Unanswered Questions in HER2+ Breast Cancer

Thomas Bachelot, MD, PhD: When you speak about metastatic breast cancer, every patient can be seen as an unmet need because every patient will die at 1 point from that disease. Very few patients are cured. Even things that are not considered to be unmet needs feel like unmet needs at some point. Therefore, this combination with tucatinib can help address these unmet needs. Patients who have progressive brain metastases who have already been treated with radiation therapy cannot get radiation therapy again, but you can give them this triplet combination. When those patients progress again, we have another unmet need because if you cannot treat them, then their prognosis will be bad. But we have some new drugs coming out to treat HER2 [human epidermal growth factor receptor 2]–positive breast cancer. The most exciting and most talked treatment is trastuzumab deruxtecan, or T-DXd. That is very impressive for an early clinical trial.

Unfortunately for this molecule, we are still waiting for the randomized study, so it is difficult to know exactly where we are going to put it. Most patients who received T-DXd [trastuzumab deruxtecan] have had very nice responses, and that is very unusual for patients with multiple pretreatments, so we are very happy to have T-DXd [trastuzumab deruxtecan] available to those patients because it will allow us to design treatment strategies that will help our patients and prolong their overall survival rates. It is difficult at the moment, because we have 2 treatments: the combination with tucatinib and this triplet combination with tucatinib on 1 hand, and on the other hand, T-DXd [trastuzumab deruxtecan], which came out around the same time. It is difficult to conduct a precise evaluation of which will be first or who will be second.

For the moment, we have to wait for a phase 3 trial with T-DXd [trastuzumab deruxtecan]. Most likely, in the months to come, there is going to be another other trial focusing on T-DXd [trastuzumab deruxtecan] vs T-DM1 [trastuzumab emtansine] in particular. In this trial, T-DXd [trastuzumab deruxtecan] was more effective than T-DM1 [trastuzumab emtansine] for the second line. Thus, the patient will receive T-DXd [trastuzumab deruxtecan] in second line, and tucatinib will be the third line after T-DXd [trastuzumab deruxtecan]. As for T-DM1 [trastuzumab emtansine], I do not know when we are going to use it. Maybe it will be used as a fourth line or in combination with tucatinib. There is another study, HER2CLIMB-02, that combined T-DM1 [trastuzumab emtansine] and tucatinib with randomization. The landscape is really going to change in the months and years to come for those patients. It will change for the better because those drugs are very efficient, so I hope that it will really improve the PFS [progression-free survival] rate, the quality of life, and the overall survival of our patients who have HER2+ breast cancer. 

Volkmar Mueller, MD: Because I am enthusiastic about this trial and all the new developments, I do think there are many unmet needs already. These unmet needs have been discussed in several meetings—even the virtual meetings—over the last year, and 1 unmet need is the prevention of brain metastases in patients with metastatic disease. It might be possible to add something to therapy—for example, tucatinib—and prevent the occurrence of brain metastases.

Some patients are unsuccessful when given local treatment for brain metastases, so radiotherapy and surgery are necessary. We may need some strategies to provide effective systemic therapy for these patients after the treatment failure of local therapy. Another point that came into my mind is that we need a better combination of endocrine therapy with HER2-targeted therapy, especially in the context of CDK4/6 inhibitors. They are not used as a standard of treatment for HER2+ breast cancer. That is a field ready for development. That is going to be a place for endocrine treatment, together with HER2-targeted therapies.

Finally, it is important to prevent metastatic disease, so the ultimate goal is to optimize earlier treatment of breast cancer and to find strategies to cure more patients. In summary, given the status of the HER2CLIMB study and the approval in Europe, I am excited that we have a new drug, a new combination that prolongs overall survival, for not only patients with brain metastases but also our entire patient cohort. I am looking forward to the developments, and I am curious about what will come up.

TRANSCRIPT EDITED FOR CLARITY