Case 3: CNS Data From Clinical Trials in HER2+ BC


A broad review of CNS-related clinical trial data in the setting of HER2+ breast cancer and concurrent brain metastases.


Sara A. Hurvitz, MD: Bill, take us through very briefly the CNS [central nervous system] subanalyses from 3 or 4 clinical trials. First, the HER2CLIMB study. What were the intracranial responses and outcomes for patients on that trial? Then we can discuss the DESTINY-Breast03 trial. We’ve danced around it a little today, but maybe you could go through some of the numbers.

William J. Gradishar, MD: If you look at the HER2CLIMB regimen, tucatinib-trastuzumab-capecitabine vs capecitabine-trastuzumab, the intracranial response rate was significantly higher in patients who received the addition of tucatinib. Most of those responses were partial, but to put it in perspective, it was 41% vs 15%—a fairly dramatic improvement in objective response rate. For patients who did get a response, the duration of that response was double, so it went from 3 months to 6.8 months; that’s meaningful. Have we cured brain metastases? No, but clearly, our response rate has improved dramatically.

If you look at DESTINY-Breast03, the patients who received T-DXd [trastuzumab deruxtecan] compared with T-DM1 [trastuzumab emtansine]: the objective response rate was more than double. These numbers are small; you’re talking about 20 patients in each treatment arm. Nonetheless, it went from 33% to 63%; that’s intracranial response. There’s evidence even though we don’t have a huge trial showing that this has some impact on the CNS.

Similarly, we haven’t talked a lot about neratinib, which is another TKI [tyrosine kinase inhibitor] option at some point in patients with progressive metastatic disease. I’d be more inclined to use that after T-DXd [trastuzumab deruxtecan], but we have evidence from the NALA trial that some patients respond. The partial response rate was similar between those getting lapatinib and neratinib, roughly around 36% to 38%. There was a patient who had a complete response in the brain, and a significant fraction of patients maintained stable disease.

If you look at objective response rate in the brain, it’s about 10% higher in patients who receive neratinib. We have several agents. Back in the day, we did not have a lot; we had anecdotes. Now we’re starting to develop a series of trials that more convincingly demonstrate the efficacy of these drugs in the CNS. The NCCN [National Comprehensive Cancer Network] Guidelines have highlighted this in patients who have brain metastases: we have a number of treatment options that could be chosen. The most compelling data category 1 remains the HER2CLIMB regimen with tucatinib, but we have data with T-DXd [trastuzumab deruxtecan], T-DM1 [trastuzumab emtansine], capecitabine as monotherapy, or capecitabine combined with a TKI such as lapatinib or neratinib. The field is evolving.

Sara A. Hurvitz, MD: It certainly is. It’s going to be very exciting to see. Given that up to half of our patients with HER2 [human epidermal growth factor receptor 2]–positive advanced disease will experience CNS metastases in their lifetime, it’s an area of unmet need. Our screening practices and our management practices are going to change.

Sara, I want to follow on 1 point that Bill made about using neratinib after tucatinib, or not having data to tell us how to sequence these. Have you in your own practice used neratinib or lapatinib after tucatinib or vice versa? These are all TKIs. When you have a patient sitting before you, who’s gone through multiple lines of therapies, sometimes we’ll use similar targeted agents. What’s been your experience?

Sara M. Tolaney, MD, MPH: That’s a good question. They are different because tucatinib is a more HER2-specific TKI. It’s a reversible inhibitor, whereas neratinib is a pan-HER TKI and an irreversible inhibitor. One could imagine there could be differences. Maybe neratinib, for example, could work post-tucatinib. But as Bill pointed out, but we don’t have data about that. The capecitabine-tucatinib-trastuzumab regimen has survival benefit, but NALA did not have survival benefit. We’ve been preferring to use tucatinib, and it’s generally better tolerated.

Have I ever done it? There was 1 patient that I had done it in because we have a trial ongoing, looking at neratinib in the current CNS trial, looking at T-DM1 [trastuzumab emtansine] with neratinib. Years ago I had a patient who was on the study and then progressed. When the HER2CLIMB regimen became available, she’d experienced further CNS progression but hadn’t seen capecitabine, so she did get capecitabine-tucatinib-trastuzumab. She did have some benefit, but it’s hard to know if it was tucatinib driven because trastuzumab can have benefit as well. It’s an important question that needs to be addressed.

Sara A. Hurvitz, MD: Those are good points. In our clinical practice, we’ll do therapies such as switching and sequencing therapies in the absence of data, but these studies are going to be critically important in helping guide our practice. What other studies are you excited to see in terms of HER2+ breast cancer brain metastases? Are there any studies or drugs you’re following very closely? Bill, you mentioned T-DXd [trastuzumab deruxtecan] earlier. It there anything else that’s exciting to you?

William J. Gradishar, MD: There are several drugs in development, other antibody-drug conjugates [ADCs]—not just for HER2+ diseases. That’s quite an exciting arena. There are of course, several therapies being combined with either immunotherapy or other targeted therapies and even novelty in how the drugs are being designed with regard to the antibody, including bispecific antibodies targeting more than 1 target simultaneously. Even though we’ve made enormous strides, the promise of some of these new drugs makes the future that much more exciting.

Sara A. Hurvitz, MD: Sara, what are you looking forward to seeing in terms of breast cancer, brain metastases, and ongoing clinical trials? You’ve heard about novel agents.

Sara M. Tolaney, MD, MPH: Even with T-DXd [trastuzumab deruxtecan], we still have a lot to learn. We’ve seen a little data from TUXEDO-1 with a high initial response rate in the CNS at an interim. We’ve seen a cohort from DEBBRAH presented with about a 50% CNS response. We’ve seen some case series, but we don’t have a large data set. We’ll see more work from TUXEDO and DEBBRAH, but DESTINY-Breast12 will have many patients with CNS involvement that we’d all love to see cleaner data for and large numbers of patients with progressive brain metastases. That will be important to understand. It will be interesting to see how T-DXd [trastuzumab deruxtecan] plus tucatinib performs.

There’s that ongoing trial that you alluded to that allows for patients with progressive brain metastases; it will be interesting to see how that performs with that robust combination. There are other novel agents. We have a few CNS trials ongoing. One is looking at a Zion [Pharma] agent, a TKI, that has good CNS penetration. There are a lot of other agents. There are other ADCs. ARX788 is 1 you’ve been very involved in with development. There’s a study in China for people with progressive CNS disease. There will be lots of new data that will come out, which will be great.

Transcript edited for clarity.

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