Future Opportunities With Novel Therapies for HER2+ Breast Cancer

Giuseppe Curigliano, MD, PhD: We have a study in the second-line setting comparing T-DM1 [trastuzumab emtansine] vs T-DM1 [trastuzumab emtansine] and tucatinib. This is an important trial because this new study might show an additional benefit from the combination of T-DM1 [trastuzumab emtansine] with tucatinib in the second-line setting. We also have a chance to use tucatinib in the context of patients with HER2 [human epidermal growth factor receptor 2]–mutant breast cancer, because I’m sure there’s also an opportunity of development for this patient population. We should explore the opportunity to combine tucatinib and endocrine therapy in HER2-positive disease as well.

The greatest unmet need is the patient population with brain metastases. The HER2CLIMB study clearly demonstrates a progression-free survival and overall survival benefit in this patient population. But the most important unmet clinical need is to avoid the development of brain metastases in this patient population. We should also think about clinical trials in the adjuvant setting, considering brain metastasis progression as the primary end point in order to understand if tucatinib can really be a game-changer as well in this setting.

In the metastatic setting, we should wait for the data from DESTINY-Breast03, which is a prospective randomized trial comparing T-DM1 [trastuzumab emtansine] to trastuzumab deruxtecan. A press release seems to confirm that trastuzumab deruxtecan can be better than T-DM1 [trastuzumab emtansine]. This means that when data will be available at ESMO [European Society for Medical Oncology Congress] 2021 in a few weeks, we’ll have a new standard of care, and the second-line treatment will be trastuzumab deruxtecan. This means that we’ll have a new generation antibody-drug conjugate in the second-line setting. In the sequence, we should consider using tucatinib in the third-line setting.

Immunotherapy may play a role. We have a K2 study exploring the combination of dual-blockade class immune checkpoint inhibitors in the PD-L1–positive population. Let’s see in the long term which would be a benefit. A trial will explore CDK4/6 inhibitors in the maintenance setting following response to taxane, pertuzumab, and trastuzumab or taxane and trastuzumab in responders. There’s a study exploring endocrine therapy plus anti-HER2 therapy vs endocrine therapy and a CDK4/6 inhibitor—in this case, palbociclib—plus anti-HER2 therapy. We’ll see the results.

We also have specific studies for PI3 kinase-mutant HER2+ breast cancer, also in the context of the maintenance setting. But in all these studies, we don’t have any antibody-drug conjugates. We have only patients who received dual blockade. I really believe we need to move novel agents to early lines of therapy. It’s also time to explore the role of tucatinib in the second-line setting when combined with T-DM1 [trastuzumab emtansine] and specific antibody-drug conjugates in the first-line setting to compare with the standard of care, pertuzumab, trastuzumab, and taxanes.

Transcript edited for clarity.