New Frontiers in Breast Cancer: Updates and Advances in Treatment - Episode 9

Clinical Trials in HER2+ mBC: DESTINY-Breast03 and HER2CLIMB


Highlights of the results from the DESTINY-Breast03 and HER2CLIMB trials, evaluating T-DXd and tucatinib, respectively, in HER2+ metastatic breast cancer.


Sara A. Hurvitz, MD: Let’s look at the DESTINY-Breast03 data. This is the clinical trial that went head-to-head against T-DM1 [trastuzumab emtansine]; T-DXd [trastuzumab deruxtecan] versus T-DM1, 1:1. Patients were allowed on if they had 1 prior line of therapy with trastuzumab and a taxane; about half of the patients had 1 prior line and half had more than that. A good number of patients were in the second-, third-, or fourth-line setting being treated here. The primary end point was blinded independent central review of PFS [progression-free survival], with the key secondary end point of OS [overall survival]. They allowed patients who had stable brain metastases, and there were about 70 or 80 patients who fell into the criteria of having known brain metastases at the beginning, so a small portion of about 15% of the patients. But these patients weren’t allowed to have progressive active brain metastases.

If you go to the next slide, you can see the progression-free survival. The primary end point, which was reported last year at ESMO [European Society for Medical Oncology annual meeting] by Javier Cortez, [MD, PhD,] showed a stunning difference in the 2 PFS curves highly in favor of T-DXd with a hazard ratio of 0.28. By blinded independent central review, the median PFS hadn’t been met for T-DXd and was under 7 months for T-DM1. Now when they did the investigator assessment of PFS, it was at 25 months, which I find compelling because if you consider the median PFS in the CLEOPATRA trial, in which 90% of the patients had never received any trastuzumab, the median PFS was 18 months. In this study where patients were more heavily pretreated, the PFS by investigator was over 2 years. This drug will probably push into the first-line setting soon.

The next slide shows you the early glimpse at overall survival, which is trending in favor of T-DXd, however, it is immature and there are too few events. It didn’t meet that crossing boundary to claim statistical significance, so all eyes are on survival data in upcoming presentations. We haven’t shown it here, but the central nervous system outcomes were presented at the San Antonio [Breast Cancer Symposium]. It was interesting, of the patients with stable brain metastases who went on the study and had their scans read by blinded independent central review, about a third treated with T-DM1 had an intracranial objective response, which is stunning in itself, that an ADC [antibody-drug conjugate] could induce an intracranial response. But in the T-DXd arm, that number was close to 64% intracranial objective response, calling into question this paradigm thinking that ADCs and bulky molecules can’t have impact in central nervous system metastases. We’re seeing evidence that, at least in patients who have been previously treated with radiation or surgery to the brain, there can be an impact.

Joyce, you’re going to go through some of the data supporting the use of tucatinib in these patients?

Joyce A. O’Shaughnessy, MD: Yes, because in your patient with the 8-mm metastasis, I might talk to her about not getting SRS [stereotactic radiosurgery], as she has liver disease too. We’re going to switch therapy anyway for her. If we look at the next slide with the HER2CLIMB trial, which was the trastuzumab, capecitabine, and placebo versus trastuzumab, capecitabine, and tucatinib. Tucatinib is very potent HER2 TKI [tyrosine kinase inhibitor], a lot of brain penetration. There was an improvement in progression-free survival in the next slide as you can see, but most importantly in the next slide, overall survival, and we see the brain metastasis data on the next slide. This is PFS, a nice improvement in PFS in the brain, and substantially improved survival in patients with brain metastasis. This is an excellent brain agent. In this study, they allowed patients who had not had any SRS or brain radiation, if they were asymptomatic progressing disease, or newly diagnosed. Most metastasis, like Sara’s patient, didn’t have to have SRS. You could use it as an indicator lesion to see if the medication was working and put off the use of the radiation therapy, which is an excellent option. It is a third-line option now because the T-DXd results are stunning with regard to PFS, survival is getting there rapidly, but the brain metastasis data are very compelling.

We’ve got a couple of great options now for patients with brain metastasis, and I would utilize T-DM1 in a later line after the TKI, after the tucatinib, in the third-line setting.

Transcript edited for clarity.