Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. Concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1–based combination therapy. Implications: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation. This article is featured in Highlights of This Issue, [p. 1439][1] [1]: /lookup/volpage/19/1439?iss=9

中文翻译：

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接受 Lenvatinib 和 Pembrolizumab 治疗的肾癌患者的 HLA 基因多样性驱动的高反应率和持久性

免疫检查点阻断 (ICB) 疗法显着改善了包括肾细胞癌 (RCC) 在内的多种癌症患者的预后。最初作为单一疗法进行研究，基于免疫疗法的联合方案改善了 ICB 单一疗法所取得的临床益处，并彻底改变了 RCC 治疗。虽然 PD-L1 和肿瘤突变负荷 (TMB) 等生物标志物已被 FDA 批准为 ICB 单一疗法的生物标志物，但联合免疫疗法尚无已知的生物标志物。在这里，我们描述了一项针对晚期 RCC 患者的 Ib/II 期临床试验的临床结果和反应的基因组决定因素，该试验评估了乐伐替尼（一种主要针对 VEGFR 和 FGFR 的多激酶抑制剂加上抗 PD1 免疫疗法派姆单抗）的疗效。lenvatinib 和 pembrolizumab 的同时治疗导致 79% (19/24) 的客观缓解率和 96% (23/24) 的患者肿瘤缩小。虽然肿瘤突变负荷 (TMB) 不能预测临床益处，但种系 HLA-I 多样性强烈影响治疗效果。具体而言，衡量患者免疫肽组广度的 HLA-I 进化差异 (HED) 与改善的临床益处和反应的持久性有关。我们的研究结果将 lenvatinib 加 pembrolizumab 确定为 RCC 的一种高效治疗策略，并揭示 HLA-I 多样性是该组合疗效的关键决定因素。HED 还预测另一组 RCC 患者在接受基于抗 PD-1 的联合治疗后的生存率更高。影响：这些发现对 RCC 治疗和了解免疫遗传学疗效机制具有重要意义，值得进一步研究。这篇文章被收录在本期的亮点中，[p. 1439][1][1]：/lookup/volpage/19/1439?iss=9