2014年12月11日讯 /生物谷BIOON/ --默沙东（Merck & Co）近日在2014年圣安东尼奥乳腺癌研讨会（SABCS）上公布了PD-1免疫疗法Keytruda（pembrolizumab）治疗转移性三阴乳腺癌（TNBC）的首批早期数据，结果显示，针对PD-L1阳性三阴乳腺癌，Keytruda表现出了令人鼓舞的抗肿瘤活性，总缓解率达到了18.5%。
这是默沙东首次官方宣布Keytruda治疗三阴乳腺癌（TNBC）的数据。默沙东表示，三阴乳腺癌（TNBC）是一种极其难以治疗的疾病，临床预后极差且鲜有治疗方案。此次公布的队列研究中，大多数患者既往已接受过多次化疗，尽管相关数据还很初步，但已经表明Keytruda在这类患者中具有令人鼓舞的抗肿瘤活性。默沙东已计划在2015年上半年启动一项II期研究，进一步推进Keytruda的乳腺癌临床项目。
此次公布的数据来自一项Ib期研究（KEYNOTE-012）的其中一个队列，该队列调查了Keytruda单药疗法（每2周注射一次，剂量10mg/kg）用于PD-L1表达呈阳性的晚期三阴乳腺癌（TNBC）的治疗。截止2014年11月10日，采用实体瘤缓解评价标准（RECIST）评价的Keytruda抗肿瘤活性数据如下：总缓解率（ORR）为18.5%（n=5/27），完全缓解率（CRR）为3.7%（n=1/27），部分缓解率（PRR）为14.8%（n=4/27），疾病稳定率25.9%（n=7/27），疾病进展率为44.4%（n=12/27），实现缓解的中位时间为18周（范围7-32），有33%的患者肿瘤缩小。在6个月时，无进展生存率为23.3%，中位缓解持续时间尚未达到。
PD-1/PD-L1免疫疗法是当前备受瞩目的新一类抗癌免疫疗法，旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，具有治疗多种类型肿瘤的潜力。而各大制药巨头也正在火速推进各自的项目，调查单药疗法和组合疗法用于多种癌症的治疗，以彻底发掘该类药物的最大临床潜力。
关于KEYNOTE-012研究：
KEYNOTE-012研究是一项多中心非随机Ib期研究，正在评估Keytruda单药疗法治疗晚期三阴乳腺癌（TNBC）、晚期头颈部癌症、晚期膀胱上皮（膀胱）癌、晚期胃癌的安全性、耐受性、治疗PD-L1阳性肿瘤的抗肿瘤活性。研究的主要终点包括整体安全性、耐受性、抗肿瘤活性；次要终点包括无进展生存期（PFS）、总生存期（OS）、缓解持续时间（DR）。研究中，58%的患者筛查确定肿瘤为PD-L1表达阳性，大多数患者曾接受2次或更多化疗，87.5%曾接受过新辅助化疗或辅助治疗。
关于三阴乳腺癌（TNBC）：
三阴乳腺癌(TNBC)特指雌激素受体（ER）、孕激素受体（PR）及人表皮生长因子受体2（HER-2）三者均为阴性表达的乳腺癌，预后极差，5年生存率不到15%。三阴乳腺癌（TNBC）对激素疗法和HER2靶向疗法（如罗氏赫赛汀Herceptin）均无效，临床治疗上主要依靠化疗。
英文原文：Data Investigating KEYTRUDA® (pembrolizumab), Merck’s Anti-PD-1 Therapy, in Patients with Advanced Triple-Negative Breast Cancer Presented at 2014 San Antonio Breast Cancer Symposium
18.5 Percent Overall Response Rate Observed in KEYTRUDA-Treated Patients with This Aggressive Form of Breast Cancer
Phase 2 Study Planned for the First Half of 2015 (KEYNOTE-086)
SAN ANTONIO--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today early study findings demonstrating an overall response rate of 18.5 percent with KEYTRUDA, the company’s anti-PD-1 therapy, as assessed by RECIST v1.1, central review (n=5/27), in PD-L1 positive, advanced triple-negative breast cancer – one of the most aggressive forms of breast cancer. At the time of analysis, the median duration of response had not been reached with three of five responders on therapy for 11 months or more (range, 15 to 40+ weeks). These early findings, from the ongoing Phase 1b KEYNOTE-012 study, were shared today for the first time as part of the official press program at the 2014 San Antonio Breast Cancer Symposium (SABCS) (ABSTRACT #S1-09) and will be presented in an oral session at 10:45 a.m. CST by Dr. Rita Nanda, the University of Chicago.
“Metastatic, triple-negative breast cancer is an aggressive and often difficult to treat disease,” said Dr. Rita Nanda, associate director, breast medical oncology, the University of Chicago and principal investigator for the KEYTRUDA triple-negative breast cancer Phase 1b study cohort. “The results presented at this year’s SABCS, while early, show encouraging anti-tumor activity in these patients, most of whom had received multiple prior chemotherapies.”
“This year, Merck has significantly advanced our immuno-oncology development program and new data for KEYTRUDA have been presented in seven different cancers, including these first findings in triple-negative breast cancer,” said Dr. Alise Reicin, vice president, global clinical development, oncology, Merck Research Laboratories. “These early data with KEYTRUDA show responses in patients with one of the most aggressive forms of breast cancer and further our understanding of the PD-1 pathway’s role in this disease. Our Phase 2 study planned for the first half of 2015 will be an important next step for our breast cancer clinical program.”
Early Findings Evaluating KEYTRUDA in Advanced Triple-Negative Breast Cancer
Data presented were from a cohort of the ongoing Phase 1b KEYNOTE-012 study which evaluated KEYTRUDA monotherapy at 10 mg/kg every two weeks in patients with advanced TNBC whose tumors were determined to be positive for PD-L1 expression (n=32). As measured by Merck’s proprietary PD-L1 immunohistochemistry (IHC) clinical trial assay, tumors were considered to be PD-L1 positive if staining was present in the stroma or in greater than or equal to one percent of tumor cells. In the study, 58 percent of patients screened had tumors determined to be positive for PD-L1 expression. Most patients enrolled in this study had received two or more prior chemotherapies for metastatic disease and 87.5 percent had received prior neo-adjuvant or adjuvant therapy.
The median time to response was 18 weeks (range, 7-32 weeks). In the study, 33 percent of patients with KEYTRUDA achieved tumor shrinkage. At six months, the progression-free survival rate with KEYTRUDA was 23.3 percent.
Adverse events were consistent with previously reported safety data for KEYTRUDA. The most common treatment-related adverse events (occurring in greater than or equal to five percent of patients) included arthralgia (n=6), fatigue (n=6), myalgia (n=5), nausea (n=5), ALT increased (n=2), AST increased (n=2), diarrhea (n=2), erythema (n=2) and headache (n=2). Grade 3-5 treatment-related adverse events occurred in a total of five patients and included anemia, disseminated intravascular coagulation (DIC), headache, meningitis aseptic, decreased blood fibrinogen, and pyrexia. Two patients discontinued KEYTRUDA due to adverse events. One treatment-related death was reported in a patient with rapidly progressive disease and was due to DIC with thrombocytopenia and decreased blood fibrinogen.
About the KEYNOTE-012 Study
KEYNOTE-012 is an ongoing multi-center, non-randomized Phase 1b trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy in patients with advanced triple-negative breast cancer (TNBC), advanced head and neck cancer, advanced urothelial (bladder) cancer, or advanced gastric cancer. The primary endpoints of the study include overall safety, tolerability and anti-tumor activity (as measured by RECIST v1.1 assessed by independent radiology review) in PD-L1 positive tumors; secondary endpoints include progression-free survival (PFS), overall survival (OS) and duration of response. In 2014, early findings were presented for all four cohorts of the Phase 1b KEYNOTE-012 study.
About KEYTRUDA (pembrolizumab)
KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.
KEYTRUDA is indicated in the United States at a dose of 2 mg/kg every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.