Background

Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored.

Objective

To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity.

Design, setting, and participants

Multicenter single arm phase 2 study enrolling 36 chemotherapy-naïve patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients.

Intervention

Two cycles of GC followed by four cycles of GC plus ipilimumab.

Outcome measurements and statistical analysis

The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival.

Results and limitations

Grade ≥3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity = 47.6%, specificity = 100%, positive predictive value = 100%, and negative predictive value = 38.9%). Limitations are related to the sample size and single-arm design.

Conclusions

GC + ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers. Trial registration: ClinicalTrials.gov NCT01524991.

Patient summary

Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit.

中文翻译：

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吉西他滨，顺铂和伊匹单抗在转移性尿路上皮癌患者中的2期试验以及DNA损伤反应基因突变对结局的影响

背景

化学疗法可发挥免疫调节作用，从而与免疫检查点阻滞相结合。这种组合的药效学作用以及潜在的预测性生物标志物尚待探索。

客观的

为了确定吉西他滨和顺铂（GC）加上ipilimumab的安全性，疗效和免疫调节作用，并探讨体细胞DNA损伤反应基因改变对抗肿瘤活性的影响。

设计，设置和参与者

多中心单臂2期研究招募了36名未接受过化疗的转移性尿路上皮癌患者。对所有患者连续进行外周血流式细胞术，并对28/36例患者进行档案肿瘤组织的全外显子组测序。

干涉

GC的两个循环，然后是GC和ipilimumab的四个循环。

成果测量和统计分析

的主要终点是1年总体存活（OS）。次要终点包括安全性，客观反应率和无进展生存期。

结果与局限性

≥3级不良事件发生在81％的患者中，其中大多数是血液学的。客观反应率为69％，1年OS为61％（下限90％置信区间：51％）。经探索性分析，仅GC后循环免疫细胞的组成和频率没有明显变化。然而，通过添加依匹莫单抗，循环CD4细胞显着扩增，这与存活率的提高有关。具有有害的体细胞DNA损伤应答突变的患者的应答率明显更高（敏感性= 47.6％，特异性= 100％，阳性预测值= 100％，阴性预测值= 38.9％）。局限性与样本量和单臂设计有关。

结论

对于1年OS> 60％，GC + ipilimumab未能达到90％置信区间下限的主要终点。但是，在一个小型单臂试验的背景下，从可行性，适当的细胞毒性骨架和潜在的预测生物标志物的角度出发，该结果可能会为结合化学疗法和免疫疗法的当前方法提供参考。试用注册：ClinicalTrials.gov NCT01524991。

病人总结

转移性尿路上皮癌患者联合化疗和免疫检查点阻断是可行的。需要进一步研究以优化最佳组合并评估可能确定最有可能受益的患者的试验。