase 3 HER2CLIMB-02 trial (NCT03975647)], prospectively, did enroll a large fraction of patients with brain metastases.⁴ This combination with T-DM1 and tucatinib [Tukysa], with 1 median prior line of therapy for most of the patients, elicited 7.8 months vs 5.7 months [for median PFS], so it was active in this setting as well. Now we’ve gone from 4 years ago having 0 trials to having this amazing amount of data. Not that the job is done, but we’re moving in the right direction here.

We’ve talked a little about this in the context of the patient, but [also] in terms of managing in the second-line setting for patients with active brain metastases. So just to recapitulate what we talked about, if appropriate, we’re going to use SRS localized therapies that we feel confident going to. The robustness of the phase 3 data—having phase 3 data—[means] many of us do lean on HER2CLIMB as an option, absolutely, but the truth is, looking at the numbers, the T-DXd does look active. I’m hearing, particularly from a lot of community providers, that this is their strong preference.

Meisel / It’s easier to give to some extent, too, and I do think, in a community [setting], that makes a big difference. You’re right; numerically, [those] data [do] speak for [themselves].

Gadi / If you can’t beat them, join them; so if we’re about to get data, hopefully [the therapy is] tolerable in that setting for the combination and gives us comprehensive coverage of brain metastases.

Rao / It’s just wonderful to have these options for patients. I’ve been practicing long enough where we had patients dying of their HER2-positive disease where they didn’t have any active, systemic disease, and they were dying because of CNS, and we didn’t have any of these treatments. It’s nice to have multiple treatment options available for these patients now.

References

1. Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022
2. Harbeck N, Ciruelos E, Jerusalem G, et al; DESTINY-Breast12 study group. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024;30(12):3717-3727. doi:10.1038/s41591-024-03261-7
3. Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005
4. Hurvitz S, Loi S, O’Shaughnessy J et al. HER2CLIMB-02: primary analysis of a randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX.