Bachelot Spotlights Impact of Tucatinib for CNS Metastases in HER2+ Breast Cancer

For patients with HER2-positive breast cancer who experience central nervous system (CNS) metastases, the best systemic treatment available will also be the best option for controlling non-progressive brain metastases, according to Thomas Bachelot, MD. However, for patients with progressive brain metastases, for whom local treatment is not possible, the best results for systemic treatment have been seen from the phase 2 HER2CLIMB trial (NCT02614794), with the triplet combination comprised of tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine.¹

“For those patients [with non-progressive CNS metastases] where you can [achieve] local control, the most important thing to know is that you do not have to change treatment; it should be the same as [what you do] for other patients. The only difference is that you add local treatment in the brain to control progression,” Bachelot said. “In terms of treatment for progressive brain metastases, the best evidence out there is the randomized study looking at tucatinib, trastuzumab, and capecitabine.”

Data from the HER2CLIMB trial, which examined tucatinib vs placebo with trastuzumab and capecitabine, resulted in the April 2020 FDA approval of tucatinib, and more recently, the February 2021 approval in Europe. Results from the study showed that of the 291 patients with CNS metastases who were enrolled, 1-year progression-free survival (PFS) the tucatinib arm was 24.9% vs 0% in the placebo arm (HR, 0.48; 95% CI, 0.34-0.69; P <.001), while the median PFS was 7.6 months for tucatinib and 5.4 months for placebo.²Additionally, the CNS-PFS for tucatinib was 9.9 months, compared to 4.2 months with placebo.³ Overall, treatment with the triplet combination led to a 68% reduction in the risk of CNS progression or death (HR, 0.32; 95% CI, 0.22-0.48; P < 0.00001).

In an interview with OncLive^®, Bachelot, the department manager of medical oncology at Centre Léon Bérard in Lyon, France, discussed how to approach treatment of patients with HER2-positive breast cancer and CNS metastases and the impact of tucatinib in this population.

OncLive^®: Could you speak to the challenges faced with treating CNS metastases in patients with HER2-positive breast cancer? What are you doing in practice for these patients?

Bachelot: CNS metastases in breast cancer is a big problem, particularly in HER2-positive disease. It is a frequent condition, and more than 30% of patients will have brain metastases at some point. If you look at…the patients who live for more than 5 years, up to 50% of them will have brain metastases. A lot of the time, patients will die from CNS progression. It is a tough challenge, and the question is: Can we have specific medical treatment for these patients?

You [may be able to] control CNS metastases with local treatment, either radiation therapy or surgery. It is very much recommended to do surgery if your [patient has] big brain metastases; if not, you do stereotactic radiation surgery. It has been shown that the best systemic treatment to control the disease for the longest time and with the best overall survival [OS] improvement will also be the best option for those with brain metastases. If you look at subgroup analyses of those randomized studies, you find the same result in the subgroup of patients who have brain metastases as the ones who do not. That is true in the first line with pertuzumab [Perjeta]/trastuzumab, in the second line with ado-trastuzumab emtansine [T-DM1; Kadcyla], and the third line with tucatinib plus trastuzumab and capecitabine. As such, in fact, there is no specific treatment for brain metastases.

It is different when [a patient has] progressive brain metastases; you want to treat [those patients] with chemotherapy. Here, the evidence is [less clear, although] many treatments have been shown to be able to control brain metastases progression. Most of the time the PFS is short, at approximately 5 months, which is not that great. However, the triplet combination of tucatinib, trastuzumab, and capecitabine that was recently examined in the HER2CLIMB study, for which there was specific analysis of brain metastases, showed a PFS of 7 to 9 months, which is much better.

Furthermore, this study was the only one that randomized patients with active brain metastases and it is the only one that has shown improvement in OS for patients with acute brain metastases. For patients with progressive brain metastases, this treatment regimen is validated with the best evidence. [Additionally,] T-DM1 can be used, specifically if it had not been used before, as well as lapatinib [Tykerb]/capecitabine or neratinib [Nerlynx]/capecitabine, although the PFS [benefit achieved with these approaches] is not as good.

What is next for tucatinib in this patient population?

The phase 3 HER2CLIMB-02 trial [NCT03975647] is ongoing; this is a randomized study that will look at T-DM1 plus tucatinib vs T-DM1 alone [in patients with metastatic HER2-positive breast cancer]. There is also a preplanned subgroup analysis for brain metastases here, so we will see if the addition of tucatinib to T-DM1 in the second-line is better than just T-DM1. This research will be very important. There is also some discussion of adding [tucatinib] into the first-line treatment setting, and specifically the adjuvant setting, for high-risk patients.

It is very important to use tucatinib, as it is easy to administer to patients and does not add much toxicity. [Additionally], it makes sense to try to give [the agent[ early and hope that is could prevent the evolution of brain metastases.

When it comes to approaches that have shown activity against CNS metastases, how do you select between them? What do you do in terms of sequencing?

There are 2 different situations. In one, there are patients who had brain metastases that have been controlled with radiation therapy or surgery, and so they have no evolution in the brain anymore. In terms of treatment for those patients, we cannot say that tucatinib is better than the other agents, because that has not been proven. If the patient is in the second-line setting, we can utilize T-DM1. If the patient is in the first line, we can utilize pertuzumab/trastuzumab. [Importantly], you should not change this treatment. We do not have any arguments that say if [a patient has CNS] progression with T-DM1 then [they] have to stop [and switch to another treatment]. We do, [however], have the argument that [continuing] with the same treatment is better.

The other situation is when you have progressive brain metastases and cannot treat with radiation therapy or surgery, and you want to give chemotherapy to improve the brain metastases evolution. In this situation, the triplet combination of tucatinib, trastuzumab, and capecitabine is the one with the best results. It has the best response rates and the best PFS.

With regard to other agents, neratinib plus capecitabine is [a feasible option]. A recently published study [examined this combination] in patients with brain metastases. [Results showed] responses rates [similar] to [what has been seen with] tucatinib, but the PFS was only approximately 5.6 months. We can say the same for lapatinib plus capecitabine.

References

1. Bachelot T. Do CNS metastases in HER2+ breast cancer require a different systemic approach? Presented at: ESMO Breast Cancer Virtual Congress 2021; May 5-7, 2021; Virtual.
2. Murthy R, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
3. Lin N, Murthy R, Anders C, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005