Oncology & Haematology Office, European Medicines Agency, Amsterdam, The Netherlands.
Oncology & Haematology Office, European Medicines Agency, Amsterdam, The Netherlands; Department of Haematology, Hospital Clinic, Barcelona, Spain.
ESMO Open. 2021 Jun;6(3):100145. doi: 10.1016/j.esmoop.2021.100145. Epub 2021 Apr 30.
On 21 January 2021, the European Commission amended the marketing authorisation granted for pembrolizumab to include the first-line treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) in adults. The recommended dose of pembrolizumab was either 200 mg every 3 weeks or 400 mg every 6 weeks by intravenous infusion. Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with bevacizumab/cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or microsatellite instability-high stage IV CRC. Subjects randomised to the SOC arm had the option to crossover and receive pembrolizumab once disease progressed. Both progression-free survival (PFS) and overall survival were primary endpoints. Pembrolizumab showed a statistically significant improvement in PFS compared with SOC, with a hazard ratio of 0.60 [95% confidence interval (CI): 0.45-0.80], P = 0.0002. Median PFS was 16.5 (95% CI: 5.4-32.4) versus 8.2 (95% CI: 6.1-10.2) months for the pembrolizumab versus SOC arms, respectively. The most frequent adverse events in patients receiving pembrolizumab were diarrhoea, fatigue, pruritus, nausea, increased aspartate aminotransferase, rash, arthralgia, and hypothyroidism. Having reviewed the data submitted, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) considered that the benefit-risk balance was positive. This is the first time the CHMP has issued an opinion for a target population defined by DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union.
2021 年 1 月 21 日，欧盟委员会修订了 pembrolizumab 的营销授权，将其纳入用于治疗成人微卫星不稳定高（MSI-H）或错配修复缺陷（dMMR）转移性结直肠癌（mCRC）的一线治疗。 pembrolizumab 的推荐剂量为每 3 周静脉输注 200mg 或每 6 周静脉输注 400mg。 pembrolizumab 在一项 III 期、开放标签、多中心、随机试验中进行了评估，与标准护理（SOC：FOLFOX6/FOLFIRI 单独或联合贝伐单抗/西妥昔单抗）作为局部确认的错配修复缺陷或微卫星不稳定高的 IV 期 CRC 的一线治疗。随机分配到 SOC 组的受试者可以选择交叉并在疾病进展时接受 pembrolizumab 治疗。无进展生存期（PFS）和总生存期都是主要终点。与 SOC 相比，pembrolizumab 在 PFS 方面显示出统计学上的显著改善，风险比为 0.60[95%置信区间（CI）：0.45-0.80]，P=0.0002。中位 PFS 分别为 pembrolizumab 组 16.5（95%CI：5.4-32.4）和 SOC 组 8.2（95%CI：6.1-10.2）个月。接受 pembrolizumab 治疗的患者最常见的不良反应是腹泻、疲劳、瘙痒、恶心、天冬氨酸氨基转移酶升高、皮疹、关节痛和甲状腺功能减退。在审查了提交的数据后，欧洲药品管理局（EMA）人用药品委员会（CHMP）认为，获益风险平衡为阳性。这是 CHMP 首次对基于 DNA 修复缺陷生物标志物定义的目标人群发表意见。本文的目的是总结导致在欧盟获得监管批准的申请的科学审查。
