Relapsed/Refractory HER2+ Metastatic Breast Cancer - Episode 6

Case 2: Looking at Data in Breast Cancer Patients With Brain Mets

The experts discuss data from clinical trials of metastatic breast cancer with brain involvement.

Joyce O’Shaughnessy, MD: Bill, let’s go back and now she’s got brain mets [metastases] for the first time. What are some of the datasets that you think about in terms of how to approach her with these brain mets? She’s also progressing in her systemic and with lung mets. What datasets do you look at?

William Gradishar, MD: This is evolving and the most robust set of data comes from the HER2CLIMB trial which was randomized and was more inclusive, including patients with active brain metastases. Whereas, the other experiences are more limited. They give us hints of activity in some. They suggest that they may be able to keep disease stable, but the most robust dataset was with tucatinib. Of course, anecdotally, we have lots of data from other agents, including T-DM1 [ado-trastuzumab emtansine] from the KAMILLA trial and others. This is an evolving area and one of the most devastating things, nobody wants breast cancer. No one wants metastatic disease, but when you start telling patients that they have disease in their brain or it’s getting worse, that is a devastating piece of news to convey to your patient. Anything we can do to offset that, delay it, and treat it is going to be something that we need.

Joyce O’Shaughnessy, MD: Prioritizing, big time. Take us through some of the data that are pertinent to HER, Bill.

William Gradishar, MD: If you look at the NCCN guidelines, these aren’t the breast guidelines but the CNS [central nervous system] guidelines. Look at one of the tables, they’re highlighted, obviously in red, the breast cancer agents that may work in this setting. We have old data with single-agent chemotherapy and there was some enthusiasm for capecitabine and then looking at partnering with CAPE [capcapecitabine]with drugs that we thought would cross the blood-brain barrier like TKIs [tyrosine kinase inhibitors], lapatinib, neratinib. Then more recently looking at drugs like not only T-DM1 but the new data from HER2CLIMB and trastuzumab deruxtecan.

If you go back in history to get a sense of what that data looked like, this is not an exhaustive list but it gives you a sense that there have been efforts to address the question of brain mets with TKIs or chemotherapy alone. If you look at the size of some of these trials, they’re modest in size, and if you go to the far right, the overall outcome of these patients remain poor. Again, there are other agents; pirotinib, an agent that came out of Asia that’s another TKI. We’ve had some data suggesting activity, but it’s not something that you can hang your hat on that is going to work well for most patients.

Then we come to the trastuzumab deruxtecan trial, and we’ve already heard from Adam about the data from that trial. If you look at the characteristics of those that were included, there were a fraction of patients with a history of brain mets, about 13% of the patients. This is a huge N [number]. It’s an N of about 24 patients, and these were not patients with active brain mets, but there is some experience with this. If you look at the patients involved, and I indicated 24 of them, the follow-up is short of a year, the median PFS [progression-free survival] was about 18 months, not far off from what the overall PFS was for the group as a whole. If you had CNS mets or not, PFS was about the same. There is at least anecdotal evidence that there was a volumetric change in at least 1 patient with documented brain mets. We need more data. This is not definitive, but it does give some potential for this drug to work in the CNS.

In the HER2CLIMB dataset, there were more patients included that did have brain mets and that included not only those that had treated stable brain mets, those that were untreated and did not need immediate treatment for any sort of neurologic symptoms, and those patients who had been treated in the past but were now progressing. This is a bigger dataset than we had before, and the characteristics of those who got tucatinib or didn’t in this randomized trial were much the same. The addition of tucatinib impacted on overall response rate and the PFS in those patients with brain mets was improved by about two months. This is a randomized experience, the addition of tucatinib impacted the course of those with brain mets.

What’s equally impressive, if you spend time looking at this table it’s no surprise that if you had CNS mets, you’re not going to get a CR [complete remission]. That’s pretty uncommon. Although, there were a few patients that did. But there was a fairly dramatic uptick in the fraction of patients who had a partial response, highlighting the fact that these are patients who received tucatinib get an objective measure of efficacy from the drug. The overall response rate was increased in the brain in those with tucatinib.

What was most impressive, if you look at the patients with brain mets and look at CNS-specific PFS on the left, a clear improvement in outcome, more than doubling the CNS PFS. On the right as well, at least numerically, a modest improvement in overall survival in those patients who received tucatinib. These are the first compelling data from a randomized trial showing that the addition of an agent impacts those patients with CNS metastases.

Transcript edited for clarity.