Granet-Vaissiere Estelle, Lefort Félix, Domblides Charlotte, Larroquette Mathieu, Ravaud Alain, Bernhard Jean-Christophe, Gross-Goupil Marine
Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France.
Faculty of Medicine, University of Bordeaux, 33000 Bordeaux, France.
Cancers (Basel). 2023 Feb 7;15(4):1048. doi: 10.3390/cancers15041048.
Over the past decade, major advances have been made in the treatment of advanced and metastatic renal cell carcinomas, specifically clear cell carcinomas. For many years the optimal approach was sequential; thus, monotherapies [principally tyrosine kinase inhibitors (TKIs)] targeting angiogenesis until toxicity or progressive disease developed. The rationale was the common mechanisms of action of the targeting agents and avoidance of the risk of overlapping toxicities. Immune checkpoint inhibitors (ICIs) are effective monotherapies, and combinations thereof with anti-angiogenic agents were thus later considered. Synergistic interactions were reported in vitro. Clinical efficacy was evident in three pivotal phase III trials with axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab combinations. Two other combinations showed interesting results but did not improve overall survival. However, the data aided our understanding of the new therapeutic approaches. A combination of the ICIs nivolumab and ipilimumab was the first to evidence better progression-free and overall survival compared to sunitinib in patients with intermediate or unfavourable prognoses as evaluated by the International mRCC Database Consortium (IMDC). Here we focus on the TKI-ICI combinations, emphasising the rationale of their use and the clinical results. To date, no biomarker facilitating the selection of an optimal treatment by disease and patient status has been reported.
在过去十年中，晚期和转移性肾细胞癌，特别是透明细胞癌的治疗取得了重大进展。多年来，最佳治疗方法是序贯治疗；因此，主要是使用靶向血管生成的单一疗法[主要是酪氨酸激酶抑制剂（TKIs）]，直到出现毒性或疾病进展。其基本原理是靶向药物的共同作用机制以及避免重叠毒性风险。免疫检查点抑制剂（ICIs）是有效的单一疗法，因此后来考虑将其与抗血管生成药物联合使用。体外研究报道了它们之间的协同相互作用。阿昔替尼-帕博利珠单抗、卡博替尼-纳武利尤单抗和乐伐替尼-帕博利珠单抗联合用药的三项关键III期试验显示出明显的临床疗效。另外两种联合用药显示出有趣的结果，但未改善总生存期。然而，这些数据有助于我们理解新的治疗方法。国际转移性肾细胞癌数据库联盟（IMDC）评估显示，对于预后中等或较差的患者，与舒尼替尼相比，纳武利尤单抗和伊匹木单抗联合用药首次证明了更好的无进展生存期和总生存期。在此，我们重点关注TKI-ICI联合用药，强调其使用原理和临床结果。迄今为止，尚未有能根据疾病和患者状况促进选择最佳治疗方案的生物标志物报道。
