辉瑞公司最近发布了PALOMA-1研究的2期临床试验结果，结果非常振奋人心，对乳腺癌患者来说可能是一个好消息。该研究发现，palbociclib联合来曲唑对绝经后的局部浸润性乳腺癌患者或新近诊断的雌激素受体（ER）阳性，HER-2阴性的转移性乳腺癌患者非常有效。

Palbociclib（正式名PD-0332991）最早进入人们视野的是在2012年圣安东尼奥乳腺癌会议上（SABCS），一经发布就引起行业广泛关注。Palbociclib是一种口服的细胞周期素依赖性激酶4、6的抑制药物，主要通过调节细胞周期发挥作用。Palbociclib主要通过抑制CDK4/6活性来阻止细胞由G1期到S期进而抑制DNA的合成。

来自加州大学洛杉矶分校Jonsson 综合癌症中心的Richard S. Finn医生在此次会议上公布了PALOMA-1研究的中期研究结果：Palbociclib联合来曲唑可将乳腺癌患者的中位无疾病生存期（PFS）提高到26.1个月，而单用来曲唑的PFS只有7.5个月。基于这一中期研究结果，2013年4月FDA授予Palbociclib治疗转移性乳腺癌突破性治疗药物。

辉瑞临床肿瘤部医疗事务高级副总裁、首席医疗官Mace Rothenberg医生称：“对于绝经后ER阳性、HER2阴性的晚期乳腺癌患者，这可能是一个非常振奋人心的消息。”palbociclib可能会改变绝经后ER阳性、HER2阴性晚期乳腺癌患者传统的治疗方案。我们不久将和FDA及其他医疗监管机构讨论该试验的一系列结果以决定接下来的研究方向，希望该药能尽快上市。

该研究中，研究人员将绝经后ER阳性、HER2阴性的晚期乳腺癌患者随机分成2组，1组66例，1组99例。1组患者每日接受2.5mg来曲唑，另一组患者每日接受2.5mg来曲唑加palbociclib 125mg ，连续用药3个星期，停药1星期，直至肿瘤进展。联合化疗的有效率为45%，而单药治疗的有效率仅为31%。单药化疗和联合化疗的总体有效率分别为70%、44%。

联合化疗最常见的并发症有以下几种：中性粒细胞减少、白细胞减少、贫血、疲劳。在研究中，研究人员未发现患者因中性粒细胞减少而出现发热的情况。

Finn称：“联合化疗可显著提高患者的PFS，这一结果临床意义重大。”PALOMA-1研究的最终数据将在4月份召开的AACR会议上公布。Pallociclib的3期临床试验正在进行，主要比较Pallociclib联合来曲唑与单用来曲唑对既往未接受过系统治疗的绝经后ER阳性、HER2阴性晚期乳腺癌患者的疗效。(PALOMA-2研究 试验号：NCT01740427).

PALOMA-3研究主要比较palbociclib联合氟维司群对HR阳性、HER2阴性的转移性乳腺癌患者的疗效，这些患者既往已接受过内分泌治疗且已进展。主要研究终点是患者的PFS，总体有效率（OS）和有效率是第二研究终点。

Final Phase II Palbociclib Results Confirm Effectiveness in Breast Cancer

Final results from the phase II PALOMA-1 trial continue to support the dramatic efficacy of palbociclib plus letrozole in postmenopausal patients with locally advanced or newly diagnosed estrogen receptor (ER)-positive, HER2-negative me-tastatic breast cancer, according to a statement released by Pfizer, Inc., the company developing the drug.

Palbociclib (formally PD-0332991) made a dramatic debut at the 2012 San Antonio Breast Cancer Symposium (SABCS) when Richard S. Finn, MD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, presented interim results from the PALOMA-1 trial. At this point, the combination of letrozole and palbociclib achieved a statistically significant median progression-free survival (PFS) of 26.1 months compared with 7.5 months for letrozole alone. Based on these interim findings, the FDA granted palbociclib a Breakthrough Therapy designation for the treatment of patients with breast cancer in April 2013.

“We are delighted with the final data, which suggest the potential for palbociclib to transform the standard of care for postmenopausal women with ER-positive and HER2-negative advanced breast cancer. This is encouraging information for these women, who represent approximately 60% of the advanced breast cancer population,” said Mace Rothenberg, MD, the senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. “We will discuss these results with the FDA and other regulatory authorities to determine next steps, with the goal of bringing a much-needed new medicine to patients.”

Palbociclib is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, which play a role in regulating cell cycle progression. Inhibition of CDK 4/6 prevents DNA synthesis by prohibiting progression from G1 to S phase. Preclinical models showed preferential activity for the drug in ER-positive breast cancer, due in part to the intact retinoblastoma pathway that is common in ER-positive tumors.

In the phase II study, continuous daily letrozole was administered at 2.5 mg with or without palbociclib at 125 mg daily for 3 weeks followed by 1 week of rest until progression. Patients with postmenopausal ER-positive, HER2-negative advanced breast cancer were randomized in a 1:1 ratio in two parts, Part 1 contained 66 patients and Part 2 had 99 patients. Data from the combination of both groups (n = 165) were presented at SABCS.

In this analysis, the median PFS was 26.1 months with letrozole plus palbociclib compared with 7.5 months for letrozole alone (hazard ratio [HR]=0.37; 95% CI, 0.21 – 0.63, P < .001). The combination resulted in a response rate of 45% compared with 31% for the monotherapy. The overall clinical benefit rate was 70% versus 44%, for the combination and single-agent, respectively.

The most commonly reported treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue. Overall, there was no evidence of febrile neutropenia with the combination.

“The dramatic improvement in progression-free survival with the combination is very encouraging and clinically meaningful,” Finn said, when results from the study were initially presented in December 2012. “These data represent a potential major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.”

Final results from the PALOMA-1 trial have been submitted for presentation at the AACR Annual Meeting in April.

Palbociclib is under investigation in a number of phase III clinical trials for patients with breast cancer. Following up on the PALOMA-1 trial, the PALOMA-2 investigation is examining treatment with letrozole in combination with palbociclib versus letrozole with placebo in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who have not received prior systemic therapies (NCT01740427).

Additionally, the PALOMA-3 trial is attempting to demonstrate superiority of palbociclib in combination with fulvestrant over fulvestrant alone in women with HR-positive, HER2-negative me-tastatic breast cancer whose disease has progressed after prior endocrine therapy (NCT01942135). PFS is the primary endpoint of the study with overall survival and response as secondary endpoints.

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