Volkmar Müller, MD, PhD: Returning to brain mets [metastases], we saw retrospective data of patients who did not have brain metastases at initial diagnosis and entry into the trial. It appears that the more active combination of tucatinib, trastuzumab, and capecitabine can prevent the occurrence of brain metastases. That’s something we have not addressed yet. Half of the patients who have HER2-positive metastatic disease will develop brain metastases, so we urgently need strategies to prevent this. We need to focus not only on treated patients who have been locally pretreated, but also prevention. That’s one of the other wishes we have, we believe this combination might help prevent the occurrence of new brain metastases. What are your thoughts?

Tiffany A. Traina, MD: That’s a generating hypothesis for moving tucatinib, as the TKI [tyrosine kinase inhibitor] that crosses the blood-brain barrier, early into the treatment algorithm. I’d love to see those studies, Dr Criscitiello mentioned a combination with T-DM1 [trastuzumab emtansine]. You can envision in the highest-risk population in early stage disease who failed pathCR [pathologic complete response], 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. The data you’re referring to are hypothesis generating, to look in that space and hopefully change the natural history of HER2+ metastatic disease.

Volkmar Müller, MD, PhD: Thanks. Dr Criscitiello?

Carmen 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 longer these patients live, the higher chance they will develop brain metastases at some point. One problem is the progression of brain metastases in patients who have already received radiation therapy and cannot do it again. Some patients undergo multiple local treatments, but eventually they are no longer feasible. Traditionally, systemic drugs are not that effective on brain metastases. We shouldn’t forget the physical and cognitive deterioration in response to radiation therapy. With effective drugs on the brain, we could be less aggressive in local treatments. Another problem is the presence of leptomeningeal metastasis, which is related to end of life in these patients. It’s important to understand if and how we can prevent brain metastases.

Volkmar Müller, MD, PhD: There were several reports, one mentioned at ESMO [European Society for Medical Oncology annual meeting], about T-DXd [trastuzumab deruxtecan] and active brain metastases. There’s also a small subset of the DESTINY-Breast01 trial that was reported at ASCO [American Society of Clinical Oncology] this year, 2021. Dr Criscitiello can you comment on that?

Carmen Criscitiello, MD, PhD: At ASCO this year was a subgroup analysis of the DESTINY-Breast01 trial. Patients with a history of brain metastases were presented. The study enrolled 24 patients with baseline brain metastases that were treated as symptomatic and did not require therapy to control symptoms. 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. Among these patients, 7 of 14 had a response in the brain. It’s important to remember that of these 14 patients, 12 had received prior radiation therapy before enrollment in the study. Trastuzumab deruxtecan works in patients with brain metastases as we have seen from the TUXEDO trial mentioned earlier. But we are talking at the moment about a few patients. 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. Most of these patients received prior radiation therapy. It’s important to differentiate between active progressing brain metastases and stable brain metastases. 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. So in patients with active brain metastases, I would choose tucatinib first. For patients with stable brain metastases, our data suggest a superior trastuzumab deruxtecan over tucatinib. While there are no direct comparisons, this may change in the future based on the results of the ongoing trials.

Volkmar Müller, MD, PhD: Dr Traina, do you agree?

Tiffany A. Traina, MD: Yes, that was beautifully said and comprehensive. 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. It’s encouraging to see the beginnings of a signal of CNS [central nervous system] penetration and activity from an antibody-drug conjugate [ADC], where we felt traditionally that kind of construct was too big or bulky to cross the blood-brain barrier. There’s evidence that that’s not the case, and perhaps the permeability and the cleavable linkers in the engineering of these new ADCs may allow for CNS penetration. They are exciting and encouraging data in both respects, to have tucatinib and [trastuzumab] deruxtecan as an option.

Volkmar Müller, MD, PhD: There are a lot more data coming. We mentioned that earlier use of tucatinib and T-DXd might offer insight if we are able to prevent [brain metastases]. The DESTINY-B12 trial will allow the recruitment of patients with active brain metastases but also those without brain metastases; it will have 2 cohorts. It will give us insight into whether we are capable of preventing brain metastases, but also about the efficacy of T-DXd, trastuzumab deruxtecan, in those patients with active brain metastases. We already have some evidence on how we can use these drugs in different patient cohorts. Moving forward there will be many new trials, exciting meetings, and new data for this big unmet need of brain metastases, but also for all the other patients.

Transcript edited for clarity.