T-DM1 shows promise in treating unresectable locally advanced or metastatic HER2-positive breast cancer
Dr Sara Hurvitz - University of Washington, Seattle, USA
The HER2CLIMB-02 clinical trial was a phase III randomised study evaluating whether adding tucatinib to T-DM1 benefits patients with HER2-positive advanced breast cancer. We know that tucatinib has activity in patients with HER2-positive metastatic disease, including patients with brain metastases from the HER2CLIMB trial, in which adding tucatinib to capecitabine and trastuzumab improved not only progression free survival, but overall survival. We also know that it is safe and has some anti-tumour efficacy to add tucatinib to T-DM1 based on a phase Ib study. So we aimed to look at whether or not adding tucatinib to T-DM1 in a larger phase III randomised study was beneficial.
Approximately 420 patients were to be randomised to either T-DM1 plus placebo or T-DM1 plus tucatinib. The primary endpoint was progression-free survival with a number of key secondary endpoints, including overall survival which would be evaluated. The evaluation would be triggered if there was a positive PFS at the analysis of PFS.
What were the results of this study?
This trial enrolled patients who had had at least one line of trastuzumab and taxane in any treatment setting. The majority of patients who enrolled in the study had received pertuzumab. No patients had received prior tucatinib or T-DXd. Our results show that the progression free survival was statistically significantly improved by adding tucatinib to T-DM1. It was improved in the intent to treat population. Because this was a positive finding, this triggered the first interim overall survival analysis. This was not statistically significantly different between the two treatment arms at this timepoint, but only 53% of the survival events had been observed, so we’ll have to see what the next interim analysis shows when 80% of events have been observed.
There was a strong trend toward improvement in median progression free survival for those patients with brain metastases. Patients with brain metastases comprised around 40-45% of the patients enrolled in this study. There was about a two-month improvement in progression free survival both for the intent to treat patient population as well as those patients with brain metastases. The objective response rate also trended in favour of the tucatinib arm.
There was a higher rate of ALT and AST elevation in patients receiving tucatinib-based therapy, as well as GI side effects, although the rates of diarrhoea were not as high as with the tucatinib/capecitabine/trastuzumab regimen observed in the HER2CLIMB trial. Overall, dose holds and dose reductions were effective at managing the transaminase elevations.
How do you think these results can impact the future treatment of breast cancer?
At this timepoint, tucatinib is not approved in combination with T-DM1, but the study does provide us additional evidence of the activity of tucatinib in patients with HER2-positive metastatic disease. It is a study that does not answer how well tucatinib works post-T-DXd, as patients who had received T-DXd were not allowed on this study. It also does not provide us evidence of how tucatinib/T-DM1 compares to tucatinib/trastuzumab/capecitabine.
There are a number of ongoing studies looking at the use of tucatinib in high-risk early stage disease in the residual disease setting after neoadjuvant therapy. There’s a study looking at combining tucatinib plus T-DXd and other studies that are ongoing and planned. So I’m excited to see these additional data mature, and perhaps have other ways of utilizing tucatinib, especially in our patients affected by brain metastases.
