在芝加哥当地时间6月1日上午的ASCO乳腺癌专场上，来自伦敦癌症研究所的Nicholas C.Turner口头报告了III期研究PALOMA-3的最新结果。该研究表明，对于经治的激素受体阳性、人类表皮生长因子受体2阴性（HR+/HER2-）的晚期乳腺癌患者，在标准的激素治疗方案（氟维司群）中加入靶向药物palbociclib,可以使疾病控制的时间延长一倍以上，并延迟大约五个月的疾病进展时间（摘要号，LBA502）。

    根据中期分析的结果，这项试验提早终止。全部乳腺癌患者中大约有75%的患者是激素受体阳性（HR+），HER2阴性的（HER2-）。对于HR+和HER2-的晚期乳腺癌的患者，初始雌激素治疗后，结合了palbociclib的激素治疗方案有可能成为一种非常有效的治疗选择。

    该研究的主要作者、皇家马斯登医学肿瘤顾问及伦敦癌症研究所组长Nicholas C.Turner表示，“当初始雌激素治疗对转移性乳腺癌不起作用后，下一步是典型的化疗，这通常是有效的，但是对于女性来说，副作用是难以承受的”.他说道，“这种相对比较容易接受的新药可以大大延迟患者需要开始化疗的时间，这是一个令人激动的新疗法”.

    Palbociclib是一种新型，阻断周期素依赖性蛋白激酶（CDKs）4和6的口服药物。之前的研究表明，CDK4和CDK6是**激素受体阳性乳腺肿瘤生长的关键性蛋白。强有力的临床前证据支持将CDK4和CDK6抑制剂与激素治疗联合的方案。对于HR+和HER2-的晚期乳腺癌患者来说，氟维司群是最有效的激素治疗方案之一。

    HR+和HER2-的女性乳腺癌患者被随机分配接受palbociclib联合氟维司群治疗，或安慰剂联合氟维司群治疗。所有患者都是经过初始激素治疗后发生疾病恶化或者复发的转移性乳腺癌患者，并且21%的患者都处在绝经前。根据研究者的报道，PALOMA-3是在包括绝经前年轻女性在内的晚期乳腺癌患者中进行，首个使用靶向治疗联合激素治疗的注册研究。

    中期分析显示，palbociclib组的疾病进展平均时间为9.2个月，而安慰剂组为3.8个月。类似的结果也出现在绝经前和绝经后的女性。

    需要更长时间的随访来确定palbociclib对总生存的影响，生活质量数据的搜集和报道将在之后进行。

    Palbociclib联合治疗的耐受性较好，仅仅只有2.6%的患者因为副作用而中止治疗，最常见的副作用是血细胞计数异常。尽管频繁出现低白细胞计数事件，但是发热***粒细胞减少这种严重并发症发生的比率非常低（0.6%）。两组的情况相同。

    另一项研究PALOMA-2探索了palbociclib用于未经激素治疗的晚期乳腺癌患者的疗效。Turner指出，研究人员也在探索运用这种方式治疗早期激素受体阳性的乳腺癌患者的可能性。

    今年早些时候，FDA加速批准palbociclib联合来曲唑用于未经激素治疗转移性疾病的ER+和HER2-晚期（转移性）乳腺癌患者。这项批准使基于先前的II期试验PALOMA-1结果。

    摘要原文

    Background: The growth of hormone receptor （HR） positive breast cancer （BC） is dependent on the cyclin dependent kinases CDK4/6, that promote G1-S phase cell cycle progression. Resistance to endocrine treatment remains a major clinical problem for patients with hormone receptor positive breast cancer. The PALOMA3 study assessed the efficacy of palbociclib and fulvestrant in endocrine-resistant advanced breast cancer.

    Methods: In this double-blind phase 3 study women with HR positive/HER2 negative advanced metastatic BC whose cancer had relapsed or progressed on prior endocrine therapy, were randomized 2:1 to palbociclib （Palbo, 125 mg/d orally for 3 wk followed by 1 wk off） and fulvestrant （F, 500 mg per standard of care） or placebo （PLB） and F. Pre- and peri-menopausal women also received goserelin. One previous line of chemotherapy for metastatic disease was permitted. The primary endpoint was investigator assessed progression-free survival （PFS）。 Secondary endpoints included overall survival （OS）， response assessment, patient-reported outcomes, and safety and tolerability. A pre-planned interim **ysis was performed after 195 PFS events by an independent data monitoring committee.

    Results: 521 pts were randomized, 347 to receive Palbo+F and 174 to PLB+F. Baseline characteristics were well balanced. The median age was 57 and 56 years, 79% were post-menopausal, 60% had visceral disease, and 79% were sensitive to prior endocrine therapy. Prior therapy included chemotherapy for advanced disease in 33% of pts. At the time of the interim **ysis the study met the primary endpoint, median PFS was 9.2 months for Palbo+F and 3.8 months for PLB+F （HR 0.422, 95% CI 0.318 to 0.560, P<0.000001）。 Consistent benefit from Palbo was seen in pre- and post-menopausal women. The most common adverse effects Palbo+F versus PLB+F were neutropenia （78.8% vs. 3.5%）， leucopenia （45.5% vs. 4.1%）， and fatigue （38.0% vs. 26.7%）。 Febrile neutropenia was reported in 0.6% pts on Palbo+F and 0.6% pts on PLB+F. The discontinuation rate due to adverse events was 2.0% on Palbo and 1.7% on PLB.

    Conclusion: Palbociclib combined with fulvestrant improved progression free survival in hormone receptor positive advanced breast cancer that had progressed on prior endocrine therapy, and can be considered as a treatment option for these patients.