The Impact of an Overall Survival Benefit in HER2+ Metastatic Breast Cancer

Kevin Kalinsky, MD, MS

Breast cancer that metastasizes to the brain is associated with poor prognosis in patients. The emergence of new targeted therapies could change this in the future. One such treatment may be tucatinib (Tukysa), which was recently granted FDA approval in combination with trastuzumab (Herceptin) and capecitabine as treatment of patients with HER2-positive metastatic breast cancer with or without brain metastases.

The FDA approval was granted on the basis of data from the phase 2 HER2CLIMB clinical trial NCT02614794. The study demonstrated a 34% reduction in the risk of death with the tucatinib triplet compared with trastuzumab and capecitabine alone. The major impact of this result was that it was the first time a systemic agent achieved such a good overall survival (OS) rate, noted Kevin Kalinksy, MD, MS, an expert in breast cancer.

In addition to the primary analysis data, the study had multiple subanalyses, 1 of which demonstrated a central nervous system (CNS) progression-free survival (PFS) benefit with tucatinib plus trastuzumab and capecitabine compared with trastuzumab and capecitabine alone. This research has become a popular topic of conversation among medical oncologists. Specifically, attendees of the Society of Neuro-Oncology Virtual Conference on Brain Metastases, questioned the role of local therapies like surgery and radiotherapy, considering the promise observed with systemic treatment like tucatinib in patients with breast cancer and brain metastases.

In an interview with Targeted Oncology following the conference, Kevin Kalinsky, MD, MS, associate professor of Medicine, New York Presbyterian Hospital/Columbia University Medical Center, gave his take on how targeted therapies are impacting the field of HER2-positive metastatic breast cancer, and he interprets the primary data from HER2CLIMB.

TARGETED ONCOLOGY: Can you discuss the prevalence of brain metastases in breast cancer, and what is the prognosis for these patients?

Kalinsky: We see a certain sort of trumpism for CNS metastases in various subtypes. In particular, we see brain metastases for patients with metastatic triple-negative breast cancer as well as for HER2-positive breast cancer. Metastatic disease in triple-negative breast may be something we see early on than in HER2-positive disease. Since we have such robust agents that can treat systemic disease, we have an unmet need regarding more heavily pretreated patients.

In general, it depends on the volume and the rate of the development of metastases.

TARGETED ONCOLOGY: Which agents appeared promising in this space prior top tucatinib? What is exciting about the tucatinib CNS PFS sub analysis data presented by Nancy Lin at the SNO Brain Mets meeting?

Kalinsky: Before agents like tucatinib, there were other tyrosine kinase inhibitors that we've been using in our patients who have HER2-positive metastatic breast cancer that included agents like neratinib (Nerlynx) and lapatinib (Tykerb). I think 1 of the things that's really compelling about the recent tucatinib data is the significance of response and seeing an overall survival benefit. That's not something that we really had seen with other TKIs, which couldn’t get to the CNS.

When we think of HER2CLIMB, we look at the overall population because they’re not only showing PFS but also OS. What’s also remarkable is the landmark analysis. The PFS in that analysis showed a significant advantage in patients who received tucatinib. The other thing that's worth mentioning is that nearly 50% of patients in this randomized trial had CNS metastases and the trial included patients who had asymptomatic brain metastases and progressing brain metastases. Looking at PFS and brain control, it was impressive how much better patients did in the tucatinib arm compared with the control arm.

Another point is that when we have patients with HER2-postive breast cancer that if have their disease under control, but have some progression in their CNS metastases, oftentimes we will think about giving local therapy. Then we would continue the systemic therapy they were given. That was 1 thing that was looked at in the HER2CLIMB trial in the subgroup of patients who were in the tucatinib arm, and as a result, the patients in the tucatinib arm did better than those in the placebo arm.

The other thing about this agent that is impacting our care in real life is the discussion with neuro-oncology as well as with radiation oncology because there may be patients that we can think about sparing radiation and have them go on tucatinib. Then, we can eventually do radiotherapy. This particularly refers to patients who may need whole-brain radiation. If we have patients with CNS control, it’s nice to have an active agent that we can consider besides local therapy.

TARGETED ONCOLOGY: How has the role of radiotherapy and surgery been impacted by targeted therapies?

Kalinsky: I think that there still is a role for targeted intervention, and I think this is evolving.

For those patients who have small lesions that are amenable to either surgery or radiotherapy, then it does make sense to give them targeted therapy. We do see with tucatinib that it may be possible to delay giving local therapy. The patients for whom this has the most potential to be practice-changing is patients who may require whole-brain radiotherapy. We see term cognitive and even short-term cognitive adverse events with whole-brain radiotherapy. If there is a small molecule that can delay progression in the CNS, then we could think about delaying whole-brain radiotherapy. So, there's still a role, but it just may change the sequencing in terms of thinking about that.

TARGETED ONCOLOGY: Based on your experience at the meeting, how important is it to have medical conferences that focus on brain metastases?

Kalinsky: In breast cancer, where we see that a lot of patients get into trouble when they develop brain metastases, particularly in triple-negative disease and HER2-positive disease. I think that we're increasingly aware of the importance of having agents that can have some clinical impact in the CNS. Having isolated conferences various disciplines like medical oncology, radiation oncology, and others get together and think about how to report the data that we have and then improve on these paradigms is important. This does reflect real life where on a weekly basis I'm emailing with those kind of specialists to think about how to treat our patients. At my institution, we also have oncology tumor boards regularly with these types of specialists.

Highlighting the kind of synergy and collaboration that happens between these specialists in a conference setting makes a lot of sense.

TARGETED ONCOLOGY: What research do you have ongoing in the realm of breast cancer with brain metastases?

Kalinsky: I am involved in a study that was reported at this year’s American Society of Clinical Oncology Annual Meeting, and we’re hoping to submit it as a manuscript. It was a study in which we looked cerebrospinal fluid One of the issues that we identified was that doing standard pathologic assessments that patient's may require a number of tests. What we were doing was asking the question of whether we could use this microfluidic device to determine the presence or absence of leptomeningeal disease and whether or not it was better than what we usually use. We did see small number of patients with some concordance and identification that we might not have seen with normal evaluation. We plan to report on this further in the future.