Individual Patient Data Meta-Analysis of Consensus Molecular Subtypes as Biomarkers of First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer.

An individual patient data (IPD) meta-analysiswas performed to test for impact on objective response rates (ORRs), progression-free survival(PFS) and overall survival(OS), and treatment interaction.

进行了个体患者数据（IPD）的荟萃分析，以测试对客观缓解率（ORRs）、无进展生存期（PFS）和总生存期（OS）的影响，以及治疗相互作用。

Methods

IPD (RAS wild-type [WT] tumors treated per protocol [fluorouracil/capecitabine, irinotecan/oxaliplatin, anti-vascular endothelial growth factor {VEGF}/anti-epidermal growth factor receptor {EGFR} antibodies] and with evaluable CMSs) were collected from five trials identified in PubMed, Embase, Medline, Cochrane Library, and proceedings of ASCO/European Society for Medical Oncology: FIRE1 (no identifier), FIRE3 (ClinicalTrials.gov identifier: NCT00433927), XELAVIRI (ClinicalTrials.gov identifier: NCT01249638), PanaMa (ClinicalTrials.gov identifier: NCT01991873), and TRIBE2 (ClinicalTrials.gov identifier: NCT02339116).

从在PubMed、Embase、Medline、Cochrane Library以及ASCO/欧洲肿瘤内科学会的会议记录中识别的五项试验中收集了IPD (RAS野生型[WT]肿瘤按方案治疗[氟尿嘧啶/卡培他滨、伊立替康/奥沙利铂、抗血管内皮生长因子{VEGF}/抗表皮生长因子受体{EGFR}抗体]且具有可评估的CMSs)：FIRE1(无标识符)、FIRE3(ClinicalTrials.gov标识符：NCT00433927)、XELAVIRI(ClinicalTrials.gov标识符：NCT01249638)、PanaMa(ClinicalTrials.gov标识符：NCT01991873)和TRIBE2(ClinicalTrials.gov标识符：NCT02339116)。

The one-step IPD meta-analysisapproach assessed data taking the clustering of patients in the studies into account (ORR: generalized estimating equations models; PFS/OS: Cox models).

一步式IPD荟萃分析方法评估了数据，考虑了研究中患者群集的情况(ORR:广义估计方程模型; PFS/OS: Cox模型)。

Results

Seven hundred ninety patients were included: CMS1, n = 77 (9.7%); CMS2, n = 345 (43.7%); CMS3, n = 74 (9.4%); and CMS4, n = 294 (37.2%).

共有790名患者纳入研究：CMS1组，n=77（9.7%）；CMS2组，n=345（43.7%）；CMS3组，n=74（9.4%）；CMS4组，n=294（37.2%）。

Between-study heterogeneity was negligible (variance < 1 × 10-6).

研究间的异质性可以忽略不计（方差<1×10^-6）。

Compared with CMS1, CMS2 and CMS4 tumors had numerically higher odds ratios (OR) for ORR (CMS2: OR, 1.668 [95% CI, 0.982 to 2.836]; P = .059; CMS4: OR, 1.369 [95% CI, 0.874 to 2.146]; P = .170), and longer PFS (CMS2: hazard ratios [HR], 0.64 [95% CI, 0.48 to 0.85]; P = .002; CMS4: HR, 0.67 [95% CI, 0.50 to 0.91]; P = .009) and OS (CMS2: HR, 0.59 [95% CI, 0.43 to 0.80]; P < .001; CMS4: HR, 0.67 [95% CI, 0.49 to 0.92]; P = .01).

与CMS1相比，CMS2和CMS4肿瘤的客观缓解率(ORR)的比值比(OR)数值上更高(CMS2: OR, 1.668 [95% 置信区间, 0.982至2.836]; P = .059; CMS4: OR, 1.369 [95% 置信区间, 0.874至2.146]; P = .170)，无进展生存期(PFS)更长(CMS2: 风险比[HR], 0.64 [95% 置信区间, 0.48至0.85]; P = .002; CMS4: HR, 0.67 [95% 置信区间, 0.50至0.91]; P = .009)和总生存期(OS)更长(CMS2: HR, 0.59 [95% 置信区间, 0.43至0.80]; P < .001; CMS4: HR, 0.67 [95% 置信区间, 0.49至0.92]; P = .01)。

The use of anti-EGFR versus anti-VEGF antibodies meaningfully improved PFS (HR, 0.67 [95% CI, 0.46 to 0.97]; P = .03) and OS (HR, 0.49 [95% CI, 0.33 to 0.72]; P < .001) in CMS4 tumors and was consistently observed for CMS4 RAS/BRAF WT (HR, 0.55 [95% CI, 0.37 to 0.83]; P = .004) or microsatellite stable status (HR, 0.52 [95% CI, 0.32 to 0.86]; P = .01).

在CMS4肿瘤中，使用抗EGFR抗体相比于抗VEGF抗体显著改善了无进展生存期(PFS) (HR, 0.67 [95% 置信区间, 0.46至0.97]; P = .03)和总生存期(OS) (HR, 0.49 [95% 置信区间, 0.33至0.72]; P < .001)，这一结果在CMS4 RAS/BRAF野生型(HR, 0.55 [95% 置信区间, 0.37至0.83]; P = .004)或微卫星稳定状态(HR, 0.52 [95% 置信区间, 0.32至0.86]; P = .01)中也一致观察到。

The interaction test of antibody treatment with CMSs was significant for PFS (P < .001) and OS (P < .001) in all patients and for OS in patients with RAS/BRAF WT tumors (P = .02).

抗体治疗与CMSs的相互作用测试对所有患者的无进展生存期（PFS）和总生存期（OS）均有显著意义（P < .001），并且在RAS/BRAF野生型肿瘤患者中对总生存期（OS）也有显著意义（P = .02）。

Conclusions

CMS4 might be an additional biomarker of anti-EGFR treatment efficacy in RAS (and BRAF) WT mCRC.

CMS4可能是RAS（和BRAF）野生型转移性结直肠癌（mCRC）抗表皮生长因子受体（anti-EGFR）治疗效果的额外生物标志物。