RD Baird, AG van Rossum, M Oliveira, KJ Beelen, M Gao, M Schrier, IA Mandjes, J Garcia-Corbacho, AL Vallier, G Dougall, E van Werkhoven, C Linossi, S Kumar, H Van Tinteren, M Callari, E Beddowes, J Pérez-Garcia, H Rosing, E Platte, PM Nederlof, M Schot, AH de Vries Schultink, R Bernards, C Saura, WM Gallagher, J Cortés, C Caldas, SC Linn
Clin Cancer Res
BACKGROUND: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in oestrogen-receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform sparing PI3 kinase inhibitor. PATIENTS AND METHODS: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20mg once daily in this phase 1b study using a 'rolling six' design. RESULTS: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%) and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 out of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. 12 out of 30 patients (40%) had disease control for 6 months or more.Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically-relevant correlates of clinical drug resistance (eg. mutations in KRAS, ERBB2) in some patients. CONCLUSIONS: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4mg given once daily on a continuous schedule. Preliminary evidence of anti-tumor activity was seen in both PIK3CAmutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.