背景 : 在 III 期研究中，随机开放标签的 keyto -177(NCT02563002) 研究帕博利珠单抗 (pembrolizumab, pembro)与化疗(chemo)对 MSI-H/dMMR mCRC 住院患者(IA2)提供了更好的无进展生存期(PFS)。该研究继续对总生存期(OS)进行最终分析，计划在 190 个 OS 事件后或 IA2 事件发生后 12 个月后进行，我们给出 IA2 后 12 个月 OS 的最终分析结果。

Background: In the phase III, randomized open-label KEYNOTE-177 (NCT02563002) study 1L pembrolizumab (pembro) versus chemotherapy (chemo) provided superior progression-free survival (PFS) at second interim analysis (IA2) in patients (pts) with MSI-H/dMMR mCRC. The study continued to final analysis of overall survival (OS), planned after 190 OS events or 12 months after IA2, whichever occurred first. We present results of the final analysis of OS, 12 months after IA2.

方法：将 307 名 MSI-H / dMMR mCRC 和 ECOG PS 0 或 1 的患者随机分配为 1：1 至 pembro200 mg Q3W，持续 2 年，或由研究者选择 mFOLFOX6 或 FOLFIRI Q2W±贝伐单抗或西妥昔单抗。继续治疗直至 PD，患者出现不可接受的毒性，研究者决定退出治疗或完成 35 个周期（仅pembro）。确诊 PD 后，接受化学治疗的患者可能会过渡到 Pembro 长达 35 个周期。主要终点为 OS 和 PFS（RECIST v1.1，中央审查）。次要终点包括 ORR，反应持续时间（DOR）（RECIST v1.1，集中审核）和安全性。对于 OS 的重要性，p 值必须达到 0.0246 的预定 a（单面）。进行灵敏度分析以调节交叉效应。最终分析的数据截止日期为 2021 年 2 月 19 日。

Methods: A total of 307 pts with MSI-H/dMMR mCRC and ECOG PS 0 or 1 were randomized 1:1 to 1L pembro 200 mg Q3W for up to 2y or investigator’s choice of mFOLFOX6 or FOLFIRI Q2W ± bevacizumab or cetuximab. Treatment continued until PD, unacceptable toxicity, pt/investigator decision to withdraw, or completion of 35 cycles (pembro only). Pts receiving chemo could crossover to pembro for up to 35 cycles after confirmed PD. Primary end points were OS and PFS (RECIST v1.1, central review). Secondary end points included ORR, duration of response (DOR) (RECIST v1.1, central review), and safety. For OS significance, the p-value had to meet a prespecified α of 0.0246 (one-sided). Sensitivity analyses to adjust for crossover effect were performed. Data cut-off for final analysis was Feb 19, 2021.

结果:Pembro 的研究中位（范围）随访为 44.5 月（36.0-60.3），而化学治疗的中位（范围）随访为 44.4 月（36.2-58.6）。从化学研究到 Pem bro 的研究共有 56（36％）分，另有 37 个接受抗 PD-1 / PD-L1 治疗的患者不在研究范围内（ITT 中有 60％的有效交叉率）。 OS 的 HR 倾向于 pembro vs chemo，并且有降低病死风险的趋势（HR 0.74； 95％CI，0.53-1.03；P = 0.0359；未达到[NR] vs 36.7 mo）；这种差异没有达到统计学意义。通过保持等级的结构失效时间模型的敏感性分析和审查加权的逆概率显示 OS HR 分别为 0.66（95％CI0.42-1.04）和 0.77（95％CI 0.44-1.38）。Pembro vs chemo 符合 IA2 规定的 PFS 优越性标准。最终分析时，PFS 中位数为 16.5 mo vs 8.2 mo（HR 0.59； 95％CI，0.45-0.79），但未根据每个分析计划进行正式测试。确认的 ORR 分别为 45.1％（20 CR，49 PR）与 33.1％（6 CR，45 PR）。中位（范围）DOR 为 NR（2.3+至 53.5+）vs 10.6 mo（2.8 至 48.3+） 。与治疗相关的不良事件（TRAE）发生率分别为 79.7％和 98.6％。等级 3 的 TRAE 分别为 21.6％和 66.4％。

Results: Median (range) study follow-up was 44.5 mo (36.0-60.3) with pembro vs 44.4 mo (36.2-58.6) with chemo. 56 (36%) pts crossed over from chemo to pembro, with 37 more receiving anti-PD-1/PD-L1 therapies off study (60% effective crossover rate in the ITT). The HR for OS favored pembro vs chemo with a trend toward reduction in the risk of death (HR 0.74; 95% CI, 0.53-1.03; P=0.0359; median not reached [NR] vs 36.7 mo); this difference did not reach statistical significance. Sensitivity analysis by the rank-preserving structure failure time model and inverse probability of censoring weighting showed OS HRs of 0.66 (95% CI 0.42-1.04) and 0.77 (95% CI 0.44-1.38), respectively. Pembro vs chemo met the prespecified criteria for PFS superiority at IA2. At final analysis, median PFS was 16.5 mo vs 8.2 mo (HR 0.59; 95% CI, 0.45-0.79), but was not formally tested per analysis plan. Confirmed ORR was 45.1% (20 CR, 49 PR) vs 33.1% (6 CR, 45 PR). Median (range) DOR was NR (2.3+ to 53.5+) vs 10.6 mo (2.8 to 48.3+), respectively. Treatment-related adverse events (TRAEs) occurred in 79.7% vs 98.6% of pts; 21.6% vs 66.4%, respectively, had grade ≥3 TRAEs.

结论:对于 MSI-H/dMMR mCRC 患者，pembro vs 化疗提供了统计学上优越的无进展生存期(PFS)和更少的 TRAEs，并且与降低死亡率的趋势相关，但由于化疗与抗 pd1 /PD-L1 治疗的高交叉率，这一趋势不符合统计学意义。这些数据共同证实了 pembro 是 MSI-H/dMMR mCRC 患者 1L 中新的 standard-of-care。

Conclusions: As 1L therapy for pts with MSI-H/dMMR mCRC, pembro vs chemo provides statistically superior PFS with fewer TRAEs, and is associated with a trend toward reduced mortality that did not meet statistical significance likely due to the high crossover rate from chemo to anti-PD1/PD-L1 therapies. Together these data confirm pembro as a new standard-of-care in the 1L for pts with MSI-H/dMMR mCRC.