在芝加哥當地時(shí)間6月1日上午的ASCO乳腺癌專(zhuān)場(chǎng)上，來(lái)自倫敦癌癥研究所的Nicholas C.Turner口頭報告了III期研究PALOMA-3的最新結果。該研究表明，對于經(jīng)治的激素受體陽(yáng)性、人類(lèi)表皮生長(cháng)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(shí)間延長(cháng)一倍以上，并延遲大約五個(gè)月的疾病進(jìn)展時(shí)間（摘要號，LBA502）。

    根據中期分析的結果，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(yáng)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、皇家馬斯登醫學(xué)腫瘤顧問(wèn)及倫敦癌癥研究所組長(cháng)Nicholas C.Turner表示，“當初始雌激素治療對轉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(lái)說(shuō)，副作用是難以承受的”.他說(shuō)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(kāi)始化療的時(shí)間，這是一個(gè)令人激動(dòng)的新療法”.

    Palbociclib是一種新型，阻斷周期素依賴(lài)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(yáng)性乳腺腫瘤生長(cháng)的關(guān)鍵性蛋白。強有力的臨床前證據支持將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(lái)說(shuō)，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(guò)初始激素治療后發(fā)生疾病惡化或者復發(fā)的轉移性乳腺癌患者，并且21%的患者都處在絕經(jīng)前。根據研究者的報道，PALOMA-3是在包括絕經(jīng)前年輕女性在內的晚期乳腺癌患者中進(jìn)行，首個(gè)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(jìn)展平均時(shí)間為9.2個(gè)月，而安慰劑組為3.8個(gè)月。類(lèi)似的結果也出現在絕經(jīng)前和絕經(jīng)后的女性。

    需要更長(cháng)時(shí)間的隨訪(fǎng)來(lái)確定palbociclib對總生存的影響，生活質(zhì)量數據的搜集和報道將在之后進(jìn)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(jiàn)的副作用是血細胞計數異常。盡管頻繁出現低白細胞計數事件，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(yáng)性的乳腺癌患者的可能性。

    今年早些時(shí)候，FDA加速批準palbociclib聯(lián)合來(lái)曲唑用于未經(jīng)激素治療轉移性疾病的ER+和HER2-晚期（轉移性）乳腺癌患者。這項批準使基于先前的II期試驗PALOMA-1結果。

    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.