POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients

Abstract

Purpose: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen 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 20 mg 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 hypergly-cemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve 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 (e.g., mutations in KRAS, ERBB2) in some patients.Conclusions: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.

Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer

“…Expression of FOXM1 was largely unaffected by treatment with PI3Kα inhibitors in all six of these drug-resistant models. The clinical relevance of these observations was supported by analysis of RNA-seq data from paired tumor samples from patients that had been treated with BYL-719 ( Le et al., 2016 ) and from immunohistochemical analysis of tumor biopsies from patients treated with tamoxifen and GDC-0032 ( Baird et al., 2019 ). FOXM1 expression was unchanged or upregulated in BYL-719-resistant tumors compared with treatment naive tumors and was sustained in patients with progressive disease that had been treated with tamoxifen and GDC-0032.…”

“…We investigated whether there was a correlation between inhibition of FOXM1 expression and response to GDC-0032 in patients with ER + metastatic breast cancer. FOXM1 expression was determined by immunohistochemical analysis of biopsies obtained from three patients with advanced breast cancer enrolled in the POSEIDON phase Ib trial, which was designed to assess the efficacy of treatment with GDC-0032 plus tamoxifen ( Baird et al., 2019 ) ( Figure 8 A). All three patients were eventually diagnosed as having progressive disease since the treatment regime failed.…”

“…FOXM1 gene expression was upregulated in three and unchanged in one of the post-relapse biopsies, LDHA gene expression was maintained in three and slightly upregulated in one, whereas HK-II was more variable, with two patients showing downregulation, one was upregulated, and one showed no change in mRNA expression.

Figure 8 Tumor FOXM1 Expression and Response to PI3Kα Inhibitors in Breast Cancer Patients (A) FFPE needle biopsies from three patients with advanced breast cancer enrolled in the POSEIDON trial ( Baird et al., 2019 ) were stained for FOXM1. All three patients progressed on treatment with GDC-0032 and tamoxifen (progressive disease [PD]).

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“…Simultaneous blockade of PI3K and ER are needed for optimal treatment of ER + breast tumors with aberrant activation of the PI3K pathway ( Bosch et al., 2015 ). A phase II trial using taselisib (GDC-0032) and tamoxifen is currently underway ( Baird et al., 2019 ), and the recently completed randomized phase III SOLAR-1 clinical trial demonstrated a clinically relevant benefit if endocrine therapy (fulvestrant) was combined with a PI3Kα inhibitor (BYL-719) in patients with HR + HER2-advanced breast cancer with PIK3CA mutations ( André et al., 2019 ). We have shown here that combining a PI3Kα inhibitor with tamoxifen or fulvestrant overcame acquired or engineered resistance to PI3Kα inhibition, resulting in decreased cell viability, marked decreases in FOXM1 and LDHA protein expression, and a decrease in hyperpolarized 13 C label exchange between pyruvate and lactate.…”

Cellular Plasticity in Breast Cancer Progression and Therapy

“…Alpelisib and taselisib are two PI3Kα specific inhibitors which are ideal drug candidates for patients with PIK3CA mutations. Studies demonstrate that these two drugs, either used as single agent or combined with endocrine therapy, showed preferential therapeutic effects against breast tumors harboring PIK3CA mutations, and as such, these drugs represent a means for personalized, tumor specific therapy (de Jonge et al, 2014;Mayer et al, 2017;Tamura et al, 2018;Baird et al, 2019;Saura et al, 2019). In addition to targeting PI3K itself, other therapeutic approaches have attempted to target the downstream target of PI3K, AKT.…”