Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275.
Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275.
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DOI：
10.1158/1078-0432.ccr-19-4162
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发表时间：
2020-10-01
期刊：
影响因子：
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通讯作者：
Sharma P
中科院分区：
文献类型：
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作者：
Galsky MD;Saci A;Szabo PM;Han GC;Grossfeld G;Collette S;Siefker-Radtke A;Necchi A;Sharma P
我们报告了II期CheckMate 275试验的延长随访和探索性生物标志物分析的有效性和安全性，以确定铂耐药转移性或不可切除的尿路上皮癌（mUC）中对nivolumab反应的生物标志物。患者接受nivolumab 3 mg/kg Q2 W，直至疾病进展、不可接受的毒性或其他方案定义的原因。主要终点是所有治疗患者中盲态独立审查委员会（BIRC;使用RECIST v1.1）评估的ORR和肿瘤PD-L1表达。关键次要终点为BIRC使用RECIST v1.1评估的PFS和所有患者的OS以及PD-L1表达。探索性终点包括肿瘤突变负荷（TMB）、PD-L1和先前确定的突变特征的安全性和生物标志物分析。在270例接受治疗的患者中，139例具有可评价的TMB。最短随访时间为33.7个月，所有治疗患者中BIRC评估的ORR、中位PFS和中位OS（95% CI）分别为20.7%（16.1-26.1）、1.9个月（1.9-2.3）和8.6个月（6.1-11.3）。未发现新的安全性信号。较高的TMB与ORR（比值比[95% CI]：2.13 [1.26-3.60]）、PFS（HR：0.75 [0.61-0.92]）和OS（HR：0.73 [0.58-0.91]）改善相关（P<0.05）。与PD-L1单药相比，TMB联合PD-L1可更好地预测ORR、PFS和OS。较高的突变特征2评分与较好的OS相关，但并没有提高TMB的预测价值。这些结果支持纳武单抗的持久抗肿瘤活性，并表明TMB可以富集以在mUC中获得更好的应答。未来有必要在随机试验中将TMB/PD-L1作为nivolumab反应的生物标志物进行研究。
We report efficacy and safety with extended follow-up, and exploratory biomarker analyses from the phase II CheckMate 275 trial to identify biomarkers of response to nivolumab in platinum-resistant metastatic or unresectable urothelial carcinoma (mUC). Patients received nivolumab 3 mg/kg Q2W until disease progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was ORR per blinded independent review committee (BIRC; using RECIST v1.1) in all treated patients and by tumor PD-L1 expression. Key secondary endpoints were PFS per BIRC using RECIST v1.1 and OS in all patients and by PD-L1 expression. Exploratory endpoints included safety and biomarker analyses of tumor mutational burden (TMB), PD-L1, and previously identified mutational signatures. Of 270 treated patients, 139 had evaluable TMB. With 33.7 months’ minimum follow-up, ORR per BIRC, median PFS, and median OS (95% CI) in all treated patients were 20.7% (16.1–26.1), 1.9 months (1.9–2.3), and 8.6 months (6.1–11.3), respectively. No new safety signals were identified. Higher TMB was associated (P<0.05) with improved ORR (odds ratio [95% CI]: 2.13 [1.26–3.60]), PFS (HR: 0.75 [0.61–0.92]), and OS (HR: 0.73 [0.58–0.91]). TMB combined with PD-L1 better predicted ORR, PFS, and OS than PD-L1 alone. Higher mutational signature 2 score was associated with better OS but did not improve the predictive value of TMB. These results support the durable antitumor activity of nivolumab and suggest that TMB may enrich for better response in mUC. Future studies of TMB/PD-L1 as biomarkers for response to nivolumab in randomized trials are warranted.