在芝加哥當(dāng)?shù)貢r間6月1日上午的ASCO乳腺癌專場上，來自倫敦癌癥研究所的Nicholas C.Turner口頭報告了III期研究PALOMA-3的最新結(jié)果。該研究表明，對于經(jīng)治的激素受體陽性、人類表皮生長因子受體2陰性（HR+/HER2-）的晚期乳腺癌患者，在標準的激素治療方案（氟維司群）中加入靶向藥物palbociclib,可以使疾病控制的時間延長一倍以上，并延遲大約五個月的疾病進展時間（摘要號，LBA502）。

    根據(jù)中期分析的結(jié)果，這項試驗提早終止。全部乳腺癌患者中大約有75%的患者是激素受體陽性（HR+），HER2陰性的（HER2-）。對于HR+和HER2-的晚期乳腺癌的患者，初始雌激素治療后，結(jié)合了palbociclib的激素治療方案有可能成為一種非常有效的治療選擇。

    該研究的主要作者、皇家馬斯登醫(yī)學(xué)腫瘤顧問及倫敦癌癥研究所組長Nicholas C.Turner表示，“當(dāng)初始雌激素治療對轉(zhuǎn)移性乳腺癌不起作用后，下一步是典型的化療，這通常是有效的，但是對于女性來說，副作用是難以承受的”.他說道，“這種相對比較容易接受的新藥可以大大延遲患者需要開始化療的時間，這是一個令人激動的新療法”.

    Palbociclib是一種新型，阻斷周期素依賴性蛋白激酶（CDKs）4和6的口服藥物。之前的研究表明，CDK4和CDK6是**激素受體陽性乳腺腫瘤生長的關(guān)鍵性蛋白。強有力的臨床前證據(jù)支持將CDK4和CDK6抑制劑與激素治療聯(lián)合的方案。對于HR+和HER2-的晚期乳腺癌患者來說，氟維司群是最有效的激素治療方案之一。

    HR+和HER2-的女性乳腺癌患者被隨機分配接受palbociclib聯(lián)合氟維司群治療，或安慰劑聯(lián)合氟維司群治療。所有患者都是經(jīng)過初始激素治療后發(fā)生疾病惡化或者復(fù)發(fā)的轉(zhuǎn)移性乳腺癌患者，并且21%的患者都處在絕經(jīng)前。根據(jù)研究者的報道，PALOMA-3是在包括絕經(jīng)前年輕女性在內(nèi)的晚期乳腺癌患者中進行，首個使用靶向治療聯(lián)合激素治療的注冊研究。

    中期分析顯示，palbociclib組的疾病進展平均時間為9.2個月，而安慰劑組為3.8個月。類似的結(jié)果也出現(xiàn)在絕經(jīng)前和絕經(jīng)后的女性。

    需要更長時間的隨訪來確定palbociclib對總生存的影響，生活質(zhì)量數(shù)據(jù)的搜集和報道將在之后進行。

    Palbociclib聯(lián)合治療的耐受性較好，僅僅只有2.6%的患者因為副作用而中止治療，最常見的副作用是血細胞計數(shù)異常。盡管頻繁出現(xiàn)低白細胞計數(shù)事件，但是發(fā)熱***粒細胞減少這種嚴重并發(fā)癥發(fā)生的比率非常低（0.6%）。兩組的情況相同。

    另一項研究PALOMA-2探索了palbociclib用于未經(jīng)激素治療的晚期乳腺癌患者的療效。Turner指出，研究人員也在探索運用這種方式治療早期激素受體陽性的乳腺癌患者的可能性。

    今年早些時候，F(xiàn)DA加速批準palbociclib聯(lián)合來曲唑用于未經(jīng)激素治療轉(zhuǎn)移性疾病的ER+和HER2-晚期（轉(zhuǎn)移性）乳腺癌患者。這項批準使基于先前的II期試驗PALOMA-1結(jié)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.