Sammons Spotlights Approaches Under Exploration for HER2+ Breast Cancer and Brain Metastases

In an interview with OncLive®, Sarah Sammons, MD, the associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute, in Boston, Massachusetts, discussed ongoing and planned research efforts focused on HER2-directed therapeutic approaches that have central nervous system (CNS) activity. Sammons also highlighted pivotal trials that have significantly impacted this treatment landscape, such as the phase 2 HER2CLIMB trial (NCT02614794) and the phase 3 HER2CLIMB-02 trial (NCT03975647), and projected what future management of this population could look like.

Sammons provided further insights on the incidence of brain metastases in patients with HER2-positive breast cancer from a real-world analysis presented at the 2023 San Antonio Breast Cancer Symposium.

OncLive: What are some of the HER2-directed therapies that are available or have been shown to have CNS activity?

Sammons: As the treatment of HER2-positive metastatic breast cancer [evolves], we’ve been very fortunate that our newest and best lines of therapy do seem to have intracranial efficacy. Fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd] is now the standard-of-care second-line therapy in HER2-positive metastatic breast cancer. We’ve been pleased to find out that it also has robust intracranial, as well as extracranial activity.

There are small, single-arm studies looking at the intracranial activity of T-DXd in HER2-positive brain metastases. [Investigators] have also done a nice job of retrospectively looking at the intracranial response rate and CNS progression-free survival [PFS] from the DESTINY-Breast01 [NCT03248492], DESTINY-Breast02 [NCT03523585], and DESTINY-Breast03 [NCT03529110] clinical trials. What we found for T-DXd is that the intracranial response rate is somewhere between 45% and 70%, which is very respectable. When thinking about that in comparison with older-generation antibody-drug conjugates [ADCs], such as ado-trastuzumab emtansine [T-DM1; Kadcyla]. Although T-DM1 seems to also have intracranial activity, it has an intracranial response rate of around 20%. We’re seeing at least double that with T-DXd. This is exciting because ADCs are larger molecules, and we weren’t sure that they were going to make it into the brain, and it seems like they are, which is great.

We also have tucatinib [Tukysa], which is a highly brain-penetrable HER2-targeted TKI that has excellent intracranial activity when given in conjunction with capecitabine [Xeloda], and trastuzumab [Herceptin]. We affectionately call this the HER2CLIMB regimen, and that has an intracranial response rate of approximately 47%.¹

When I have a patient with active brain metastases, that for some reason, I’m trying to delay local therapy, I consider using T-DXd or a tucatinib-based regimen.

How may ADCs and localized radiation be used in tandem to improve outcomes?

Now that we’re seeing such robust intracranial activity with T-DXd, [the question becomes,] should [this] be used in tandem [with radiation?] For asymptomatic smaller lesions, should we hold off on radiation and give a highly effective ADC or TKI by itself to delay radiation? The reason why we’re asking these questions is because a small series came out this year that was published by the Memorial Sloan Kettering Cancer Center group that showed that patients who received concurrent radiation with ADCs experienced slightly higher rates of radiation necrosis, which can lead to a lot of local adverse effects [AEs] from swelling in the brain that can be morbid in the clinic.²

I don’t have an answer on what the best sequence is with regard to radiation and ADCs. Should it be radiation and then ADCs or ADCs and then radiation? How much time needs to be put between them? Should we use one and then the other or should we defer one altogether? These are questions that we’re going to have to answer with prospective trials that we’re very interested in.

What might be the feasibility of combining HER2-directed ADCs with HER2-directed TKIs in this population?

We saw some data at the 2023 San Antonio Breast Cancer Symposium that looked at combining ADCs with HER2-targeted TKIs. Specifically, we saw the results of the phase 3 HER2CLIMB-02 trial, which combined T-DM1 and tucatinib. This was a long-awaited clinical trial and we saw that the extracranial or the RECIST PFS was prolonged by about 2 months with the addition of tucatinib to T-DM1.

Looking at the forest plots, the patients who seemed to benefit the most were the ones who had a history of brain metastases, and HER2CLIMB-02 did enroll about 40% of patients who had a history of either active or stable brain metastases. We still haven’t seen the data from HER2CLIMB-02 on intracranial response rates, CNS PFS, and overall survival [OS] with the combination. I suspect that investigators will certainly publish all those results in subsequent meetings and I look forward to seeing all that, mostly because we’re not sure whether to use tucatinib right now with the regimen that we’ve been using it with—capecitabine and trastuzumab—which is where my allegiance lies until I see more of these data, or whether we should be switching and using T-DM1 with tucatinib, in the third line. I think it was feasible; the toxicity profile was consistent with each agent. Tucatinib and T-DM1 did have a slightly higher incidence of elevated liver enzymes. [That said,] if you stopped either agent, [those levels] did [drop].

Overall, it was feasible, and we await more data to figure out which regimen to use tucatinib with. We’ve also seen data in the past with neratinib [Nerlynx] in combination with T-DM1. In terms of intracranial response rates, it was respectable; the intracranial response rate in patients without prior T-DM1 was around 33%. Interestingly, even in patients who had received prior T-DM1, intracranial response rates were approximately 30%. I think that speaks to some kind of synergy together.

I think it’s possible, and I think there’s going to be added toxicity with an ADC and a TKI combination. [This area is] coming along, but I don’t think we’re quite there yet; we’re still figuring out when to use tucatinib and T-DM1.

What does the future look like for the management of breast cancer brain metastases?

In terms of HER2-positive breast cancer, brain metastases outcomes are better than they’ve ever been before. We know that metastatic disease to the brain does denote a worse OS compared with patients whose disease never goes to the brain. However, we’re seeing that every new therapy that we’ve had approved in the past few years, such as T-DXd, tucatinib, and the HER2CLIMB regimen, even T-DM1 more than a decade ago, has better and better intracranial activity.

That intracranial activity is leading to better OS for our patients with HER2-positive brain metastases. This is all very positive. It’s also extremely exciting that ADCs, which are poised to replace standard chemotherapy in the next decade, do get into the brain and they probably get into the brain better than historical systemic chemotherapy.

Between T-DXd and tucatinib-based regimens, which are our second- and third-line therapies, intracranial efficacy, CNS PFS, and OS are improving for our patients with brain metastases, and we can only go up from here.

References

1. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775
2. Lebow ES, Pike LRG, Seidman AD, et al. Symptomatic necrosis with antibody-drug conjugates and concurrent stereotactic radiotherapy for brain metastases. JAMA Oncol. 2023;9(12):1729-1733. doi:10.1001/jamaoncol.2023.4492
3. Hurvitz SA, 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, Texas. Abstract GS01-10.