PALLAS 研究

　　细胞周期蛋白依赖型激酶CDK4/6抑制剂哌柏西利可阻断乳腺癌细胞有丝分裂周期由DNA合成前期进入DNA合成期，3项随机对照研究PALOMA-1、2、3已经证实内分泌治疗＋哌柏西利可显著改善激素受体阳性HER2阴性晚期乳腺癌患者的无进展生存。内分泌治疗＋哌柏西利对激素受体阳性HER2阴性早期乳腺癌患者的有效性和安全性尚不明确。

　　2021年1月15日，英国《柳叶刀》肿瘤学分册在线发表美国辉瑞、哈佛大学达纳法伯癌症研究所、印第安纳大学、德克萨斯大学MD安德森癌症中心、纽约纪念医院斯隆凯特林癌症中心、旧金山加利福尼亚大学、霍普金斯大学、宾夕法尼亚大学、西班牙乳腺癌协作组、马德里大学、巴塞罗那大学、塞维利亚大学、拉科鲁尼亚大学、匈牙利国家癌症研究所、奥地利乳腺结直肠癌研究协作组、维也纳医科大学、因斯布鲁克医科大学、波兰居里夫人纪念癌症中心、德国乳腺癌协作组、英国伦敦大学皇家马斯登医院、加拿大拉瓦尔大学、瑞士巴塞尔大学、爱尔兰癌症研究协作组、比利时国际乳腺癌协作组的PALLAS研究中期分析报告，对激素受体阳性HER2阴性早期乳腺癌术后内分泌治疗±2年哌柏西利的有效性和安全性进行了比较。

PALLAS (PALbociclib CoLlaborative Adjuvant Study): A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR ) / Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Early Breast Cancer (ClinicalTrials.gov NCT02513394, EudraCT 2014-005181-30)

　　该国际多中心非盲随机对照三期临床研究于2015年9月1日～2018年11月30日从全世界21个国家或地区406个癌症中心入组II～III期乳腺癌首次诊断12个月内、经组织学确认为激素受体阳性HER2阴性、美国东部肿瘤学协作组（ECOG）体力状态评分为0或1、年龄≥18岁患者5760例，按1∶1随机分为两组：

• 仅内分泌治疗组2877例：术后标准内分泌治疗（他莫昔芬或芳香酶抑制剂±促黄体激素释放激素激动剂）

• 内分泌治疗＋哌柏西利组2883例：术后标准内分泌治疗＋哌柏西利（每28天第1～21天每天口服125毫克连续2年）

　　对意向治疗人群进行有效性分析，主要终点为无浸润病变生存，关键次要终点为无远处复发生存。按解剖分期、既往化疗、年龄和地理区域进行亚组分析。对开始哌柏西利或内分泌治疗的全部随机分组患者进行安全性评定。2020年1月9日，当无浸润病变生存事件总数达预计的三分之二时，进行预先计划的第二次中期分析。

　　结果，第二次中期分析时，中位随访23.7个月（四分位：16.9～29.2）。

　　内分泌治疗＋哌柏西利组2883例与仅内分泌治疗组2877例意向治疗患者相比：

• 无浸润病变生存事件：170例比181例

• 无远处复发生存事件：136例比135例

• 3年无浸润病变生存率：88.2%比88.5%（95%置信区间：85.2～90.6、85.8～90.7；比值比：0.93，95%置信区间：0.76～1.15，对数秩P=0.51）

• 3年无远处复发生存率：89.3%比90.7%（95%置信区间：86.3～91.7、88.1～92.8；比值比：1.00，95%置信区间：0.79～1.27，对数秩P=0.9997）

　　由于两组相比，无浸润病变生存、无远处复发生存的统计学检验数据都超过预设无效临界值，故独立数据监测委员会建议仍在接受内分泌治疗＋哌柏西利的患者停用哌柏西利。

　　哌柏西利＋内分泌治疗组2840例与仅内分泌治疗组2903例（其中37例来自哌柏西利＋内分泌治疗组）实际治疗患者相比，最常见的3～4级不良事件：

• 中性粒细胞减少：1742比11例（61.3%比0.3%）

• 白细胞减少：857例比3例（30.2%比0.1%）

• 疲劳：60例比10例（2.1%比0.3%）

• 严重不良事件：351例比220例（12.4%比7.6%）

• 治疗相关死亡：0比0

　　因此，该研究第二次中期分析结果表明，对于激素受体阳性HER2阴性早期乳腺癌患者，术后内分泌治疗±2年哌柏西利辅助治疗相比，无浸润病变生存、无远处复发生存并未改善，安全性较差。根据这些结果，该方案不能被推荐用于激素受体阳性HER2阴性早期乳腺癌术后治疗。该研究人群长期随访和相关研究仍在进行，不知长期随访结局能否反转？

　　对此，中国医学科学院附属肿瘤医院徐兵河和樊英等学者发表同期评论：早期乳腺癌CDK4/6抑制剂成为标准治疗还有多远？

Lancet Oncol. 2021 Jan 15. Online ahead of print.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

Erica L Mayer, Amylou C Dueck, Miguel Martin, Gabor Rubovszky, Harold J Burstein, Meritxell Bellet-Ezquerra, Kathy D Miller, Nicholas Zdenkowski, Eric P Winer, Georg Pfeiler, Matthew Goetz, Manuel Ruiz-Borrego, Daniel Anderson, Zbigniew Nowecki, Sibylle Loibl, Stacy Moulder, Alistair Ring, Florian Fitzal, Tiffany Traina, Arlene Chan, Hope S Rugo, Julie Lemieux, Fernando Henao, Alan Lyss, Silvia Antolin Novoa, Antonio C Wolff, Marcus Vetter, Daniel Egle, Patrick G Morris, Eleftherios P Mamounas, Miguel J Gil-Gil, Aleix Prat, Hannes Fohler, Otto Metzger Filho, Magdalena Schwarz, Carter DuFrane, Debora Fumagalli, Kathy Puyana Theall, Dongrui Ray Lu, Cynthia Huang Bartlett, Maria Koehler, Christian Fesl, Angela DeMichele, Michael Gnant.

Dana-Farber Cancer Institute, Boston, MA, USA; Mayo Clinic, Phoenix, AZ, USA; Hospital Gregorio Maranón, Universidad Complutense, CIBERONC, GEICAM, Madrid, Spain; National Institute of Oncology, Budapest, Hungary; Hospital Universitari Vall d'Hebron and Vall d'Hebron Institute of Oncology, Barcelona, Spain; Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, USA; Lake Macquarie Private Hospital, Gateshead, NSW, Australia; Medical University of Vienna, Vienna, Austria; Mayo Clinic, Rochester, MN, USA; Hospital Virgen del Rocio Sevilla, GEICAM Spanish Breast Cancer Group, Sevilla, Spain; Regions Hospital Cancer Care Center, Saint Paul, MN, USA; The Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; German Breast Group, Neu-Isenburg, Germany; The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Royal Marsden NHS Foundation Trust, London, UK; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hollywood Private Hospital, Nedlands, WA, Australia; University of California San Francisco, San Francisco, CA, USA; Centre hospitalier universitaire de Québec-Université Laval, QC, Canada; Hospital Universitario Virgen Macarena, Sevilla, Spain; Missouri Baptist Medical Center, St. Louis, MO, USA; A Coruna University Hospital, A Coruna, Spain; Johns Hopkins University Sidney Kimmel Cancer Center, Baltimore, MD, USA; Universitatsspital Basel, Basel, Switzerland; Medizinische Universitat Innsbruck, Innsbruck, Austria; Cancer Trials Ireland, Dublin, Ireland; Orlando Health, Orlando, FL, USA; Institut Català d'Oncologia Hospitalet & GEICAM Spanish Breast Cancer Group, Barcelona, Spain; Hospital Clinic of Barcelona, Barcelona, Spain; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria; Alliance Foundation Trials, Boston, MA, USA; Breast International Group, Brussels, Belgium; Pfizer, New York, NY, USA; Penn Medicine, Philadelphia, PA, USA.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.

METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).

FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23.7 months (IQR 16.9-29.2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88.2% (95% CI 85.2-90.6) for palbociclib plus endocrine therapy and 88.5% (85.8-90.7) for endocrine therapy alone (hazard ratio 0.93 [95% CI 0.76-1.15]; log-rank p=0.51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61.3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0.3%] of 2903 on endocrine therapy alone), leucopenia (857 [30.2%] vs three [0.1%]), and fatigue (60 [2.1%] vs ten [0.3%]). Serious adverse events occurred in 351 (12.4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7.6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.

INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.

FUNDING: Pfizer

DOI: 10.1016/S1470-2045(20)30642-2

Lancet Oncol. 2021 Jan 15. Online ahead of print.

CDK4/6 inhibition in early-stage breast cancer: how far is it from becoming standard of care?

Binghe Xu, Ying Fan.

National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital - Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Although patients with hormone-receptor-positive, HER2-negative, early breast cancers present with the best outcome among all breast cancer subtypes, about a third of patients will relapse at some point, even after receiving standard multimodal treatments. Efforts to improve survival in this population are ongoing, such as through the development of new endocrine agents or extended duration of endocrine treatment. Novel strategies are of considerable interest. CDK4/6 inhibition has been the most successful strategy in the treatment of hormone-receptor-positive, HER2-negative, advanced breast cancer. The three currently approved CDK4/6 inhibitors have shown efficacy in patients with hormone-receptor-positive, HER2-negative, advanced breast cancer, with significantly longer progression-free survival and even overall survival. Thus, expectations are high for CDK4/6 inhibitors in the adjuvant setting. In the monarchE study, 5637 patients with high-risk, early-stage breast cancer were randomly assigned to receive standard adjuvant endocrine therapy, with or without abemaciclib 150 mg twice daily for 2 years. At a preplanned second efficacy interim analysis, 2-year invasive disease-free survival was 92.2% with abemaciclib versus 88.7% without (hazard ratio [HR] 0.75 [95% CI 0.60-0.93]), a difference that was significant and clinically meaningful.

DOI: 10.1016/S1470-2045(20)30757-9