It’s difficult to make cross-trial comparisons when recognizing patient populations in the DESTINY-Breast01 trial and how that differs from the HER2CLIMB population. Traina, MD: Yes, that was beautifully said and comprehensive. Volkmar Müller, MD, PhD: Dr Traina, do you agree? While there are no direct comparisons, this may change in the future based on the results of the ongoing trials. For patients with stable brain metastases, our data suggest a superior trastuzumab deruxtecan over tucatinib. So in patients with active brain metastases, I would choose tucatinib first. Also, in the best sequencing of tucatinib versus trastuzumab deruxtecan in patients with brain metastases, tucatinib is the only data in this setting in which we have, from a phase 3 randomized controlled trial, proof of efficacy on acting brain metastases. It’s important to differentiate between active progressing brain metastases and stable brain metastases. Most of these patients received prior radiation therapy. In the subanalysis of the DESTINY-Breast01 trial, we’re talking about patients with stable brain metastasis patients with active brain metastases were ineligible for this study. But we are talking at the moment about a few patients. Trastuzumab deruxtecan works in patients with brain metastases as we have seen from the TUXEDO trial mentioned earlier. It’s important to remember that of these 14 patients, 12 had received prior radiation therapy before enrollment in the study. Among these patients, 7 of 14 had a response in the brain. In the subanalysis, the outcomes of efficacy were comparable to those in the total patient population 14 of 24 patients had the baseline diameters of brain metastases.
The study enrolled 24 patients with baseline brain metastases that were treated as symptomatic and did not require therapy to control symptoms. Patients with a history of brain metastases were presented. Dr Criscitiello can you comment on that?Ĭarmen Criscitiello, MD, PhD: At ASCO this year was a subgroup analysis of the DESTINY-Breast01 trial. There’s also a small subset of the DESTINY-Breast01 trial that was reported at ASCO this year, 2021. Volkmar Müller, MD, PhD: There were several reports, one mentioned at ESMO, about T-DXd and active brain metastases. It’s important to understand if and how we can prevent brain metastases. Another problem is the presence of leptomeningeal metastasis, which is related to end of life in these patients. With effective drugs on the brain, we could be less aggressive in local treatments. We shouldn’t forget the physical and cognitive deterioration in response to radiation therapy. Traditionally, systemic drugs are not that effective on brain metastases.
Some patients undergo multiple local treatments, but eventually they are no longer feasible. One problem is the progression of brain metastases in patients who have already received radiation therapy and cannot do it again.
The longer these patients live, the higher chance they will develop brain metastases at some point. Dr Criscitiello?Ĭarmen Criscitiello, MD, PhD: We have performed a big part of the process with these new drugs, but there is still an unmet need in treating patients with brain metastases. The data you’re referring to are hypothesis generating, to look in that space and hopefully change the natural history of HER2+ metastatic disease. You can envision in the highest-risk population in early stage disease who failed pathCR, if you had evidence that the combination with tucatinib could prevent the development of brain metastases, that would be an answer to a huge unmet need. I’d love to see those studies, Dr Criscitiello mentioned a combination with T-DM1. Traina, MD: That’s a generating hypothesis for moving tucatinib, as the TKI that crosses the blood-brain barrier, early into the treatment algorithm. That’s one of the other wishes we have, we believe this combination might help prevent the occurrence of new brain metastases. We need to focus not only on treated patients who have been locally pretreated, but also prevention. Half of the patients who have HER2-positive metastatic disease will develop brain metastases, so we urgently need strategies to prevent this. That’s something we have not addressed yet. It appears that the more active combination of tucatinib, trastuzumab, and capecitabine can prevent the occurrence of brain metastases.
Volkmar Müller, MD, PhD: Returning to brain mets, we saw retrospective data of patients who did not have brain metastases at initial diagnosis and entry into the trial.