POSEIDON phase 1b results: safety, efficacy and ctDNA response of taselisib combined with tamoxifen in hormone receptor positive metastatic breast cancer patients

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 9rolling six9 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.