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

Matthew D. Galsky, Huan Wang, Noah M. Hahn, Przemyslaw Twardowski, Sumanta K. Pal, Costantine Albany, Mark T. Fleming, Alexander Starodub, Ralph J. Hauke, Menggang Yu, Qianqian Zhao, Guru Sonpavde, Michael J. Donovan, Vaibhav G. Patel, John P. Sfakianos, Josep Domingo-Domenech, William K. Oh, Nicholas Akers, Bojan Losic, Sacha GnjaticEric E. Schadt, Rong Chen, Seunghee Kim-Schulze, Nina Bhardwaj, Andrew V. Uzilov

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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. Administration of gemcitabine and cisplatin plus immune checkpoint blockade is feasible and concurrent chemotherapy does not preclude immunomodulatory effects. Tumors with DNA damage response gene mutations may be particularly sensitive to this approach.

Original languageEnglish (US)
Pages (from-to)751-759
Number of pages9
JournalEuropean urology
Volume73
Issue number5
DOIs
StatePublished - May 2018

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gemcitabine
Cisplatin
DNA Damage
Mutation
Genes
Neoplasms
Drug Therapy
Survival
Biomarkers
Confidence Intervals
Exome
Safety
ipilimumab
Sample Size
Immunotherapy
Disease-Free Survival

Keywords

  • CTLA-4
  • Chemotherapy
  • Cisplatin
  • DDR
  • DNA damage response
  • Gemcitabine
  • Immunotherapy
  • Metastatic
  • Urothelial cancer

ASJC Scopus subject areas

  • Urology

Cite this

Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes. / Galsky, Matthew D.; Wang, Huan; Hahn, Noah M.; Twardowski, Przemyslaw; Pal, Sumanta K.; Albany, Costantine; Fleming, Mark T.; Starodub, Alexander; Hauke, Ralph J.; Yu, Menggang; Zhao, Qianqian; Sonpavde, Guru; Donovan, Michael J.; Patel, Vaibhav G.; Sfakianos, John P.; Domingo-Domenech, Josep; Oh, William K.; Akers, Nicholas; Losic, Bojan; Gnjatic, Sacha; Schadt, Eric E.; Chen, Rong; Kim-Schulze, Seunghee; Bhardwaj, Nina; Uzilov, Andrew V.

In: European urology, Vol. 73, No. 5, 05.2018, p. 751-759.

Research output: Contribution to journalArticle

Galsky, MD, Wang, H, Hahn, NM, Twardowski, P, Pal, SK, Albany, C, Fleming, MT, Starodub, A, Hauke, RJ, Yu, M, Zhao, Q, Sonpavde, G, Donovan, MJ, Patel, VG, Sfakianos, JP, Domingo-Domenech, J, Oh, WK, Akers, N, Losic, B, Gnjatic, S, Schadt, EE, Chen, R, Kim-Schulze, S, Bhardwaj, N & Uzilov, AV 2018, 'Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes', European urology, vol. 73, no. 5, pp. 751-759. https://doi.org/10.1016/j.eururo.2017.12.001
Galsky, Matthew D. ; Wang, Huan ; Hahn, Noah M. ; Twardowski, Przemyslaw ; Pal, Sumanta K. ; Albany, Costantine ; Fleming, Mark T. ; Starodub, Alexander ; Hauke, Ralph J. ; Yu, Menggang ; Zhao, Qianqian ; Sonpavde, Guru ; Donovan, Michael J. ; Patel, Vaibhav G. ; Sfakianos, John P. ; Domingo-Domenech, Josep ; Oh, William K. ; Akers, Nicholas ; Losic, Bojan ; Gnjatic, Sacha ; Schadt, Eric E. ; Chen, Rong ; Kim-Schulze, Seunghee ; Bhardwaj, Nina ; Uzilov, Andrew V. / Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes. In: European urology. 2018 ; Vol. 73, No. 5. pp. 751-759.
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title = "Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes",
abstract = "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-na{\"i}ve 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. Administration of gemcitabine and cisplatin plus immune checkpoint blockade is feasible and concurrent chemotherapy does not preclude immunomodulatory effects. Tumors with DNA damage response gene mutations may be particularly sensitive to this approach.",
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author = "Galsky, {Matthew D.} and Huan Wang and Hahn, {Noah M.} and Przemyslaw Twardowski and Pal, {Sumanta K.} and Costantine Albany and Fleming, {Mark T.} and Alexander Starodub and Hauke, {Ralph J.} and Menggang Yu and Qianqian Zhao and Guru Sonpavde and Donovan, {Michael J.} and Patel, {Vaibhav G.} and Sfakianos, {John P.} and Josep Domingo-Domenech and Oh, {William K.} and Nicholas Akers and Bojan Losic and Sacha Gnjatic and Schadt, {Eric E.} and Rong Chen and Seunghee Kim-Schulze and Nina Bhardwaj and Uzilov, {Andrew V.}",
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TY - JOUR

T1 - Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes

AU - Galsky, Matthew D.

AU - Wang, Huan

AU - Hahn, Noah M.

AU - Twardowski, Przemyslaw

AU - Pal, Sumanta K.

AU - Albany, Costantine

AU - Fleming, Mark T.

AU - Starodub, Alexander

AU - Hauke, Ralph J.

AU - Yu, Menggang

AU - Zhao, Qianqian

AU - Sonpavde, Guru

AU - Donovan, Michael J.

AU - Patel, Vaibhav G.

AU - Sfakianos, John P.

AU - Domingo-Domenech, Josep

AU - Oh, William K.

AU - Akers, Nicholas

AU - Losic, Bojan

AU - Gnjatic, Sacha

AU - Schadt, Eric E.

AU - Chen, Rong

AU - Kim-Schulze, Seunghee

AU - Bhardwaj, Nina

AU - Uzilov, Andrew V.

PY - 2018/5

Y1 - 2018/5

N2 - 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. Administration of gemcitabine and cisplatin plus immune checkpoint blockade is feasible and concurrent chemotherapy does not preclude immunomodulatory effects. Tumors with DNA damage response gene mutations may be particularly sensitive to this approach.

AB - 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. Administration of gemcitabine and cisplatin plus immune checkpoint blockade is feasible and concurrent chemotherapy does not preclude immunomodulatory effects. Tumors with DNA damage response gene mutations may be particularly sensitive to this approach.

KW - CTLA-4

KW - Chemotherapy

KW - Cisplatin

KW - DDR

KW - DNA damage response

KW - Gemcitabine

KW - Immunotherapy

KW - Metastatic

KW - Urothelial cancer

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