Department of Medical Oncology, Institut Curie, Université Versailles Saint-Quentin, Université Paris-Saclay, Saint-Cloud, France; Circulating Tumour Biomarkers Laboratory, Inserm CIC-BT 1428, Institut Curie, Paris, France.
Department of Medical Oncology, Centre Armoricaind'Oncologie, Plérin, France.
Lancet Oncol. 2022 Nov;23(11):1367-1377. doi: 10.1016/S1470-2045(22)00555-1. Epub 2022 Sep 29.
In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1), while assessing the global safety of combination fulvestrant and palbociclib.
We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1 during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1 in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1 detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete.
From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1 and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related.
PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1 results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials.
Pfizer.
在晚期雌激素受体阳性、HER2 阴性乳腺癌中，芳香酶抑制剂获得性耐药通常源于 ESR1 突变亚克隆，这些亚克隆可能对氟维司群敏感。PADA-1 试验旨在基于血液中 ESR1 突变（bESR1）的升高来显示早期改变治疗的疗效，同时评估氟维司群和 palbociclib 联合治疗的全球安全性。
我们在法国 83 家医院进行了一项随机、开放标签、3 期试验。招募了年龄至少 18 岁的雌激素受体阳性、HER2 阴性晚期乳腺癌患者，ECOG 体能状态为 0-2，在一线芳香酶抑制剂（2.5 mg 来曲唑、1 mg 阿那曲唑或 25 mg 依西美坦，每日口服一次，连续服用）和 palbociclib（每日 125 mg，连续 28 天周期的第 1-21 天服用）治疗期间监测 bESR1 的升高情况。新出现或 bESR1 在循环肿瘤 DNA 中增加且无同步疾病进展的患者随机分配（1:1）继续接受相同的治疗或改用氟维司群（500 mg 肌肉注射，每 28 天周期的第 1 天和第 1 周期的第 15 天）和 palbociclib（剂量不变）。随机序列使用最小化方法（随机因子 80%）在交互式网络响应系统中生成；患者根据内脏受累（存在或不存在）和从纳入到 bESR1 检测的时间（<12 个月或≥12 个月）分层。主要终点是研究者评估的从随机分组开始的无进展生存期，在意向治疗人群（即所有随机分组的患者）中进行分析，以及所有患者的 3 级或更高级别的血液学不良事件。该试验在 Clinicaltrials.gov （NCT03079011）上注册，现已完成。
从 2017 年 3 月 22 日到 2019 年 1 月 31 日，共纳入了 1017 名患者，其中 279 名（27%）患者出现 bESR1 升高，172 名（17%）患者随机分组：88 名患者换用氟维司群和 palbociclib，84 名患者继续接受芳香酶抑制剂和 palbociclib 治疗。截至 2021 年 7 月 31 日数据库锁定时，随机分组患者的中位随访时间为从纳入到随机分组的 35.3 个月（IQR 29.2-41.4）和从随机分组到 26.0 个月（13.8-34.3）。从随机分组开始的中位无进展生存期在氟维司群和 palbociclib 组为 11.9 个月（95%CI 9.1-13.6），在芳香酶抑制剂和 palbociclib 组为 5.7 个月（3.9-7.5）（分层 HR 0.61，0.43-0.86；p=0.0040）。最常见的 3 级或更高级别的血液学不良事件是中性粒细胞减少症（1017 名患者中有 715 名，70.3%）、淋巴细胞减少症（66 名，6.5%）和血小板减少症（20 名，2.0%）。第 2 步中最常见的 3 级或更高级别的不良事件是中性粒细胞减少症（在芳香酶抑制剂和 palbociclib 组的 84 名患者中有 35 名，41.7%，在氟维司群和 palbociclib 组的 88 名患者中有 39 名，44.3%）和淋巴细胞减少症（3 名，3.6%，4 名，4.5%）。在总体人群中，有 31 名（3.1%）患者有 3 级或更严重的与治疗相关的不良事件。在第 2 步中随机分组的 172 名患者中有 3 名（1.7%）有 1 例严重不良事件：在芳香酶抑制剂和 palbociclib 组的 84 名患者中有 1 例（1.2%）4 级中性粒细胞减少症和 1 例（1.2%）3 级疲劳，在氟维司群和 palbociclib 组的 88 名患者中有 1 例（1.1%）4 级中性粒细胞减少症。1 例在第 1 步中死于肺栓塞被宣布与治疗相关。
PADA-1 是第一项前瞻性随机试验，表明早期针对 bESR1 的治疗靶向治疗可显著带来临床获益。此外，PADA-1 中的原始设计可能有助于在未来的试验中用新药解决获得性耐药问题。
辉瑞公司。
