Sara A. Hurvitz, MD, FACP, on New Therapeutic Strategies for HER2-Positive Metastatic Disease Including Brain Metastases

At IBC West this year. I spoke about HER2-positive metastatic breast cancer and the standard of care therapy for patients with this disease, as well as emerging therapies. And this discussion included a discussion on those patients affected by brain metastases. We know that the survival for HER2-positive metastatic breast cancer is greatly improved. In fact, the natural history of this disease has reversed from the worst prognostic subgroup of breast cancer to probably the best, and that is because of the armamentarium available now to target the HER2 alteration in HER2 over expressing an amplified disease. In the frontline setting our standard of care as of 2024 remains taxane, usually docetaxel, some-times paclitaxel, in combination with trastuzumab and pertuzumab. And this is based on the CLEO-PATRA results, which came out back in 2012 and were practice changing at that time because it was shown that adding pertuzumab to taxane plus trastuzumab actually improved not only progres-sion-free survival, but also overall survival. And the median overall survival, at that time, was just under five years. The second line therapy to be used after taxane and trastuzumab was based on the EMILA clinical trial around 2012/2013, where TDM-1, the first antibody drug conjugate approved for breast can-cer, was tested against lapatinib capecitabine and shown to be associated with an improved pro-gression-free survival and overall survival. So up until a few years ago, TDM-1 became the standard of care in patients who had trastuzumab and taxane. However, in recent years, we've seen data of novel agents that have begun to challenge this sec-ond line setting standard of care, TDM-1. The first of this was a study called DESTINY - Breast03, looking at a newer antibody drug conjugate trastuzumab deruxtecan, which also targets HER2. This was compared to TDM-1 in patients with HER2-positive metastatic breast cancer, and was shown in those patients who had all received trastuzumab and a taxane to be associated with a better pro-gression-free survival and a better overall survival. In fact, the data with respect to progression-free survival was so good the median PFS was over 28 months in this more heavily pretreated patient population, which looks better than the frontline setting data we saw with CLEOPATRA. So we may see T TDXD move up into the frontline setting once the results of DESTINY-Breast09 come out. That's an ongoing study looking at TDXD in the frontline setting. Another agent that tested the efficacy of TDM-1 alone versus a novel regimen was tucatinib. In the HER2CLIMBO2 study, tucatinib was added to TDM-1 and compared to TDM-1 alone in patients who'd had trastuzumab and taxane, the combination regimen was shown to have a better progres-sion-free survival. But the overall survival was not statistically significant at the early analysis. And there was a higher rate of grade three, ALT and AST elevation with tucatinib. So this regimen is not yet approved or indicated in this setting. After patients have experienced disease progression on TDM-1, one could utilize TDXD based on DESTINY-Breast02 or could use tucatinib plus capecitabine based on the HER2CLIMB study that showed that tucatinib added to capecitabine and trastuzumab improves progression-free survival, and overall survival, and has significant activity in those patients with brain metastases. Selecting between these therapies, TDXD versus tucatinib-based therapy is really an individual de-cision, and many clinicians are making that decision based on the presence or absence of brain me-tastases, given the level one evidence supporting tucatinib-based therapy in the presence of brain mets. Brain mets are a fairly common occurrence with HER2-positive breast cancer. Up to a third or half of patients with HER2-positive metastatic disease will develop brain mets in their lifetime. And as I said, tucatinib, capecitabine and trastuzumab has been shown to be beneficial in this set-ting. But also, antibody drug conjugates have shown efficacy here, including TDXD, which has shown benefits in patients with brain mets in the TUXEDO study, the DEBRA Study, and in a pooled analysis of DESTINY-Breast01, 02, and 03, where the intracranial objective response rate with TDXD in pa-tients with stable brain mets was around 45%. Ongoing studies are now interrogating whether or not TDXD in a prospective study of patients with active brain metastases, whether TDXD is benefi-cial, so we'll all have to stay tuned. For now, although there's a ton of clinical trials in this space and many agents being looked at like zanidatamab and zenocutuzumab, other agents as well, looking at HER2 targeted approaches. The standard of care for a patient in the frontline setting with HER2-positive metastatic breast cancer is THP, followed by TDXD. In some situations, you could use tucatinib, capecitabine, trastuzumab, such as in the situation of active brain mets in that second line setting. And after that, you have multiple agents available, TDM-1, tucatinib-based regimens, lapatinib, neratinib, and trastuzumab with other chemotherapy options, not to mention endocrine therapy. So it's an exciting time with a lot of hope and a lot of activity. Thank you.