背景 : 在 III 期研究中，隨機開放標簽的 keyto -177(NCT02563002) 研究帕博利珠單抗 (pembrolizumab, pembro)與化療(chemo)對 MSI-H/dMMR mCRC 住院患者(IA2)提供了更好的無進展生存期(PFS)。該研究繼續對總生存期(OS)進行最終分析，計劃在 190 個 OS 事件後或 IA2 事件發生後 12 個月後進行，我們給出 IA2 後 12 個月 OS 的最終分析結果。

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：將 307 名 MSI-H / dMMR mCRC 和 ECOG PS 0 或 1 的患者隨機分配為 1：1 至 pembro200 mg Q3W，持續 2 年，或由研究者選擇 mFOLFOX6 或 FOLFIRI Q2W±貝伐單抗或西妥昔單抗。繼續治療直至 PD，患者出現不可接受的毒性，研究者決定退出治療或完成 35 個周期（僅pembro）。確診 PD 後，接受化學治療的患者可能會過渡到 Pembro 長達 35 個周期。主要終點為 OS 和 PFS（RECIST v1.1，中央審查）。次要終點包括 ORR，反應持續時間（DOR）（RECIST v1.1，集中審核）和安全性。對於 OS 的重要性，p 值必須達到 0.0246 的預定 a（單麵）。進行靈敏度分析以調節交叉效應。最終分析的數據截止日期為 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.

結果:Pembro 的研究中位（範圍）隨訪為 44.5 月（36.0-60.3），而化學治療的中位（範圍）隨訪為 44.4 月（36.2-58.6）。從化學研究到 Pem bro 的研究共有 56（36％）分，另有 37 個接受抗 PD-1 / PD-L1 治療的患者不在研究範圍內（ITT 中有 60％的有效交叉率）。 OS 的 HR 傾向於 pembro vs chemo，並且有降低病死風險的趨勢（HR 0.74； 95％CI，0.53-1.03；P = 0.0359；未達到[NR] vs 36.7 mo）；這種差異沒有達到統計學意義。通過保持等級的結構失效時間模型的敏感性分析和審查加權的逆概率顯示 OS HR 分別為 0.66（95％CI0.42-1.04）和 0.77（95％CI 0.44-1.38）。Pembro vs chemo 符合 IA2 規定的 PFS 優越性標準。最終分析時，PFS 中位數為 16.5 mo vs 8.2 mo（HR 0.59； 95％CI，0.45-0.79），但未根據每個分析計劃進行正式測試。確認的 ORR 分別為 45.1％（20 CR，49 PR）與 33.1％（6 CR，45 PR）。中位（範圍）DOR 為 NR（2.3+至 53.5+）vs 10.6 mo（2.8 至 48.3+） 。與治療相關的不良事件（TRAE）發生率分別為 79.7％和 98.6％。等級 3 的 TRAE 分別為 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.

結論:對於 MSI-H/dMMR mCRC 患者，pembro vs 化療提供了統計學上優越的無進展生存期(PFS)和更少的 TRAEs，並且與降低死亡率的趨勢相關，但由於化療與抗 pd1 /PD-L1 治療的高交叉率，這一趨勢不符合統計學意義。這些數據共同證實了 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.