PI3K Inhibition in Combination with Tamoxifen in Patients with Metastatic HR+/HER2- Breast Cancer: Clinical and Circulating Tumor DNA Results.

patients_and_methods

POSEIDON is a phase II, randomized, placebo-controlledtrial conducted from June 2016 to March 2020.

POSEIDON是一项II期、随机、安慰剂对照试验，从2016年6月进行至2020年3月。

Eligible patients were refractory upon prior endocrine therapy.

符合条件的患者在接受先前内分泌治疗后表现出耐药性。

Prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and everolimus was allowed.

允许先前使用细胞周期依赖性激酶4/6（CDK4/6）抑制剂和依维莫司进行治疗。

Patients were randomized (1:1) to receive either taselisib (4 mg) + tamoxifen (20 mg) or placebo + tamoxifen.

患者被随机分配（1:1）接受taselisib（4毫克）+他莫昔芬（20毫克）或安慰剂+他莫昔芬。

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).

该试验的主要终点是研究者评估的无进展生存期（PFS），在意向治疗（ITT）人群中进行（双侧α 0.2，90%的功效）。

Exploratory biomarker analysis with regards to prognosis and treatment resistance was conducted in circulating tumor (ct)DNA.

在循环肿瘤（ct）DNA中进行了关于预后和治疗抵抗性的探索性生物标志物分析。

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 ratio0.69; 80% confidence interval, 0.49-0.98, P = 0.17).

POSEIDON试验达到了其主要终点，接受taselisib加他莫昔芬治疗的患者与接受安慰剂加他莫昔芬治疗的患者相比，无进展生存期（PFS）有所改善，意向治疗（ITT）人群中的中位PFS为4.8个月对比3.2个月；分层风险比为0.69；95%置信区间为0.49-0.98，P = 0.17。

However, toxicity of taselisib was significant, with diarrhea (40% any grade) as the most common adverse event.

然而，taselisib的毒性显著，其中腹泻（任何级别的发生率为40%）是最常见的不良事件。

Exploratory analyses indicated that high tumor fraction (TF) determined in ctDNA at baseline is associated with worse PFS and overall survival(P < 0.0001).

探索性分析表明，在基线时通过ctDNA确定的高肿瘤分数（TF）与较差的无进展生存期（PFS）和总生存期（OS）相关（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.

我们的研究结果表明，在二线治疗及之前接受过包括CDK4/6抑制剂在内的靶向治疗后，PI3K抑制剂联合他莫昔芬在转移性HR+/HER2-乳腺癌中的疗效显著，尽管这种联合治疗的益处并未超过其可耐受性。

Exploratory biomarker analysis indicates that TF determined in ctDNA differentiates patients based on prognosis and may help optimize patient selection for targeted treatment strategies.

探索性生物标志物分析表明，通过ctDNA确定的TF可以基于预后区分患者，并可能有助于优化靶向治疗策略的患者选择。