The Impact of Brain Metastases on Treatment Selection in Patients with HER2+ mBC

Neil M. Iyengar, MD: So in terms of patients with brain metastases, we have data from HER2CLIMB prospective randomized data demonstrating a benefit of the tucatinib containing regimen versus a non tucatinib containing regimen. We also have subgroup analyses from the DESTINY-Breast trials showing activity of trastuzumab deruxtecan in stable treated brain metastasis. Now, if we look specifically at the tucatinib containing regimen, we know from HER2CLIMB that this regiment is active in patients both with stable treated brain metastasis, but perhaps more importantly also in patients with active brain metastasis. In fact, in HER2CLIMB, about half of the patients who enrolled had brain metastasis at baseline. And of those patients, 60% had active brain metastasis, which were either newly diagnosed or treated, but progressive. And this is a very unique feature of that trial, one of the few trials that allowed for progressive brain mets to be enrolled. Fortunately the trial demonstrated both a progression free survival as well as an overall survival benefit in the overall population, as well as the population with brain metastasis. In addition, at San Antonio last year, we saw a subgroup analysis that looked at intracranial response in patients with brain metastasis. And we saw a favorable intracranial response specifically in the brain lesions, as well as an improved CNS progression free survival with tucatinib capecitabine and trastuzumab. Now, if we look at trastuzumab deruxtecan, we are starting to get some data suggesting its activity in patients with stable or treated brain metastasis. Specifically if we look at the subgroup analysis from the DESTINY-Breast01 trial, we know that there were about 24 patients in that study who had stable treated brain metastasis and had a favorable progression free survival similar to the intention to treat population in that subgroup analysis. In addition, we are now getting some data that suggests that trastuzumab deruxtecan may be helpful for both patients with classically HER2 overexpressed disease, as well as HER2 low disease and brain metastasis. Here at ESMO, we saw a subgroup analysis of the DAISY trial, which is an ongoing phase two trial that has three cohorts of patients, that are divided by HER2 expression status, either overexpressed low or HER2 zero. And we saw the brain metastasis subgroup presented here at ESMO. In that presentation, we saw a progression free survival benefit of trastuzumab deruxtecan across all three subgroups in patients with metastatic breast cancer and stable brain metastasis. Now, I will say that the subgroup of patients with HER2 zero breast cancer in the DAISY trial and brain metastasis accounted for only two patients. So we still have more data or more to learn about that population and the activity of trastuzumab deruxtecan in that population. We also have a small phase two trial, single arm phase two trial demonstrating activity of trastuzumab deruxtecan in patients with active or progressing brain metastasis. [00:12:00] This was from the TUXEDO-1 trial, which was a single arm phase two trial that included 15 patients. And the response rate, the intracranial response rate of trastuzumab deruxtecan was approximately 75%. And again, this is patients with progressive brain metastasis. In addition, we saw a subgroup, or we saw a quality of life analysis, I should say, which showed a- that quality of life was maintained with trastuzumab deruxtecan. And interestingly, we also saw an analysis of neurocognitive function. And neurocognitive function scores were preserved in patients with active brain metastasis who received trastuzumab deruxtecan.