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An additional analysis of the data provided even stronger evidence of the benefits of tucatinib (Tukysa) in combination with trastuzumab and capecitabine in women with HER2-positive breast cancer with brain metastasis.

The results, published in the , showed "clinically meaningful and statistically significant improvements" in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in all patients treated with tucatinib, trastuzumab, and capecitabine. Based largely on this data, for these patients in April 2020.

The secondary analysis focused on the 48% of patients with brain metastasis and showed a 68% reduced risk of intracranial progression and death in these patients. Significant challenges, however, still remain in treating breast cancer patients with brain metastasis.

In the following interview, Nancy Lin, MD, director of the Metastatic Brain Cancer Program at Dana-Farber Cancer Institute in Boston, elaborated on the team's findings and discussed some of those challenges as well as new therapies on the horizon.

What would you most like oncologists to understand about treating patients with tucatinib in combination with trastuzumab and capecitabine?

Lin: In the HER2CLIMB trial, benefits in both PFS and OS were seen in the population of patients with and without brain metastases, as well as the subset of patients with brain metastases. Furthermore, this trial was unique in that patients with active/progressive brain metastases at study entry, arguably the group of patients with the fewest standard options, were included, and these patients experienced prolongation in time to CNS [central nervous system] progression or death and in overall survival that were clinically meaningful.

What are some of the biggest challenges that remain in treating patients with HER2-positive breast cancer and brain metastasis?

Lin: As patients live longer, they remain at risk for additional episodes of CNS progression and/or new CNS metastases. While radiation therapy can be effective, we don't have as robust data on many systemic therapy options and very much need to develop new and better systemic options for treatment of brain metastases.

Are there any other promising therapies on the horizon for these patients?

Lin: There are planned studies evaluating whether Enhertu -- DS-8201, trastuzumab deruxtecan -- could have CNS activity. The reported studies have excluded patients with active/progressive brain metastases, but preclinical data suggests potential CNS efficacy, and this should be evaluated in prospective studies.

There is also work on HER2 inhibitors with better CNS penetration, including across an intact blood brain barrier. In ALK-rearranged lung cancer, improved CNS efficacy has been seen with more brain-penetrant ALK inhibitors, and there is hope that the same may be true in breast cancer.

What are some of the biggest challenges for patients with other types of breast cancer, such as triple negative, and brain metastasis?

Lin: Unlike HER2-positive breast cancer, where prospective studies have reported CNS efficacy of multiple systemic regimens, and where median survival after a diagnosis of brain metastasis has improved over the past 2 decades, we have made very little progress in the treatment of patients with brain metastases from triple-negative breast cancer. The vast majority of clinical trials testing new agents for triple-negative breast cancer still routinely exclude patients with active brain metastases.

Are there any promising therapies on the horizon for patients with triple negative or other types of breast cancer and brain metastasis?

Lin: There is some interesting data regarding abemaciclib in patient with hormone receptor positive breast cancer; the intracranial response rate was very low but some patients did have prolonged stable disease. Combining some of the newer endocrine agents -- oral SERDs [selective estrogen receptor degraders], CERANs [complete estrogen receptor antagonists], etc. -- with CDK4/5 inhibitors or other targeted agents has a lot of promise, especially as many of the novel endocrine agents cross the blood-brain barrier.

For triple-negative breast cancer, an important question, as of yet unanswered, is whether there is a role for immunotherapy in the treatment of patients with brain metastases.

In addition, there are data from a study conducted at MD Anderson, including seven patients with breast cancer, where sacituzumab govitecan (Trodelvy) was dosed prior to craniotomy resection of brain metastases, and then continued postoperatively, that suggest that SN-38 is present in brain metastases. [That study was presented at the .] SWOG will be launching a prospective study very soon that will test the role of sacituzumab in patients with HER2-negative breast cancer brain metastases.

Read the study here and expert commentary about the clinical implications here.