Sara Hurvitz, MD, Fred Hutchinson Cancer Center at University of Washington, Seattle, Washington, discusses results from the double-blind, placebo-controlled, phase 3 HER2CLIMB trial evaluating tucatinib plus trastuzumab emtansine among patients with previously-treated HER2-positive, metastatic breast cancer.

Dr Hurvitz concluded this study is “the second to show a significant improvement in progression-free survival by adding tucatinib to a standard of therapy, in this case, T-DM1.” She went on to add, “These data really do validate the importance and clinical activity associated with tucatinib in patients with CNS."

These results were first presented at the 2023 San Antonio Breast Cancer Symposium.

Transcript:

I'm Sarah Hurvitz, medical oncologist, professor of medicine and Head of the Division of Hematology/Oncology at University of Washington, Senior Vice President of the Clinical Research Division at the Fred Hutchinson Cancer Center.

I presented the results of HER2CLIMB-02. HER2CLIMB-02 is a randomized phase 3 clinical trial evaluating whether tucatinib added to trastuzumab emtansine (T-DM1) improves outcomes for patients with HER2-positive advanced breast cancer. In this clinical trial, about 460 patients were randomly assigned to receive tucatinib plus T-DM1, or placebo plus T-DM1. Patients were allowed as long as they had received prior trastuzumab and taxane in any setting. It's notable that patients with brain metastases, whether they're stable or untreated or progressing were allowed on this clinical trial, and about 44% of patients enrolled in this study actually had metastases, half of which were active.

The primary endpoint of the study was progression-free survival (PFS) by investigator assessment. There was a hierarchical testing strategy such that if PFS was positive at the primary analysis, then we would test overall survival at the interim analysis. It'd be the first of 2 tests. In general, this study was well-balanced for patient characteristics and demographics. It is, as I said, notable 44% of patients had brain metastases. The median number of prior lines of therapy was 1 on this trial, and 90% of patients had received prior pertuzumab. Nobody had received prior [trastuzumab deruxtecan) T-Dxd. That was exclusionary on this study.

The primary endpoint of progression free survival was met. The addition of tucatinib to T-DM1 improved progression-free survival by about 2 months with a hazard ratio of 0.76. The overall survival was not met at the time of this interim analysis for survival, but it's important to note there are only 53% of observed events, and only 24 months of median follow-up, so these data are immature, and we'll look again at survival when 80% of events have occurred. The progression-free survival in patients who have brain metastases showed a very strong trend toward improvement, with a hazard ratio of around 0.64 with the use of tucatinib. This wasn't formally tested, due to the hierarchical testing design.

In terms of the safety profile, the manageability and safety of this regimen was consistent with the phase 1 study looking at this combination. We do see higher rates of therapy discontinuations and grade 3 or greater adverse events with adding tucatinib to T-DM1, not unexpected. In terms of looking at what the grade 3/4 adverse events were, there are higher rates of transaminase elevation, hepatic events, as well as diarrhea. Both of these things were manageable with dose reductions and dose discontinuations.

In general and conclusion, this study is the second randomized, large clinical trial looking at the use of tucatinib in metastatic HER2-positive breast cancer and the second to show a significant improvement in progression-free survival by adding tucatinib to a standard of therapy, in this case, T-DM1. It's also the second large, randomized trial to allow patients with active or aggressive brain metastases. These data really do validate the importance and clinical activity associated with tucatinib in patients with CNS.

Source:

Hurvitz S, Loi S, O‘Shaughnessy J, et al. (GS01-10) HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer. Presented at San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas. Abstract GS01-10.