Mirza Mansoor R, Bjørge Line, Marmé Frederik, Christensen René DePont, Gil-Martin Marta, Auranen Annika, Ataseven Beyhan, Rubio Maria Jesús, Salutari Vanda, Luczak Adam A, Runnebaum Ingo B, Redondo Andrés, Lindemann Kristina, Trillsch Fabian, Ginesta M Pilar Barretina, Roed Henrik, Kurtz Jean-Emmanuel, Petersson Karen S, Nyvang Gitte-Bettina, Sehouli Jalid
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Department of Obstetrics and Gynaecology, Haukeland University Hospital and Center of Biomarkers CCBIO, University of Bergen, Bergen, Norway.
Gynecol Oncol. 2025 Jan;192:128-136. doi: 10.1016/j.ygyno.2024.12.003. Epub 2024 Dec 9.
The CDK4/6 inhibitor palbociclib inhibits cyclin A, which is overexpressed in endometrial cancer. Combining palbociclib with endocrine therapy improves efficacy in hormone receptor-positive breast cancer. We investigated palbociclib combined with endocrine therapy for estrogen receptor-positive advanced/recurrent endometrial cancer.
This placebo-controlled double-blind, randomized phase II screening trial (NCT02730429) enrolled women with measurable/evaluable estrogen receptor-positive endometrioid endometrial cancer that was primary metastatic or had relapsed after ≥1 prior systemic therapy. Patients were randomized in a 1:1 ratio, stratified by number of prior chemotherapy lines, measurable versus evaluable non-measurable disease, and prior medroxyprogesterone/megestrol acetate treatment, to receive oral letrozole 2.5 mg on days 1-28 plus either oral palbociclib 125 mg or placebo on days 1-21, repeated every 28 days until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS).
Among 77 patients randomized between February 16, 2017, and December 21, 2018, 73 were treated (36 with palbociclib-letrozole, 37 with placebo-letrozole). Median follow-up was 21.9 (95 % CI, 16.7 to 22.3) months. Median PFS was 8.3 (95 % CI, 4.6 to 11.2) versus 3.1 (95 % CI, 2.7 to 6.8) months, respectively. In a landmark analysis at 12 months the PFS hazard ratio was 0.57 (95 % CI, 0.32 to 0.99; P = .044). Grade ≥ 3 adverse events were more common with palbociclib-letrozole (67 %) than placebo-letrozole (30 %), most commonly neutropenia (44 % v 0 %, respectively).
These results support a potential role of the palbociclib-letrozole combination as treatment for hormone receptor-positive advanced/recurrent endometrial cancer. Based on these encouraging results, phase III evaluation of letrozole combined with a CDK4/6 inhibitor is planned.
NCT02730429.
细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂帕博西尼可抑制细胞周期蛋白A，该蛋白在子宫内膜癌中过表达。帕博西尼与内分泌治疗联合应用可提高激素受体阳性乳腺癌的疗效。我们研究了帕博西尼联合内分泌治疗雌激素受体阳性的晚期/复发性子宫内膜癌的效果。
这项安慰剂对照、双盲、随机II期筛查试验（NCT02730429）纳入了患有可测量/可评估的雌激素受体阳性子宫内膜样子宫内膜癌的女性，这些癌症为原发性转移癌或在≥1次先前的全身治疗后复发。患者按1:1比例随机分组，根据先前化疗疗程数、可测量与可评估的不可测量疾病以及先前的甲羟孕酮/甲地孕酮治疗情况进行分层，在第1 - 28天口服来曲唑2.5mg，同时在第1 - 21天口服帕博西尼125mg或安慰剂，每28天重复一次，直至疾病进展或出现不可接受的毒性。主要终点是研究者评估的无进展生存期（PFS）。
在2017年2月16日至2018年12月21日期间随机分组的77例患者中，73例接受了治疗（36例接受帕博西尼 - 来曲唑治疗，37例接受安慰剂 - 来曲唑治疗）。中位随访时间为21.9（95%CI，16.7至22.3）个月。中位PFS分别为8.3（95%CI，4.6至11.2）个月和3.1（95%CI，2.7至6.8）个月。在12个月时的一项标志性分析中，PFS风险比为0.57（95%CI，0.32至0.99；P = 0.044）。≥3级不良事件在帕博西尼 - 来曲唑组（67%）比安慰剂 - 来曲唑组（30%）更常见，最常见的是中性粒细胞减少（分别为44%和0%）。
这些结果支持帕博西尼 - 来曲唑联合用药作为激素受体阳性晚期/复发性子宫内膜癌治疗方法的潜在作用。基于这些令人鼓舞的结果，计划对来曲唑与CDK4/6抑制剂联合应用进行III期评估。
NCT02730429。
