大家这么关心PD-1，这是一个pembrolizumab在不同肿瘤中的报道

Encouraging data for PD-1 inhibitor pembrolizumab in different PD-L1-positive tumors
Pembrolizumab (MK-3475; Merck & Co.) is a highly selective anti-PD-1 humanized monoclonal antibody (MAb) that has shown antitumor activity in several types of cancer, is not cytotoxic and can be administered every 2 or 3 weeks, as seen in previous pharmacokinetic studies.
Researchers in Japan reported initial data corresponding to patients with gastric cancer being treated in one of the cohorts of the KEYNOTE-012 study (ClinicalTrials.gov Identifier NCT01848834), a phase Ib trial intended to evaluate the safety, tolerability and efficacy of pembrolizumab in patients with different types of advanced solid tumors. Patients (n = 19 Asian; n = 20 non-Asian) were treated with i.v. pembrolizumab 10 mg/kg every 2 weeks and were followed up to 24 months until complete response, disease progression or unacceptable toxicity. The more frequent treatment-related adverse events (TEAEs) were hypothyroidism and fatigue, both in 12.8% of patients, with no patient discontinuations. The primary efficacy endpoint of overall response rate (ORR) showed strong evidence of antitumor activity in both groups, 30 and 31.6% for non-Asian and Asian subjects, respectively, and a phase II in this type of cancer is planned to begin enrollment shortly (Muro, K. et al. 39th Eur Soc Med Oncol (ESMO) Congr (Sept 26-30, Madrid) 2014, Abst LBA15).
Other results from the multi-cohort KEYNOTE-012 trial were presented regarding the cohort of patients with recurrent or metastatic HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC). Patients (N = 60; median age = 63 years) received i.v. pembrolizumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or completion of 24 months of treatment. After 10.2 months of follow-up all patients remained on the treatment. Frequent reasons for discontinuation were progressive disease and adverse events (AEs), in 57 and 10% of patients, respectively, and the primary endpoint was ORR and secondary endpoints were progression-free survival (PFS), overall survival (OS) and duration of response. Assessment of antitumor activity revealed that 51% either decreased or maintained the size of their lesions compared with baseline. ORR was 19.6% and was similar in HPV+ and HPV- subjects, and PD-L1 correlated with response. OS was longer in HPV+ than in HPV- tumor patients (73.9 vs. 58.1%) and PFS was also longer, with a median number of weeks of 17.2 for HPV+ and 8.1 weeks for HPV- subjects. The more frequent AEs were fatigue (18.3%) and pruritus (10%). Pembrolizumab was well tolerated and showed antitumor activity in patients with HPV+ and HPV- advanced HNSCC. Phase III studies in this subset of patients will follow the expansion cohort of KEYNOTE-012, currently ongoing (Chow, L. et al. 39th Eur Soc Med Oncol (ESMO) Congr (Sept 26-30, Madrid) 2014, Abst LBA31).
Pembrolizumab has previously shown antitumor activity and tolerability in both treatment-naive and pretreated advanced non-small cell lung cancer (NSCLC) patients. Results of a pooled analysis of patients were allocated in two randomized and three non-randomized cohorts of the phase I KEYNOTE-001 study (ClinicalTrials.gov Identifier NCT01295827). Patients (N = 307) received 2 mg/kg of i.v. pembrolizumab every 3 weeks or 10 mg/kg every 2 or 3 weeks until disease progression or unacceptable toxicity. The most frequently reported AE was fatigue (25%), and in terms of grade 3-5 AEs, the most common was pneumonitis (2%). ORR was 33, 21 and 21% for the dose groups of 2 mg/kg every 2 weeks, 10 mg/kg every 3 weeks and 10 mg/kg every 2 weeks, respectively. Median PFS was 13 weeks, and at 6 months the PFS was 30%, and median OS was 8.2 months and at 6 months it was 64% of the pooled population. Pembrolizumab was safe and showed strong antitumor activity both in treatment-naive and previously treated NSCLC in all treatment subgroups (Garon, E. et al. 39th Eur Soc Med Oncol (ESMO) Congr (Sept 26-30, Madrid) 2014, Abst LBA43).
Early data were also reported in patients allocated in the advanced urothelial bladder cancer cohort of the ongoing phase Ib KEYNOTE-012 study. Patients received pembrolizumab (10 mg/kg every 2 weeks) with a median follow-up of 11 months. Of these, approximately 75% had also received one or more previous treatments. Among patients eligible for response (N = 29), 3 experienced a complete response, 4 a partial response, 4 disease stabilization and 14 disease progression. The most frequent AEs were fatigue (18%), peripheral edema (12%) and nausea (9%). Four patients experienced grade 3 to 4 AEs, with one discontinuation due to TEAEs, and the ORR was 24.1%. A decrease in target lesions was seen in 64% of patients, median time to response was 8 weeks, and median OS and PFS was 9.3 months and 8.6 weeks, with OS and PFS at 6 months of 58.0 and 23.1%, respectively. Pembrolizumab presented an acceptable safety profile and significant antitumor activity when administered as monotherapy in patients with advanced PD-L1-positive bladder cancer. These results led to the initiation of a phase III trial for pembrolizumab in advanced urothelial cancer at the end of 2014 to confirm this anti-PD-1 therapy feasibility for this devastating disease (Plimack, E. et al. 39th Eur Soc Med Oncol (ESMO) Congr (Sept 26-30, Madrid) 2014, Abst LBA23).
To further compare the efficacy and safety of pembrolizumab, an additional 244 patients were enrolled in KEYNOTE-001 and randomized 1:1 to receive pembrolizumab 10 mg/kg every 3 weeks (n = 121) or 10 mg/kg every 2 weeks (n = 123). The median follow-up as of February 2014 was approximately 35 weeks, with all patients having had >= 26 weeks of follow-up. The median treatment duration was 21 weeks for the every-3-weeks arm and 22 weeks for the every-2-weeks arm. No significant difference in ORR was observed between the two schedules, with an ORR of 28% every 3 weeks and 33% every 2 weeks. This consisted of 1 complete response and 29 partial responses in the every-3-week cohort, while 4 complete responses and 34 partial responses were seen in the every-2-week cohort. The 24-week PFS rates were 43% every 3 weeks and 47% every 2 weeks, with no significant difference observed in PFS between schedules. Twelve and 15% of patients receiving the every 3 week and the every 2 week schedule, respectively, reported grade 3 to 4 AEs. Discontinuations due to TEAEs resulted in 1% of patients every 3 weeks and 3% of patients every 2 weeks. No treatment-related deaths were reported. Overall, the results of this study demonstrated that pembrolizumab has similar efficacy and safety at 10 mg/kg every 3 weeks and 10 mg/kg every 2 weeks in patients with advanced melanoma. Since previous randomized data showed no significant difference in efficacy and safety between pembrolizumab doses of 10 mg/kg every 3 weeks and 10 mg/kg every 2 weeks, the recommended pembrolizumab dose and schedule was determined to be 2 mg/kg every 3 weeks (Robert, C. et al. 39th Eur Soc Med Oncol (ESMO) Congr (Sept 26-30, Madrid) 2014, Abst LBA34).

机器翻译的

令人鼓舞的数据可以在不同的PD-L1阳性肿瘤的PD-1抑制剂pembrolizumab
Pembrolizumab（MK-3475;默克公司）是一种高选择性的抗PD-1的人源化单克隆抗体（MAb），该显示抗肿瘤活性的几种类型癌症，是没有细胞毒性，可给予每2～3周，如以前的药代动力学研究观察。
研究人员在日本报告对应于胃癌患者正在接受治疗的基调-012研究的同伙中的一个初始数据（ClinicalTrials .GOV标识符NCT01848834）中，Ib期试验旨在评估安全性，耐受性和pembrolizumab的功效的患者具有不同类型的晚期实体瘤。患者（n = 19的亚洲，N = 20个非亚洲）分别用四pembrolizumab 10毫克/公斤，每2周，随访24个月，直到完全反应，疾病进展或不可接受的毒性。更频繁的与治疗相关的不良事件（的TEAE）是甲状腺功能减退和疲劳，无论是在患者的12.8％，没有病人停药。整体回应率的主要疗效终点（ORR）具有抗肿瘤活性的有力证据两组，对非亚洲和亚洲科目，分别在这类型的癌症II期30和31.6％，计划不久将开始招生（穆罗，K等39欧元SOC医学肿瘤学（ESMO）Congr（9月26日至30日，马德里）2014年，ABST LBA15），
从多队列主旨-012试验的其他研究结果发表有关患者的队列复发或转移性的HPV +和HPV-头颈部鳞状细胞癌（头颈部鳞癌）。患者（n = 60，平均年龄= 63岁）接受静脉pembrolizumab 10毫克/公斤，每2周，直至疾病进展，不可接受的毒性或治疗24个月完成。后10.2个月随访所有患者保持对治疗。常见原因中止是渐进性疾病和不良事件（AE），在57和10％的患者，分别与主要终点是ORR和次要终点是无进展生存期（PFS），总生存期（OS）和持续时间回应。抗肿瘤活性的评估显示，51％的任一减少或维持其病变与基线相比的大小。ORR为19.6％，是在HPV +和HPV-主题相似，和PD-L1与相关回应。操作系统是在较长的HPV +比HPV-肿瘤患者（73.9对比58.1％）和PFS也较长，中位周数为17.2 HPV +和8.1周，HPV-科目。较常见的不良反应有乏力（18.3％）和瘙痒（10％）。Pembrolizumab的耐受性良好，并显示患者的抗肿瘤活性与HPV +和HPV-先进的头颈部鳞癌。III期临床试验的患者子集将遵循主旨-012，目前正在进行扩建队列（周湖等39欧元SOC医学肿瘤学（ESMO）Congr（九月26日至30日，马德里）2014年，ABST LBA31） 。
Pembrolizumab先前已经显示抗肿瘤活性和耐受性在两种治疗过的和预处理的晚期非小细胞肺癌（NSCLC）的患者。患者的汇总分析的结果进行分配阶段的两项随机和三个非随机队列í基调-001的研究（ClinicalTrials.gov标识符NCT01295827）。患者（n = 307）接受静脉pembrolizumab为2毫克/千克，每3周或10毫克/公斤，每2～3周，直至疾病进展或不可接受的毒性。最常报告的AE是疲劳（25％），并在3-5级不良事件而言，最常见的是肺炎（2％）。ORR为33，21和21％为2毫克/公斤，每2周，10毫克/公斤，每3周和10 mg / kg，每2周给药组，分别。中位PFS为13周，6个月的PFS为30％，中位生存期为8.2个月，6个月时是64％的人口集中的。Pembrolizumab是安全的，无论是在治疗初治表现出较强的抗肿瘤活性，以前治疗非小细胞肺癌中的所有治疗亚组（加龙，E等，39欧元的SoC医学肿瘤学（ESMO）Congr（9月26日至30日，马德里）2014年，ABST LBA43 ）。
早期的数据也报道了分配正在进行的Ib期主旨-012研究的先进尿路上皮膀胱癌患者的队列。患者接受pembrolizumab（10毫克/公斤，每2周），中位随访时间为11个月。其中，大约75％的人也获得了一个或多个先前的治疗。在病人符合响应组（n = 29），3经历了一个完整的响应，4部分缓解，4病情稳定，14病情恶化。最常见的不良事件是疲劳（18％），外周水肿（12％）和恶心（10％）。四名病人经历了3～4级不良事件，有一个停药因的TEAE和ORR为24.1％。靶病变的减少主要出现在64％的患者，中位时间为响应为8周，中位OS和PFS为9.3个月，8.6周，在OS和PFS在6个月的58.0和23.1％，分别。Pembrolizumab提出了一个可接受的安全性和显著的抗肿瘤活性，当作为单药治疗晚期PD-L1的阳性膀胱癌的管理。这些结果导致了III期临床试验的pembrolizumab晚期尿路上皮癌，在2014年年底开始，以确认该抗PD-1治疗的可行性，这种破坏性疾病（Plimack，E等，39欧元的SoC医学肿瘤学（ 。ESMO）Congr（9月26日至30日，马德里）2014年，ABST LBA23）
为了进一步比较的疗效和pembrolizumab的安全性，额外的244例患者参与了主题演讲，001和1：1随机接受pembrolizumab 10毫克/每公斤3周组（n = 121）或10毫克/公斤，每2周（N = 123）。在中位随访时间为2014年2月的是约35周，所有患者有过> = 26周随访。中位治疗时间为21周的每3个星期的手臂和22周的每2周的手臂。两地时间表的观察ORR无显著差异，28％，每3周为33％，每2周的ORR。这包括了1完全缓解，并在每3个星期的队列29例部分缓解，而4完全缓解和34例部分缓解主要出现在每2个星期的队列。24周PFS率分别为43％，每3周和47％，每2周，观察到加油站的时间表之间没有显著差异。对接收的每3周，每2为期三周的患者十二和15％，分别报3～4级不良事件。由于的TEAE导致停药的患者，每3周1％的患者每2周3％。报道没有治疗相关性死亡。总体而言，本研究的结果表明，pembrolizumab具有类似的功效和安全性，在10毫克/公斤，每3周和10毫克/公斤，每2周治疗晚期黑色素瘤。因为先前随机化的数据表明：在pembrolizumab剂量为10毫克/公斤，每3周和10毫克之间的疗效和安全性没有显著差/公斤，每2周，推荐pembrolizumab剂量和时间表被确定为2毫克/公斤，每3周（罗伯特C.等。39欧元SOC医学肿瘤学（ESMO）Congr（9月26日至30日，马德里）2014年，ABST LBA34）。

是不是还没有在乳腺癌的数据？