European Commission Approval of Tucatinib in HER2+ BC

Volkmar Mueller, MD: Today I am going to talk a little about the approval of tucatinib for the treatment of HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer. Actually, the European authorities approved tucatinib after 2 lines of previous therapy for HER2+ metastatic breast cancer. The compound is also available in many countries, including Germany. The approval is based on the HER2CLIMB trial. HER2CLIMB was a trial that examined patients with metastatic HER2+ breast cancer who had all received a previous line of treatment with trastuzumab, pertuzumab, as well as T-DM1 [trastuzumab emtansine]. This is the standard for first- and second-line therapy. Patients were randomized 2:1. Overall, 612 patients received either tucatinib or a placebo, each combined with trastuzumab and capecitabine.

The patients had a median 4 previous lines of therapy, and all patients were required to have a brain MRI [magnetic resonance imaging] at baseline. The primary end point was progression-free survival, and secondary end points included overall survival and progression-free survival in some patients with brain metastases. Actually, the trial also assessed the quality of life of the patients, and this is something I am going to talk about a little later. Regarding the efficacy of the results, the HER2CLIMB trial met all its primary end points. This is a little unusual. I do not think I have ever seen a trial—maybe there was, but I cannot remember—that met all the end points, both primary and secondary. The risk—that was the primary end point, progression-free survival—for progression fell by 46% in the trial.

The results of the trial showed that progression-free survival for 1 year was at 33% with tucatinib and only at 12% for the patients in the placebo group. The outcome for overall survival was positive. The risk of death reduced by 34%, and overall survival at 2 years was 45% likely with tucatinib and 27% likely with the placebo. For me, this is the most impressive result because this is a very positive outcome for patients overall. I also already mentioned that patients with brain metastases—patients received an MRI at baseline—were allowed to enter the trial, which was a little unusual. In many trials, patients with brain metastases were excluded. Patients with brain metastases were allowed and joined the study.

Entering the HER2CLIMB trial, 48% of the patients had brain metastases, and about half of them had treated and stable brain metastases. The other half of these patients with brain metastases had untreated or progressing brain metastases, or active brain metastases. For this group, the overall outcome was positive; overall survival was prolonged. The overall survival duration was 18.1 months with tucatinib and only 12 months with the placebo. The risk of death decreased by 42%. The intracranial response rate was about 47% for tucatinib and only 20% for the placebo. The additional data shown at ESMO [European Society for Medical Oncology Congress] 2020 and retrospective data analyses indicated that the occurrence of brain metastases in the overall patient crowd, or progression of brain metastases, was reduced by 50% when adding tucatinib to trastuzumab and capecitabine. Almost 40% of all patients with HER2+ metastatic breast cancer developed brain metastases, so this is a clinically relevant result.

TRANSCRIPT EDITED FOR CLARITY