辉瑞（Pfizer）4月6日公布了实验性抗癌药palbociclib一项II期研究（PD-0332991）的数据。该项研究在绝经后女性雌激素受体阳性（ER+）、人表皮生长因子受体2阴性（HER2-）局部晚期或转移性乳腺癌患者中开展，研究数据表明，与标准治疗药物曲唑（letrozole）治疗组相比，palbociclib+letrozole联合用药组疾病无进展生存期（PFS）取得了统计学意义的显著延长（20.2个月vs 10.2个月，p=0.0004），达到了研究的主要终点。最终PFS分析时的总生存期（OS）初步数据表明，联合用药组平均总生存期为37.5个月，letrozole治疗组为33.3个月，无统计学显著差异。后续将开展完整的OS分析。研究中，联合用药组耐受性和安全性良好。相关数据已提交至癌症研究协会2014年年会（AACR-2014）。

palbociclib是一种实验性、口服、靶向性制剂，能够选择性抑制细胞周期蛋白依赖性激酶4和6（CDK4/6），恢复细胞周期控制，阻断肿瘤细胞增殖。此前，FDA于2013年4月授予palbociclib治疗晚期或转移性ER+/HER2-乳腺癌的突破性疗法认定。

竞争对手诺华（Novartis）已于去年11月将其CDK4/6抑制剂LEE011推进至III期研究，礼来（Eli Lilly）的药物LY2835219的推进则相对缓慢，研究进程落后于辉瑞和诺华。

 据研究人员在4月6日的美国癌症研究协会会议上发布的最新数据显示，同时使用Palbociclib与抗雌激素药物来曲唑的患者，其无进展生存期平均为20.2个月。相比之下，单独使用来曲唑的患者的无进展生存期则为10.2个月。

 法国古斯塔夫•鲁西研究所癌症专家叙泽特•德拉洛热表示，Palbociclib能够延长患者生命，这的确是抗癌研究的一大进展。但是人们还需等待一年半之后的3期临床实验结果才能得知Palbociclib是否真能有效抗癌。

 报道指出，Palbociclib到底何时上市还不得而知。不过，辉瑞公司可能会仅根据2期临床试验结果即向美国食品药监局申请上市批准，而不会等待3期临床试验结果。预计，如果这款药物能够获得批准，其年销售额可能会达到50亿美元(约合人民币309.98亿元)。

Pfizer’s Novel CDK 4/6 Inhibitor Palbociclib plus Letrozole Significantly Prolonged Progression-Free Survival in Patients with Advanced Breast Cancer

Final Phase 2 PALOMA-1 Data to Be Presented Today for Potential First-in-Class Palbociclib

Webcast of Conference Call with Securities Analysts to Review Data Scheduled for Today at 1:30 PDT

NEW YORK, N.Y., April 6 – Pfizer Inc. today announced detailed results from the PALOMA-1 study, a randomized Phase 2 study of palbociclib (PD-0332991) in combination with letrozole. PALOMA-1 achieved its primary endpoint by significantly prolonging progression-free survival (PFS) compared with letrozole alone in post-menopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or me-tastatic breast cancer. For women treated with the combination of palbociclib plus letrozole, the median PFS was 20.2 months, a statistically significant improvement compared to the 10.2 months of PFS in women who received letrozole alone (HR=0.488 [95% CI: 0.319, 0.748]; p=0.0004). These data will be presented today by Dr. Richard S. Finn, associate professor of medicine at University of California, Los Angeles (UCLA) at the American Association of Cancer Research (AACR) Annual Meeting 2014 in San Diego (Abstract #CT101).

"These data demonstrate the potential of palbociclib to be a major advance in the treatment of women with this type of advanced breast cancer," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "We are proud to be at the forefront of research and development with respect to this promising new class of investigational anticancer agents and have initiated a broad clinical development program for palbociclib that includes breast and non-breast cancers.”

Final results for the secondary efficacy endpoints of duration of treatment and clinical benefit rate demonstrated superiority in the palbociclib plus letrozole arm compared to the letrozole-only arm. Per the PALOMA-1 trial protocol, an initial assessment of overall survival (OS), a secondary endpoint, was also performed. Based on the events at the time of the assessment, a median OS of 37.5 months was observed in the combination arm versus 33.3 months for those who received letrozole alone, a difference of 4.2 months (HR = 0.813, 95% CI: 0.492, 1.345). This OS observation at the time of final PFS analysis was not statistically significant. A follow-up OS analysis will be conducted following the accrual of additional events.

The combination of palbociclib and letrozole was generally well-tolerated and the safety profile of the combination was consistent with previously reported data. The most common adverse events in the palbociclib plus letrozole arm were neutropenia (a decrease of the neutrophil count), leukopenia (a decrease in the total white blood cell count), fatigue and anemia. The neutropenia observed with the combination in this study was non-cumulative and clinically manageable. No cases of febrile neutropenia were reported in either arm of the study. Neutropenia is an on-target, anti-proliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone marrow.

Palbociclib received Breakthrough Therapy designation from the United States Food and Drug Administration (FDA) in April 2013, for the initial treatment of women with advanced or me-tastatic ER+, HER2- breast cancer. This designation was based on interim data from the PALOMA-1 trial. Pfizer continues to work with the FDA and other regulatory authorities to define the appropriate regulatory path forward for palbociclib.

Pfizer invites investors and the general public to view and listen to a webcast of a presentation by Pfizer’s Oncology leadership today at 1:30 p.m. Pacific Daylight Time, in connection with the presentation of the final results of PALOMA-1. To view and listen to the webcast, visit our website at www.pfizer.com and click on the “Review of Palbociclib Phase 2 PALOMA-1 Results at AACR Annual Meeting 2014” webcast 1ink in the For Investors section located on the lower right-hand corner of that page.

ab0ut PALOMA-1

PALOMA-1 (also known as Study 1003 and TRIO-18) is a Phase 2 trial designed to assess PFS in post-menopausal women with ER+, HER2- advanced breast cancer receiving palbociclib (125 mg once daily for three out of four weeks in repeated cycles) in combination with letrozole versus letrozole alone (2.5 mg once daily on a continuous regimen). This trial consisted of two parts. Part 1 enrolled 66 patients with ER+, HER2- advanced breast cancer. Part 2 enrolled 99 additional patients whose tumors were selected for presence of biomarkers: cyclin D1 amplification and/or p16 loss. Final results from PALOMA-1 showed that statistically significant improvement in PFS was achieved for the study arm (palbociclib + letrozole) in both Parts 1 and 2. PFS is comprised of time from randomization to time of disease progression or death from any cause.

PALOMA-1 is conducted in collaboration with the Jonsson Cancer Center’s Revlon/UCLA Women’s Cancer Research Program, led by Dr. Dennis Slamon. PALOMA-1 is a multi-center trial with 101 global sites participating.

Palbociclib Development Program in ER+, HER2- Breast Cancer

Pfizer has worked closely with investigators and international breast cancer experts to establish a robust development program for palbociclib in ER+, HER2- breast cancer across stages and treatment settings.

Pfizer has initiated two Phase 3 studies of palbociclib in advanced/me-tastatic breast cancer. PALOMA-2 (also known as Study 1008) is a randomized (2:1), multi-center, double blind Phase 3 study that eva1uates palbociclib in combination with letrozole versus letrozole plus placebo as a first-line treatment for post-menopausal patients with ER+, HER2- advanced breast cancer. PALOMA-3 (also known as Study 1023) is a randomized (2:1), multi-center, double blind Phase 3 study that eva1uates palbociclib in combination with fulvestrant versus fulvestrant plus placebo in women with hormone receptor-positive (HR+), HER2- me-tastatic breast cancer whose disease has progressed after prior endocrine therapy.

Additional, investigator-led studies of palbociclib in advanced/me-tastatic breast cancer and in early breast cancer are open and enrolling patients, including the PEARL and PENELOPE-B studies. PEARL, sponsored by Grupo Español de Investigación en Cáncer de Mama (GEICAM, Spanish Breast Cancer Research Group), with participation from the Central European Cooperative Oncology Group (CECOG), is a randomized (1:1), multi-center, open-label Phase 3 study eva1uating palbociclib in combination with exemestane versus capecitabine in post-menopausal women with ER+, HER2- me-tastatic breast cancer whose disease was refractory to previous non-steroidal aromatase inhibitors (letrozole or anastrozole). PENELOPE-B is a randomized (1:1), double blind, placebo-controlled Phase 3 study comparing palbociclib plus standard endocrine therapy to placebo plus standard endocrine therapy in patients with HR+, HER2-normal (also known as HER2-) early-stage breast cancer with certain features that suggest an increased risk for recurrence after completing pre-operative chemotherapy followed by surgery. This international study is sponsored by the German Breast Group (GBG).

For more information on these and other ongoing clinical trials of palbociclib in breast cancer and other tumor types, please visit www.clinicaltrials.gov.

ab0ut Palbociclib

Palbociclib is an investigational oral targeted agent that selectively inhibits cyclin-dependent kinases (CDKs) 4 and 6 to regain cell cycle control and block tumor cell proliferation.

Loss of cell cycle control is a hallmark of cancer and CDK 4/6 are overactivated in numerous cancers, leading to loss of proliferative control. , CDK 4/6 are key regulators of the cell cycle that trigger cellular progression from growth phase (G1) into phases associated with DNA replication (S). , CDK 4/6, whose increased activity is frequent in estrogen receptor-positive (ER+) breast cancer (BC), are key downstream targets

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