哌柏西利单药二或三线治疗转移性乳腺癌非盲随机对照二期临床研究

　　编者按：哌柏西利（帕柏西利、帕泊昔布）属于细胞周期蛋白依赖型激酶4和6（CDK4/6）抑制剂。根据PALOMA-1研究结果，哌柏西利联合来曲唑一线治疗雌激素受体阳性HER2阴性晚期乳腺癌，可以显著延长患者的无进展生存。根据PALOMA-3研究结果，哌柏西利联合氟维司群二线治疗对内分泌治疗耐药的雌激素受体阳性HER2阴性转移性乳腺癌，可以显著延长患者的无进展生存。哌柏西利单药治疗晚期乳腺癌的效果尚不明确，虽然临床前数据表明哌柏西利可能部分逆转内分泌耐药，但是尚未获得临床研究证实。

　　2018年6月11日，欧洲肿瘤内科学会和牛津大学出版社旗下《肿瘤学年鉴》在线发表意大利普拉托医院、米兰大学、欧洲肿瘤研究所、乌迪内大学综合医院、布林迪西医院、教宗圣若望二十三世医院、国际药物开发研究所、那不勒斯腓特烈二世大学、帕维亚医院、锡耶纳波吉邦西医院、乌迪内大学、国家癌症研究所、托斯卡纳肿瘤研究所、美国旧金山国际药物开发研究所的TREnd研究报告，探讨了哌柏西利单药治疗以及哌柏西利联合疾病进展之前相同的内分泌治疗，二或三线治疗雌激素受体阳性HER2阴性晚期乳腺癌绝经后女性的效果。

　　该多中心非盲随机对照II期研究（TREnd）于2012年10月～2016年7月入组一或二线内分泌治疗后疾病进展的雌激素受体阳性HER2阴性晚期乳腺癌绝经后女性115例，按1∶1随机分配接受哌柏西利、哌柏西利＋既往接受过的内分泌治疗。主要终点为临床获益率，次要终点包括无进展生存。

　　结果发现，联合治疗与单药治疗相比，临床获益率较低：

• 联合治疗：54%（95%置信区间：41.5～63.7）

• 单药治疗：60%（95%置信区间：47.8～72.9）

　　联合治疗与单药治疗相比，中位无进展生存时间较长（风险比：0.69，95%置信区间：0.4～1.1，初步P=0.12）

• 联合治疗：10.8个月（95%置信区间：5.6～12.7）

• 单药治疗：  6.5个月（95%置信区间：5.4～  8.5）

　　亚组分析，表明联合治疗与单药治疗相比：

• 既往内分泌治疗>6个月患者亚组的无进展生存时间较长（风险比：0.53，95%置信区间：0.3～0.9，初步P=0.02）

• 既往内分泌治疗≤6个月患者亚组的无进展生存时间较短（风险比：1.59，95%置信区间：0.6～4.0，初步P=0.33）

　　因此，该研究结果表明，哌柏西利单药对于既往内分泌治疗≤6个月的雌激素受体阳性HER2阴性晚期乳腺癌患者具有临床效果。对于既往内分泌治疗缓解时间较长的患者，哌柏西利联合内分泌治疗可能逆转内分泌耐药。

Kaplan-Meier plot of the duration of clinical benefit (CB) in the intention-to-treat (ITT) population.

Kaplan-Meier plot of progression-free survival (PFS) in the intention-to-treat (ITT) population.

Ann Oncol. 2018 Jun 11. [Epub ahead of print]

Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial.

L Malorni; G Curigliano; A M Minisini; S Cinieri; C A Tondini; K D'Hollander; G Arpino A Bernardo; A Martignetti; C Criscitiello; F Puglisi; M Pestrin; G Sanna; E Moretti; E Risi C Biagioni; A McCartney; L Boni; M Buyse; I Migliaccio; L Biganzoli; A Di Leo.

Hospital of Prato, Prato, Italy; Istituto Europeo di Oncologia, University of Milan, Milan, Italy; Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy; ASL Brindisi, Brindisi, Italy; Hospital Papa Giovanni XXIII, Bergamo, Italy; International Drug Development Institute, Louvain-La-Neuve, Belgium; University of Naples Federico II, Naples, Italy; ICS Maugeri IRCCS, Pavia, Italy; Hospital Alta Val D'Elsa, Poggibonsi Siena, Italy; Istituto Europeo di Oncologia, Milan, Italy; University of Udine; IRCCS, CRO National Cancer Institute, Aviano, Italy; Istituto Toscano Tumori, Florence, Italy; International Drug Development Institute, San Francisco, USA.

BACKGROUND: The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pre-treated patients. Pre-clinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multi-center study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in post-menopausal women with moderately pre-treated, estrogen receptor-positive, HER2 negative advanced breast cancer.

PATIENTS AND METHODS: Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1:1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary endpoint was clinical benefit rate (CBR); secondary endpoints included progression-free survival (PFS).

RESULTS: Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% (95% CI 41.5-63.7) for combination therapy, and 60% (95% CI 47.8-72.9) for monotherapy. Median PFS was 10.8 months (95% CI 5.6-12.7) for combination therapy, and 6.5 months (95% CI, 5.4 to 8.5) for monotherapy (hazard ratio [HR] 0.69; 95% CI 0.4-1.1, exploratory P-value = 0.12). Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI 0.3-0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months.

CONCLUSION: Palbociclib has clinical activity as a single agent in women with moderately pre-treated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET.

CLINICAL TRIAL INFORMATION: NCT02549430

DOI: 10.1093/annonc/mdy214

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