Biomarker analyses from the phase III randomized CLEAR trial: lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma.

We report results from CLEAR biomarker analyses.

我们报告了CLEAR生物标志物分析的结果。

patients_and_methods

Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and next-generation sequencing assays (whole exome sequencing/RNA sequencing) were carried out on archival tumor specimens.

程序性死亡配体1（PD-L1）免疫组化（IHC）和下一代测序检测（全外显子组测序/RNA测序）在存档的肿瘤标本上进行。

For IHC-derived/RNA sequencing analyses, a continuous analysis was carried out adjusting by Karnofsky performance status (KPS) score for: PD-L1 combined positive score (CPS) versus best overall response (BOR)/progression-free survival(PFS); and each gene signature score [T-cell inflamed gene expression profile (TcellinfGEP)/non-TcellinfGEP signatures including proliferation and angiogenesis] versus BOR/PFS.

对于IHC衍生的/RNA测序分析，进行了连续分析，根据卡诺夫斯基表现状态（KPS）评分进行调整，比较PD-L1组合阳性评分（CPS）与最佳总反应（BOR）/无进展生存期（PFS）；以及每个基因签名评分[T细胞炎症基因表达谱（TcellinfGEP）/非TcellinfGEP签名，包括增殖和血管生成]与BOR/PFS。

Association between mutation status of RCC driver genes and PFS were analyzed for genes for which ≥20 patients per arm had oncogenic alterations.

对每组≥20名患者有致癌性改变的RCC驱动基因突变状态与无进展生存期(PFS)之间的关联进行了分析。

Association of molecular subtypes with outcome was evaluated with baseline KPS adjustments.

在基线KPS调整后，评估了分子亚型与临床结果之间的关联。

The set of biomarkers evaluated and statistical significance criteria for PD-L1 CPS, gene signature scores, and molecular subtypes were prespecified.

评估的生物标志物集合以及PD-L1 CPS、基因签名评分和分子亚型的统计显著性标准是预先设定的。

Results

Within-arm analyses using continuous values showed no association between PD-L1 levels and BOR/PFS for either treatment.

使用连续值的组内分析显示，对于任一治疗，PD-L1水平与最佳客观反应(BOR)/无进展生存期(PFS)之间没有关联。

PFS hazard ratios between arms were similar regardless of the mutant or wild-type subgroups of RCC driver genes (VHL, PBRM1, SETD2, BAP1, KDM5C).

无论RCC驱动基因（VHL、PBRM1、SETD2、BAP1、KDM5C）是突变型还是野生型亚组，各组之间的无进展生存（PFS）风险比相似。

No associations between PFS and gene signature scores were observed for L + P.

对于L + P，未观察到PFS与基因特征评分之间的关联。

With sunitinib, high proliferation and MYC signature scores showed shorter PFS; high angiogenesis and microvessel density signature scores showed longer PFS.

在接受舒尼替尼治疗的情况下，高增殖和MYC特征评分显示出较短的无进展生存期（PFS）；高血管生成和微血管密度特征评分显示出较长的无进展生存期（PFS）。

Six new molecular subtypes were defined.

定义了六种新的分子亚型。

Tumors of patients with favorable/intermediate risk were enriched in angiogenesis and angiogenesis/stromal clusters; those with poor risk were enriched in proliferative and unclassified (low-TcellinfGEP/low-angiogenesis/low-proliferation) clusters.

具有良好/中等风险的患者的肿瘤在血管生成和血管生成/基质簇中富集；而具有较差风险的患者的肿瘤在增殖和未分类（低T细胞infGEP/低血管生成/低增殖）簇中富集。

No association between molecular subtypes and PFS for L + P/sunitinib was observed (after adjustment for KPS and gene signatures that were individually associated with PFS).

在调整KPS和与PFS单独相关的基因签名后，未观察到分子亚型与L + P/舒尼替尼的无进展生存期（PFS）之间的关联。

Conclusions

Improvements in objective response rateand PFS for L + P versus sunitinib in aRCC were observed consistently across a range of biomarker subgroups defined using RCC driver mutations, PD-L1, gene expression signatures, and molecular subtypes.

在使用RCC驱动突变、PD-L1、基因表达特征和分子亚型定义的一系列生物标志物亚组中，观察到L+P与舒尼替尼相比在晚期肾细胞癌（aRCC）中的客观缓解率和无进展生存期（PFS）的持续改善。