The phase III JAVELIN Renal 101 trial demonstrated prolonged progression-free survival (PFS) in patients (N = 886) with advanced renal cell carcinoma treated with first-line avelumab + axitinib (A+Ax) versus sunitinib. We report novel findings from integrated analyses of longitudinal blood samples and baseline tumor tissue. PFS was associated with elevated lymphocyte levels in the sunitinib arm and an abundance of innate immune subsets in the A+Ax arm. Treatment with A+Ax led to greater T-cell repertoire modulation and less change in T-cell numbers versus sunitinib. In the A+Ax arm, patients with tumors harboring mutations in ≥2 of 10 previously identified PFS-associated genes (double mutants) had distinct circulating and tumor-infiltrating immunologic profiles versus those with wild-type or single-mutant tumors, suggesting a role for non–T-cell–mediated and non–natural killer cell–mediated mechanisms in double-mutant tumors. We provide evidence for different immunomodulatory mechanisms based on treatment (A+Ax vs. sunitinib) and tumor molecular subtypes. Significance: Our findings provide novel insights into the different immunomodulatory mechanisms governing responses in patients treated with avelumab (PD-L1 inhibitor) + axitinib or sunitinib (both VEGF inhibitors), highlighting the contribution of tumor biology to the complexity of the roles and interactions of infiltrating immune cells in response to these treatment regimens.

中文翻译：

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肿瘤和外周生物标志物在晚期肾细胞癌治疗中的综合分析

III 期 JAVELIN Renal 101 试验证明，与舒尼替尼相比，一线 avelumab + 阿西替尼 (A+Ax) 治疗的晚期肾细胞癌患者 (N = 886) 的无进展生存期 (PFS) 更长。我们报告了纵向血液样本和基线肿瘤组织综合分析的新发现。PFS 与舒尼替尼组中淋巴细胞水平升高以及 A+Ax 组中丰富的先天免疫亚群相关。与舒尼替尼相比，A+Ax 治疗导致 T 细胞库调节更大，T 细胞数量变化更小。在 A+Ax 组中，与野生型或单突变肿瘤患者相比，先前确定的 10 个 PFS 相关基因（双突变体）中含有≥2 个突变的肿瘤患者具有不同的循环和肿瘤浸润免疫学特征，这表明非 T 细胞介导和非自然杀伤细胞介导的机制在双突变肿瘤中的作用。我们为基于治疗（A+Ax 与舒尼替尼）和肿瘤分子亚型的不同免疫调节机制提供证据。意义：我们的研究结果为控制使用 avelumab（PD-L1 抑制剂）+ 阿西替尼或舒尼替尼（两种 VEGF 抑制剂）治疗的患者的反应的不同免疫调节机制提供了新的见解，强调了肿瘤生物学对其作用和相互作用的复杂性的贡献。渗透免疫细胞响应这些治疗方案。