New heights.

Top Line: Despite the tremendous efficacy of HER2-targeted therapies, progressive, late-stage HER2(+) breast cancer is an aggressive disease with limited treatment options.

The Study: In the HER2CLIMB trial, women with advanced HER2(+) breast cancer (including brain metastases) who had previously been treated with trastuzumab, pertuzumab, and trastuzumab-emtansine received trastuzumab and capecitabine +/- tucatinib. That’s right, they had to have gone through the three big HER2-targeted agents. Tucatinib is an oral, small molecule tyrosine kinase inhibitor that is highly selective for HER2. The patients with brain metastases (almost 50%) couldn’t be in need of immediate treatment (i.e. symptomatic)—but if they did need treatment, they could get it and then enroll. In addition, patients with stable brain mets over 2 cm could enroll, but patients with leptomeningeal disease (nodular or classic?) could not enroll. Tucatinib significantly increased progression-free survival (PFS) at one year from 12 → 33% and median PFS from 6 → 8 months. Yeah, yeah. But wait. There was also a significant improvement in overall survival (OS) at one year from 27→ 45% and median OS from 17→ 22 months. How did Tucatinib work for brain mets? Well, PFS at one year went from 0→ 24%. For anyone who’s tried to chase disseminated HER2 brain mets, this is a big victory. One of the many interesting side effects of tucatinib is that it increases serum creatinine without affecting GFR. Something to ponder when ordering your surveillance imaging.

TBL: The addition of tucatinib to capecitabine and trastuzumab improves PFS and OS among patients who progress on the big HER2-three (i.e., Herceptin, Perjeta, and Kadcyla), including those with brain metastases. | Murthy, N Engl J Med 2019