Multicenter phase 2 trial of trametinib alone and in combination with uprosertib for metastatic triple negative breast cancer

MEK inhibitors like trametinib demonstrated activity in metastatic triple negative breast cancer (mTNBC) but many patients rapidly develop resistance. Part 1 of a multicenter phase 2 trial in the USA evaluated trametinib monotherapy for mTNBC in patients who previously received chemotherapy, while at progression the AKT inhibitor uprosertib (GSK2141795) was added in part 2. In part 1, the objective response rate was 5.4% and the clinical benefit rate was 21.6%, while the progression-free survival was 7.7 weeks. In part 2, the ORR was 15.8% and the CBR was 31.6%, while the PFS was 7.8 weeks. Circulating tumor DNA clearance at C2D1 of trametinib monotherapy was associated with improved PFS. The authors conclude that in patients with mTNBC, trametinib monotherapy demonstrated limited efficacy, while addition of uprosertib was associated with numerically greater objective responses but no difference in PFS. Exploratory analysis suggests ctDNA clearance as a potential early biomarker of response.