Bellmunt Joaquim, de Wit Ronald, Fradet Yves, Climent Miguel A, Petrylak Daniel P, Lee Jae-Lyun, Fong Lawrence, Necchi Andrea, Sternberg Cora N, O'Donnell Peter H, Powles Thomas, Plimack Elizabeth R, Bajorin Dean F, Balar Arjun V, Castellano Daniel, Choueiri Toni K, Culine Stephane, Gerritsen Winald, Gurney Howard, Quinn David I, Vuky Jacqueline, Vogelzang Nicholas J, Cristescu Razvan, Lunceford Jared, Saadatpour Assieh, Loboda Andrey, Ma Junshui, Rajasagi Mohini, Godwin James Luke, Homet Moreno Blanca, Grivas Petros
Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, and IMIM-PSMAR Lab Harvard Medical School, Boston, Massachusetts.
Department of MedOnc, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Clin Cancer Res. 2022 May 13;28(10):2050-2060. doi: 10.1158/1078-0432.CCR-21-3089.
In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell-inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC).
Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at α = 0.05.
In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment.
Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.
在一项探索性分析中，我们研究了程序性死亡配体1（PD-L1）、肿瘤突变负荷（TMB）、T细胞炎症基因表达谱（TcellinfGEP）和基质特征与帕博利珠单抗治疗尿路上皮癌（UC）疗效之间的关联。
在单臂II期KEYNOTE-052试验（NCT02335424）中，晚期UC患者每3周接受一次200mg的一线帕博利珠单抗治疗；在随机III期KEYNOTE-045试验（NCT02256436）中，患者每3周接受一次200mg的挽救性帕博利珠单抗治疗或化疗（紫杉醇/多西他赛/长春氟宁）。使用逻辑回归（客观缓解率[ORR]）和Cox PH（无进展生存期[PFS]、总生存期[OS]）评估每个生物标志物（连续变量）与ORR、PFS和OS的关联，并根据东部肿瘤协作组体能状态（ECOG PS）进行调整；未进行多重校正计算名义P值（单侧，帕博利珠单抗；双侧，化疗）。显著性预先设定为α=0.05。
在KEYNOTE-052试验中，PD-L1、TMB和TcellinfGEP与改善的疗效显著相关；基质特征与较差的疗效显著相关。在KEYNOTE-045试验中，虽然帕博利珠单抗治疗时TMB和TcellinfGEP的结果与KEYNOTE-052试验一致，但PD-L1与改善的疗效无显著关联，帕博利珠单抗治疗时基质特征与较差的疗效也无关联；对于任何生物标志物，化疗与疗效均无一致的关联。预先设定的临界值处的风险比（HR）估计显示，无论PD-L1或TMB如何，帕博利珠单抗对比化疗均具有优势，在联合阳性评分≥10和TMB≥175个突变/外显子亚组中HR有降低趋势。对于TcellinfGEP，无论接受何种治疗，TcellinfGEP非低亚组的PFS和OS HR均较低。
多个表征肿瘤微环境的生物标志物可能有助于预测UC患者对帕博利珠单抗单药治疗的反应，这些生物标志物的潜在临床应用价值可能因情况而异。
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