晚癌患者福音: “抗癌神药”PD-1抑制剂 最新临床数据速览
说起PD-1,应该大家都不陌生,作为一款曾治愈美国前总统卡特的抗癌神药已然成为了新近网红,从2018年7月20日,CFDA批准默沙东公司PD-1抑制剂Keytruda(Pembrolizumab,商品名可瑞达)上市,用于晚期黑色素瘤的治疗。目前,关于Keytruda的研究也如火如荼地展开,使得该药在未来获批更多的适应症。
PD-1,曾治愈美国前总统卡特的抗癌神药已然成为了新近网红

俗话说知其然还要知其所以然,下面先详细像大家介绍一下PD-1抑制剂到底何方神圣。


程序性死亡受体-1( Programmed death-1,PD-1)是T细胞上的一种抑制性受体。免疫哨卡(Immune check point)是机体共刺激或抑制信号转换的开关,能控制T细胞应答的幅度和持续时间,而PD-1能够与配体(Programmed death-1 ligand,PD-Ls)PD-L1、PD-L2相互作用,抑制T细胞增殖、活化和细胞因子的分泌,因此是调节T细胞反应的重要免疫哨卡。在正常机体中,PD1、PD-Ls信号通路对维持机体的免疫耐受具有重要作用;而在肿瘤发生时,PD1、PD-Ls信号通路能抑制T细胞的免疫反应而促进肿瘤免疫逃逸的发生。

PD1、PD-Ls信号通路的作用机制如下图所示。PD-1作为T细胞上的抑制性受体,与PD-Ls结合后,PD-1胞质区ITSM结构域中的酪氨酸发生磷酸化,募集SHP-2磷酸酶,使TCR-CD3分子和下游的ZAP70发生去磷酸化,此外,通过阻断细胞抗凋亡因子Bcl-XL的表达,进一步阻断PI3K的活化,下调IL-2表达和葡萄糖代谢。而IL-2的表达下调又进一步诱导CD8+T细胞和CD4+T细胞处于功能失活状态,起到免疫负调控作用。


因此,以PD1、PD-Ls信号通路为靶标,研发针对PD1或PD-Ls 的阻断剂,能够增强T细胞对肿瘤细胞的杀伤,而PD1、PD-L1的阻断剂因其良好的疗效和较低的不良反应也已经成为近年来在肿瘤免疫治疗领域的一大热点。


接下来,小编将就PD-1抑制剂Keytruda方面的取得的最新临床数据做一个简单汇总

新英格兰

Pembrolizumab联合化疗治疗转移性NSCLC

结果发现,在10.5个月的中位随访后,pembrolizumab联合治疗组12个月的总生存率估计为69.2%(95% [CI], 64.1 – 73.8),安慰剂联合治疗组为49.4%(95%可信区间为42.1 – 56.2)(危险比为0.49;95% CI 0.38 ~ 0.64;P < 0.001)。所有被评估的PD-L1类别的总体生存率都有所提高。Pembrolizumab联合组无进展生存期中位数为8.8个月(95% CI, 7.6 ~ 9.2),安慰剂联合组无进展生存期中位数为4.9个月(95% CI, 4.7 ~ 5.5)(疾病进展或死亡的危险比,0.52;95% CI 0.43 – 0.64;P < 0.001)。pembrolizumab联合组中3级以上不良事件发生率为67.2%,安慰剂联合组中不良事件发生率为65.8%。


对于没有EGFR或ALK突变的转移性非鳞状细胞非小细胞肺癌患者,在标准化疗和基于铂类的药物中加入pembrolizumab,与单独化疗相比,显著延长了总体生存期和无进展生存期。


摘要原文:

METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.

RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.

CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. 


新英格兰

 Pembrolizumab与安慰剂对照治疗三期术后黑色素瘤

结果发现在15个月的中位随访中,pembrolizumab在总体意向治疗人群中的无复发生存率显著高于安慰剂(1年无复发生存率75.4%[95% {CI}, 71.3 ~ 78.9] vs 61.0% [95% CI, 56.5 ~ 65.1];复发或死亡的危险比,0.57;98.4% CI 0.43 ~ 0.74;pembrolizumab组853例pd - l1阳性率(1年无复发生存率,pembrolizumab组77.1% [95% CI, 72.7 ~ 80.9],安慰剂组62.6% [95% CI, 57.7 ~ 67.0];风险比,0.54;95% CI 0.42 ~ 0.69;P < 0.001)。在pembrolizumab组中14.7%的患者和安慰剂组中3.4%的患者报告了与试验方案相关的3 ~ 5级不良事件。在pembrolizumab组中,有1例患者因肌炎而死亡。


因此,pembrolizumab作为三期黑素瘤高危期的辅助治疗,每3周服用200 mg pembrolizumab,为期1年,与安慰剂相比,明显延长了无复发生存期,没有发现新的毒副作用。


原文摘要:

METHODS: Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.

RESULTS: At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.

CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified.


柳叶刀

Pembrolizumab对比紫杉醇治疗进展期胃食管交界癌

2015年6月4日至2016年7月26日,共收治592例患者。在395例PD-L1 CPS大于等于1的患者中,196例患者被分配接受pembrolizumab治疗,199例患者被分配接受紫杉醇治疗。截至2017年10月26日,pembrolizumab组196例患者死亡326例(151[77%],紫杉醇组199例患者死亡175[88%])。pembrolizumab的总体生存率中位数为9·1个月(95% CI 6·2-10·7),紫杉醇(危险比[HR] 0·82,95% CI 0·66-1·03;单侧p = 0·0421)。pembrolizumab无进展生存期中位数为1·5个月(95% CI 1·4-2·0),紫杉醇无进展生存期中位数为4·1个月(3·1-4·2)(HR 1·27,95% CI 1·03-1·57)。在人群中,294例患者中42例(14%)发生3-5级治疗相关不良事件,276例患者中96例(35%)发生紫杉醇治疗相关不良事件。


该研究发现,与紫杉醇相比,Pembrolizumab并没有显著提高晚期胃癌或胃食管交界处PD-L1 CPS大于或等于1的二线治疗的整体生存率。Pembrolizumab的安全性评价优于紫杉醇。pembrolizumab用于胃癌和胃食管癌的进一步试验正在进行中。


摘要原文:

METHODS: This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1:1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0·0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498.

FINDINGS: Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9·1 months (95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.

INTERPRETATION: Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing.

参考文献:

  • Gandhi L et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018 May 31;378(22):2078-2092.

  • Eggermont AMM et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801.

  • Shitara K et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018 Jul 14;392(10142):123-133.


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