Recap: Treating Patients With HER2+ Metastatic Breast Cancer: Insights From Experts at Dana- Farber Cancer Institute

During an Around the Practice^® presentation hosted by CancerNetwork^®, expert oncologists from Dana-Farber Cancer Institute in Boston, Massachusetts, reviewed the evolving treatment landscape of HER2-positive breast cancer with a focus on brain metastases while analyzing 2 patient cases. The panel was hosted by Sara M. Tolaney, MD, MPH, chief of the Division of Breast Oncology and associate director of Susan F. Smith Center for Women’s Cancers at Dana-Farber and an associate professor of medicine at Harvard Medical School.

Other panelists included Nancy U. Lin, MD, an associate professor of medicine at Harvard Medical School and associate chief of the Division of Breast Oncology at Susan F. Smith Center for Women’s Cancers and director of the metastatic breast cancer program at Dana-Farber; Sarah Sammons, MD, faculty member at Harvard Medical School and associate director of the metastatic breast cancer program at Dana-Farber; Adrienne G. Waks, MD, associate director of clinical research at Dana-Farber and an instructor in medicine at Harvard Medical School; and Ayal Aizer, MD, MHS, senior physician at Dana-Farber and an assistant professor in radiation oncology at Harvard Medical School.

Patient Case 1

TOLANEY: When you’re thinking about a patient with metastatic HER2–positive breast cancer, how do you approach that patient in general?

LIN: In terms of first-line therapy, our general algorithms are to use first-line taxane [with trastuzumab plus pertuzumab (Perjeta)], with a choice of taxane being either docetaxel [Taxotere] or weekly paclitaxel depending on toxicity considerations as well as the [dosing] schedule. However, in this case, this is a patient whose disease recurred while on adjuvant T-DM1. We would take out that part of the algorithm and move towards what would ordinarily be second-line therapy. That would be T-DXd, which indeed does have an indication for the subset of patients who have less than a 6-month disease-free interval after neoadjuvant therapy.

TOLANEY: If you have a patient who was getting standard first-line therapy, including taxane with dual HER2- directed therapy of trastuzumab and pertuzumab, and they progress on that first-line treatment, what are the options for the second line and beyond?

SAMMONS: We have seen a real paradigm shift in the past 2 years. Until about 18 months ago when we saw the results of [the phase 3] DESTINY-Breast03 trial [NCT03529110], we would have given her T-DM1. But after DESTINY-Breast03, which compared second-line T-DXd with T-DM1, T-DXd markedly outperformed T-DM1 in terms of progression-free survival and is now the new standard of care for most patients.¹

In DESTINY-Breast03, there were about 82 patients on the trial with stable brain metastases, and they did benefit from T-DXd over T-DM1. For those without brain metastases or stable brain metastases, T-DXd is usually our second-line option. Another second-line regimen that’s FDA-approved in the second line is tucatinib, trastuzumab, and capecitabine.² I generally consider that regimen in patients who have brain metastasis–predominant disease, and that would be my second-line option for those patients. So second- and third-line options are usually T-DXd and tucatinib plus trastuzumab with capecitabine for intracranial predominant disease.

Beyond that, we have a paucity of data. We don’t know what to do, and we don’t know what works. There are a lot of options; after tucatinib and T-DXd, we have T-DM1, neratinib [Nerlynx]-based combinations, lapatinib [Tykerb]-based combinations, and modotuximab with chemotherapy. Those are all options, but we don’t know how well they perform after T-DXd and tucatinib or how to sequence them.

TOLANEY: When the patient ended up having a relapse while on T-DM1, what was your thought process in trying to figure out what to give them at that time?

WAKS: There were 2 main things in play for me. The first one was choosing between T-DXd or the tucatinib-based regimen for this patient in the second- or third-line setting. She did not have any known intracranial disease. Because the DESTINY-Breast03 trial was a second-line trial that [was randomly assigning] patients who had only [received] first-line THP [docetaxel, trastuzumab, and pertuzumab], whereas the phase 2 HER2CLIMB trial [NCT02614794] was more of a third-line trial, I usually reach for T-DXd in the second-line setting in the absence of some really significant intracranial disease or other subset circumstances. I was considering her as a second-line patient; that was one reason to put her on T-DXd in this case, just looking at the very impressive PFS [progression-free survival] data from DESTINY-Breast03.

That in and of itself was probably enough for me to choose T-DXd, but the other thing that made me enthusiastic to use T-DXd was that she did not have a super-high HER2 status. We now know from [the phase 3] DESTINY-Breast04 trial [NCT03734029] that T-DXd is an agent that works well in patients who are HER2-low.³ That was not her category. She was technically HER2-positive based on her fluorescence in situ hybridization ratio. Given how unusual and how unfavorable it is to have recurred in this early adjuvant setting, I wasn’t feeling so confident in the HER2-driven nature of this tumor. It didn’t behave like a standard HER2-positive tumor, which should have done better after adjuvant therapy. That low-level but positive HER2 status was also something that led me to using T-DXd.

TOLANEY: What if the scenario had been a little different? For example, what if the interval of time from her last dose of T-DM1 to the time of recurrence existed? Would that have changed your mind in this case?

WAKS: I adhere strictly to the eligibility criteria of the [phase 3] CLEOPATRA trial [NCT00567190], the first-line THP trial that allowed patients to enter if they had previously received a taxane and trastuzumab– containing regimen after more than 12 months.⁴ If this patient had a longer disease-free interval, around 18 or 24 months, I would go back to the CLEOPATRA regimen and consider her a first-line patient. We know in that setting that THP is a regimen associated with an overall survival [OS] benefit. Otherwise, for the shorter-interval patients in the second-line setting, I would go with T-DXd.

Patient Case 2

TOLANEY: Should we be screening our patients for brain metastases since that does seem to influence decisions?

LIN: The current American Society of Clinical Oncology [ASCO] as well as European Society for Medical Oncology guidelines still do not proactively recommend screening for all patients who have HER2-positive metastatic breast cancer.⁵ However, I will say that the wording of the guidelines has changed over time. The initial ASCO HER2 guidelines recommended against screening. Now the guidelines say that there’s no strong evidence for or against screening, and that just reflects the reality that we don’t have prospective data to demonstrate whether there is a benefit to routine surveillance screening with brain MRIs in patients with metastatic breast cancer. If we look at the first-line setting, less than 10% of patients have clinically evident brain metastases at the time of their initial HER2-positive metastatic breast cancer diagnosis.

I have not routinely screened patients, but I do make a point to ask about neurological symptoms in my review systems. I ask about changes in headaches and nausea and unexplained vomiting. If somebody is already on some sort of HER2-based therapy and through 10 cycles and they develop new nausea, it’s probably not from the chemotherapy that they tolerated for the past 9 cycles. I have a low threshold to consider MRI with any suggestive symptoms.

AIZER: I’d point out that in patients with lung cancer, both non–small cell and small cell, as well as in some patients with melanoma, we do screening MRIs of the brain to look for intracranial disease. Part of the reason is that the management of the brain is often contingent upon when you find cancer in the brain. If you find it earlier, when there are fewer numbers of tumors and they’re smaller, you can often use less-intense management modalities: perhaps the drug alone, or more focal radiation. If tumors are bulky or very symptomatic, you might be steering a patient down the road for surgery because that’s the best therapy to manage that. Had you screened, maybe the tumor would’ve been picked up earlier.

In breast cancer, screening has not been evaluated all that well in any prospective fashion. We have a prospective study that seeks to determine whether screening of the brain in patients with metastatic breast cancer is a good strategy. It also has a small inflammatory cohort, which is nonmetastatic. The idea is that we’re doing up to 2 brain MRIs in patients with metastatic disease and trying to determine if catching brain involvement early makes a difference.

TOLANEY: When is the time to provide radiation, and what are the benefits of doing so?

AIZER: In breast cancer, radiation has an important role, mainly in the domain of palliation. If patients have painful bone metastasis, radiation can be very effective in either alleviating that pain or removing the pain entirely. Another example that could come up is patients with spinal cord compression, where there’s a tumor near the spinal cord or compressing the spinal cord, or [if there is] impending spinal cord compression. Radiation can be very effective in preventing neurological deterioration in those patients and keeping patients as functional as possible. Radiation is predominantly useful for symptom relief, symptom mitigation, and sometimes symptom prevention.

TOLANEY: How do you treat patients with active brain metastases?

WAKS: This situation where you don’t have good control in the central nervous system [CNS] in the brain but you do have good control systemically in the rest of the body absolutely comes up all the time, and it is scary and frustrating for patients and providers alike. In terms of the distinction between active and progressing brain metastases vs stable brain metastases, there are a couple things that come into play. Which category does this patient fit into, and then how should I extrapolate that into the best treatment approach for them?

One question is, “How symptomatic is the patient?” This patient had small lesions but was developing new headaches, and her symptoms were changing, so that would make me put her in the active category. Another thing we often put into the symptomatology is whether they’re needing steroids to control them. In terms of active or stable metastases, there’s the question of what you are seeing radiographically. In this patient’s case, it’s not like you had multiple scans where you were doing surveillance MRIs, which would be the standard approach. In some cases, you might be following MRIs for certain reasons, so you’ll know whether things are progressing radiographically in the CNS. In many cases, you may not have that, as you didn’t here. Another important question is whether the brain metastasis has been previously treated. Is it a brain metastasis that’s progressing after having undergone salvage stereotactic radiosurgery [SRS] at some point in the past, or is it a brain metastasis [in a patient who] has never had any local therapy and is progressing on a systemic regimen? Those are the sort of features that make me think about whether a [patient with] brain metastasis is in a stable, maybe previously treated category vs an active, progressing with or without treatment category.

TOLANEY: When you see a patient with a CNS lesion, how do you approach [managing] it?

SAMMONS: Brain metastases are a very multidisciplinary problem. We rely heavily on our radiation oncologists. If the lesion is large, single-space occupying lesion that is causing a lot of symptoms, then I would engage my neurosurgery team as well to see if they think resection is feasible and a good plan. In a situation with a new brain metastasis, I always engage my radiation oncologists. If it’s a large, very symptomatic lesion, we engage the neurosurgery [team]. Then we think about systemic therapies. Generally, when I think about systemic therapies in brain metastases, I think their need is evolving. We think about a lot of things before choosing a [patient’s] therapy. We think about the status of their extracranial disease and what’s going on in their visceral lesions. What have [the patients] had before, and what are their comorbidities? There are a lot of factors to consider in terms of choosing a systemic therapy.

TOLANEY: How do you make a decision about who’s a candidate for SRS and who needs whole brain radiation?

AIZER: The first thing we always ask is, “Do we need radiation?” SRS and whole brain radiation can have some toxicities, and that requires us to rely on our guidance as to what the viable systemic therapies are for a given patient. Thankfully, in the HER2 realm, there’s much more available and much more effective options than in other subtypes of breast cancer for intracranial management, which is always nice to see. We’re often giving interdigitated radiation with a systemic approach and thinking about the long-term plan for a given patient.

When it comes to making a decision with SRS vs whole brain radiation, there have been a number of randomized trials on this topic. They included patients with many different [primary cancers,] including lung cancer, breast cancer, and melanoma. [Results of] those studies generally told us that whole brain radiation, although it lowers the likelihood that a new tumor will develop, doesn’t tend to improve survival and is associated with decreases in quality of life and neurocognitive function. The catch with those studies is that they typically capped the number of tumors that were eligible for enrollment. Some studies included 1 brain tumor, some up to 3 or 4. There are very early data for more than that. Thankfully, we’re hopefully going to have 3 additional randomized studies published going up to 15 or 20 tumors in the next few years. Then we’ll really have a better answer.

TOLANEY: Could you discuss HER2CLIMB [NCT02614794], the results observed, and the benefits for patients who had active brain metastases vs stable brain metastases?

LIN: The phase 2 HER2CLIMB study randomly assigned about 600 patients.⁷ Approximately half, so 300 patients, had known brain metastases at study entry. They were known because patients were required to have a brain MRI as part of their screening study. The brain metastases status on HER2CLIMB is very well characterized. The study included not only patients with stable treated brain [metastases], but also included patients with active brain metastases, including previously treated ones who have subsequently progressed as well as patients with newly diagnosed brain metastases where they didn’t receive any radiation therapy and went straight on to the trial. What was seen in the brain metastasis population was an improvement in OS; the absolute Δ was about 9 months, going from about a year to about 21 months. This was an impressive improvement in OS in these patients.

There was an improvement in overall PFS, considering both the brain and extracranial sites. There was a prolongation of time to progression in the CNS or death, which was characterized as CNS-PFS in the study. There was also an improvement in the objective response rate, both systemically and in the CNS.

When it comes to this question of whether we should or can offer up-front systemic therapy vs radiation, one of the important metrics in the study was looking at the rate of disease control at that first restaging time point. This was done in the trial 6 weeks after patients started therapy, which was after 2 cycles. Very few patients, fewer than 10%, came off the study at that point for CNS progression. The data are also reassuring in that a HER2CLIMB-type of regimen can be a safe alternative to offer to patients if appropriately counseled about the alternative of radiation to consider instead of whole brain radiation. This is particularly important in our HER2-positive patients because these are the patients who tend to live the longest after a brain metastasis diagnosis.

TOLANEY: When you’re treating a patient with this regimen, what are some of the adverse effects that you see, and how do you manage those?

WAKS: One that I would not say is the most common but was highlighted by our patient case here is that you can see some transaminitis associated with the regimen. In some cases, such as in this patient’s case, you can see the transaminase is reasonably high early on in therapy. Though the good news is that it’s typically manageable by doing a brief hold so that you can get the transaminases back down to normal and then dose-reducing and resuming [treatment]. I wouldn’t say that’s the most common toxicity, but it’s a good one to highlight and to be aware of since it can be seen with other HER2 TKIs [tyrosine kinase inhibitors] as well.

TOLANEY: How would you decide between the HER2CLIMB regimen or T-DXd?

SAMMONS: In a patient with a brain metastasis, [you have to ask,] “Are they active or are they stable?” Stable means that they’ve undergone local therapy with radiation and/or resection. In a stable brain metastasis population in the second line progressing extracranially, I will give them T-DXd. For a patient with active brain metastases, meaning that they have a high number of brain metastases and are trying to avoid whole brain radiation, I would choose the HER2CLIMB [regimen].

TOLANEY: What does the future for T-DXd with brain metastases in a large study look like?

LIN: The global phase 3 DESTINY-Breast12 study [NCT04739761] is designed with 2 cohorts. One is patients without brain metastases where T-DXd is being looked at in the second- and third-line settings in a larger group of patients globally. Then the cohort that is most interesting is the brain metastasis cohort, which will enroll up to 250 patients, which is getting more on the lines of the sample size of HER2CLIMB. That study will enroll patients both with active and stable brain metastases. The study is enrolling well, and I think it will provide us with important prospective data in a large set of patients and allow us to fill in the gaps that we have right now.

TOLANEY: In terms of treating patients who have HER2-positive brain metastases whether they are stable or active, what do you think is a good take-home message for them?

LIN: I would point to 2 concepts. One of local therapy vs systemic therapy, and one just about systemic therapies. These are patients who unfortunately often run through both tucatinib and T-DXd, and you’re wondering about the next thing to do. The NCCN [National Comprehensive Cancer Network] does have guidelines for systemic therapy for patients with HER2-positive as well as HER2-negative brain metastases. They’re not found in the breast cancer guidelines; they’re found in the CNS tumor guidelines. You’ll find there listed a number of regimens, including T-DM1, high-dose intravenous trastuzumab with pertuzumab for left meningeal disease, and intrathecal trastuzumab. There are a number of other regimens that can be considered in the later-line setting along with references to where the data come from. That’s a very useful reference.

Then the concept related for the choice of therapy is the idea of brain metastasis velocity. The idea is after [a patient] has had initial SRS, how many additional brain metastases are they developing per year after that SRS? It makes sense that if you develop more rapidly; there’s a shorter time and a higher chance of the need for salvage brain radiation therapy. There’s also a shorter OS. That’s a very useful concept. If a patient has SRS on HP and they have 2 lesions with SRS, and a year and a half later 3 small lesions appear, I’m more often likely to send them to radiation oncology and ask them to reradiate those lesions. If a patient has SRS, and the 3-month post SRS scan now shows 6 metastases, that’s a patient for whom I am more likely to switch their systemic therapy because I’m hoping to manage both what I can see and what I can’t see.

References

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2. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. FDA. Updated April 20, 2020. Accessed January 11, 2023. https://bit.ly/3ZruVIt
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4. Swain SM, Miles D, Kim SB, et al; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0
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