Therapeutic Sequencing in HER2+ MBC

Volkmar Müller, MD, PhD: What’s the treatment sequence we could imagine with these new data? It’s nice to have many things, but how should we put it together? Dr Curigliano, please continue your vision on the treatment sequence.

Giuseppe Curigliano, MD, PhD: Everything should be based on leading evidence and grade of recommendation. The first line is still pertuzumab, trastuzumab, and taxanes for patients with a treatment-free interval of 1 year. For patients who have relapsed or who will progress to trastuzumab, pertuzumab, and taxanes, the standard of care in the second-line setting should be trastuzumab deruxtecan, because according to the DESTINY-Breast03 trial, compared with T-DM1 [trastuzumab emtansine], there’s a dramatic improvement in progression-free survival and a trending overall survival. In the DESTINY-Breast03 trial, there were only patients with stable brain metastases. Should we consider patients with active brain metastases for tucatinib, trastuzumab, and capecitabine? For the third line, should we use T-DM1 [trastuzumab emtansine] because there’s a payload that’s different from deruxtecan? Or should we give trastuzumab tucatinib and capecitabine? In HER2CLIMB, there were no patients treated with trastuzumab deruxtecan. We are clear in the first and second lines, but we need to look at active brain metastases and the positioning of tucatinib after trastuzumab deruxtecan.

Volkmar Müller, MD, PhD: I don’t think there’s much of a difference. I would consider several factors. For patients with brain metastases, I’d choose third-line tucatinib, but I would address the adverse effects. Some patients might prefer an IV [intravenous] regimen; others might prefer oral regimens. The situation in Germany is not as described. There’s no difference for a patient from the reimbursement situation; everything is reimbursed. I tend to go for tucatinib as a third-line option and trastuzumab deruxtecan in the second line. Dr Traina, what’s the US or the New York perspective?

Tiffany A. Traina, MD: I don’t know if I can speak for the entire United States, but I’ll share a couple of points. First, around the DESTINY-Breast03 study, about half those patients were treated in the second-line setting, and the other half were third line and later, with a bit of the DESTINY-Breast01 population. About 60% of patients in DESTINY-Breast03 saw pertuzumab previously. That’s not to take away from the incredible efficacy that we see in the trial, but we consider how those data apply to patients we’re seeing in clinic. There are a lot of unknowns. We don’t know how T-DM1 [trastuzumab emtansine] is going to perform in the third line or later if agents like tucatinib and trastuzumab deruxtecan move up. We have a highly active agent, and I’m more inclined to use that earlier rather than reserve it for later.

The tucatinib data are powerful in patients with active, untreated brain metastases. There was a small report at ESMO [European Society for Medical Oncology Congress] of the TUXEDO-1 trial, which had about 15 patients. Patients were treated with trastuzumab deruxtecan in the setting of CNS [central nervous system] metastases. There were 6 evaluable patients, and 5 had CNS response by RANO [Response Assessment in Neuro-Oncology] criteria. It was a small, randomized trial, but it hinted that there’s CNS activity even with that antibody-drug conjugate. My paradigm is first-line, taxane–HP [trastuzumab, pertuzumab]. For the second-line setting, CNS metastases may be a differentiator. Patient preference is important, but the activity around trastuzumab deruxtecan was so profound that they may position it in the second-line setting. For the third line, we have agents like tucatinib and TDM-1 [trastuzumab emtansine] to consider, but we also have indication in the United States for margetuximab with chemotherapy in that third-line setting and other agents in the pipeline. We’re fortunate to have so many agents to choose from.

Transcript edited for clarity.