Department of Oncology, Georges Pompidou European Hospital, Paris Association Pour la Recherche de Thérapeutiques Innovantes en Cancérologie, Paris
St André Hospital, Bordeaux, France.
Ann Oncol. 2015 Feb;26(2):378-85. doi: 10.1093/annonc/mdu552. Epub 2014 Dec 1.
Although sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1).
Retrospective multicenter study (2004-2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123).
Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM).
Sequence effect in the overall cohort was in favor of the TKI-TKI sequence over the TKI-mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI-TKI superiority was attributed in large part to the 11-22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9-12.2) versus 3.9 (3.0-5.5), P = 0.003; TTF(months): 8.0 (5.5-11.0) versus 3.6 (3.0-4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI.
m-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.
虽然转移性透明细胞肾细胞癌（m-ccRCC）患者的序贯靶向治疗是标准治疗，但药物的选择和最佳给药顺序尚未确定。本研究旨在探讨长期应答一线酪氨酸激酶抑制剂（TKI）的患者再次使用 TKI 或改用哺乳动物雷帕霉素靶蛋白抑制剂（mTORi）是否更优；确定二线治疗反应是否取决于一线反应的持续时间（TD1）。
回顾性多中心研究（2004-2011 年）纳入 241 例接受一线 TKI 治疗≥6 个月后接受二线 TKI（n=118）或 mTORi（n=123）治疗的连续 mRCC 患者（透明细胞组织学）。
二线治疗的无进展生存期（PFS）和治疗失败时间（TTF）。多变量全模型：二线药物、TD1、一线和二线前 ECOG-PS、最佳客观缓解（一线）、Fuhrman 分级、转移部位数量和骨转移存在情况。调整协变量：国际肾细胞癌数据库联盟（IMDC）风险评分。使用多种倾向评分和缺失数据方法。使用删失分位数回归模型（CQRM）研究一线和二线 PFS 之间的任何相关性。
在整个队列中，序贯效应有利于 TKI-TKI 序贯治疗，而不是 TKI-mTORi 序贯治疗，将 TD1 作为连续协变量（PFS 和 TTF 的 HR≈0.75）。TKI-TKI 的优势在很大程度上归因于 11-22 个月（TD1）亚组患者，该亚组患者的结局明显更好[HR≈0.5；中位 PFS（月）：9.4（5.9-12.2）vs.3.9（3.0-5.5），P=0.003；TTF（月）：8.0（5.5-11.0）vs.3.6（3.0-4.6），P=0.009]。在完全 CQRM 后，长期二线应答者更有可能接受二线 TKI 而不是 mTORi，并且对一线 TKI 长期应答。
在 11-22 个月期间仍接受一线 TKI 治疗的 m-ccRCC 患者，TKI 再挑战优于二线 mTORi。
