Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes

Eur Urol. 2018 May;73(5):751-759. doi: 10.1016/j.eururo.2017.12.001. Epub 2017 Dec 13.


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: 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.

Keywords: CTLA-4; Chemotherapy; Cisplatin; DDR; DNA damage response; Gemcitabine; Immunotherapy; Metastatic; Urothelial cancer.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Transitional Cell / drug therapy*
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / mortality
  • Carcinoma, Transitional Cell / pathology
  • Cisplatin / administration & dosage
  • DNA Damage / drug effects
  • DNA Mutational Analysis
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Disease-Free Survival
  • Female
  • Humans
  • Ipilimumab / administration & dosage
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Mutation / genetics*
  • Neoplasm Invasiveness / pathology
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Prognosis
  • Prospective Studies
  • Risk Assessment
  • Survival Analysis
  • Treatment Outcome
  • Urologic Neoplasms / drug therapy*
  • Urologic Neoplasms / genetics*
  • Urologic Neoplasms / mortality
  • Urologic Neoplasms / pathology


  • Ipilimumab
  • Deoxycytidine
  • gemcitabine
  • Cisplatin

Associated data