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PI3K Inhibition in Combination with Tamoxifen in Patients with Metastatic HR+/HER2- Breast Cancer: Clinical and
Rosie A B Voorthuis1, Mafalda Oliveira2, Annelot G J van Rossum1
1Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Purpose:
To determine the safety and efficacy of taselisib, a selective PI3K inhibitor, in combination with tamoxifen.
Patients And Methods:
POSEIDON is a phase II, randomized, placebo-controlled trial conducted from June 2016 to March 2020. Eligible patients were refractory upon prior endocrine therapy. Prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and everolimus was allowed. Patients were randomized (1:1) to receive either taselisib (4 mg) + tamoxifen (20 mg) or placebo + tamoxifen. The primary endpoint of the trial was investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) population (two-sided α 0.2, 90% power). Exploratory biomarker analysis with regards to prognosis and treatment resistance was conducted in circulating tumor (ct)DNA.
Results:
POSEIDON met its primary endpoint, in which patients treated with taselisib + tamoxifen had improved PFS compared with patients treated with placebo + tamoxifen in the ITT population (median PFS 4.8 months vs. 3.2 months; stratified hazard ratio 0.69; 80% confidence interval, 0.49-0.98, P = 0.17). However, toxicity of taselisib was significant, with diarrhea (40% any grade) as the most common adverse event. Exploratory analyses indicated that high tumor fraction (TF) determined in ctDNA at baseline is associated with worse PFS and overall survival (P < 0.0001).
Conclusions:
Our findings suggest efficacy of PI3K inhibition + tamoxifen beyond second-line treatment and after prior targeted therapies, including CDK4/6 inhibition in metastatic HR+/HER2- breast cancer, although the magnitude of benefit did not outweigh the tolerability of this combination. Exploratory biomarker analysis indicates that TF determined in ctDNA differentiates patients based on prognosis and may help optimize patient selection for targeted treatment strategies.
Insights
Taselisib combined with tamoxifen showed improved progression-free survival in metastatic breast cancer patients, but significant toxicity limited its benefit. Circulating tumor DNA analysis may help select patients for targeted therapies.
Area of Science:
- Oncology
- Pharmacology
Background:
- Metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer often requires novel therapeutic strategies.
- Prior treatments, including endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, can lead to treatment resistance.
Purpose of the Study:
- To evaluate the safety and efficacy of taselisib, a selective phosphoinositide 3-kinase (PI3K) inhibitor, in combination with tamoxifen.
- To explore the role of circulating tumor DNA (ctDNA) in predicting prognosis and treatment resistance.
Main Methods:
- The POSEIDON trial was a phase II, randomized, placebo-controlled study involving patients with refractory metastatic HR+/HER2- breast cancer.
- Patients received either taselisib + tamoxifen or placebo + tamoxifen.
- Progression-free survival (PFS) was the primary endpoint, with ctDNA analysis conducted for biomarker assessment.
Main Results:
- The taselisib + tamoxifen combination demonstrated improved PFS compared to placebo + tamoxifen (median 4.8 vs. 3.2 months).
- Diarrhea was the most frequent adverse event associated with taselisib.
- High ctDNA tumor fraction at baseline correlated with worse PFS and overall survival (OS).
Conclusions:
- PI3K inhibition with tamoxifen shows potential efficacy in heavily pretreated metastatic HR+/HER2- breast cancer, but tolerability concerns exist.
- ctDNA analysis, specifically tumor fraction, may aid in patient selection for targeted therapies and prognostication.
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