Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer
Christophe Massard, Michael S Gordon, Sunil Sharma, Saeed Rafii, Zev A Wainberg, Jason Luke, Tyler J Curiel, Gerardo Colon-Otero, Omid Hamid, Rachel E Sanborn, Peter H O'Donnell, Alexandra Drakaki, Winston Tan, John F Kurland, Marlon C Rebelatto, Xiaoping Jin, John A Blake-Haskins, Ashok Gupta, Neil H Segal, Christophe Massard, Michael S Gordon, Sunil Sharma, Saeed Rafii, Zev A Wainberg, Jason Luke, Tyler J Curiel, Gerardo Colon-Otero, Omid Hamid, Rachel E Sanborn, Peter H O'Donnell, Alexandra Drakaki, Winston Tan, John F Kurland, Marlon C Rebelatto, Xiaoping Jin, John A Blake-Haskins, Ashok Gupta, Neil H Segal
Abstract
Purpose: To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC).
Methods: A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1.
Results: A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks).
Conclusion: Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.
Conflict of interest statement
Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.
© 2016 by American Society of Clinical Oncology.
Figures
![Fig 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5569690/bin/JCO679761f1.jpg)
Fig 2.
(A) Best change from baseline…
Fig 2.
(A) Best change from baseline in tumor size over time by programmed cell…
Fig 3.
Time to response and duration…
Fig 3.
Time to response and duration of response. Note: programmed cell death ligand-1–positive was…
- Programmed Cell Death Ligand-1 Blockade in Urothelial Bladder Cancer: To Select or Not to Select.Drake CG, Bivalacqua TJ, Hahn NM. Drake CG, et al. J Clin Oncol. 2016 Sep 10;34(26):3115-6. doi: 10.1200/JCO.2016.68.4696. Epub 2016 Jul 25. J Clin Oncol. 2016. PMID: 27458310 No abstract available.
- Re: Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients with Advanced Urothelial Bladder Cancer.Chang SS. Chang SS. J Urol. 2018 Feb;199(2):341-342. doi: 10.1016/j.juro.2017.11.024. Epub 2017 Nov 9. J Urol. 2018. PMID: 29357560 No abstract available.
- Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.Garassino MC, Cho BC, Kim JH, Mazières J, Vansteenkiste J, Lena H, Corral Jaime J, Gray JE, Powderly J, Chouaid C, Bidoli P, Wheatley-Price P, Park K, Soo RA, Huang Y, Wadsworth C, Dennis PA, Rizvi NA; ATLANTIC Investigators. Garassino MC, et al. Lancet Oncol. 2018 Apr;19(4):521-536. doi: 10.1016/S1470-2045(18)30144-X. Epub 2018 Mar 12. Lancet Oncol. 2018. PMID: 29545095 Free PMC article. Clinical Trial.
- Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study.Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, Lee JL, Ong M, Sridhar SS, Vogelzang NJ, Fishman MN, Zhang J, Srinivas S, Parikh J, Antal J, Jin X, Gupta AK, Ben Y, Hahn NM. Powles T, et al. JAMA Oncol. 2017 Sep 14;3(9):e172411. doi: 10.1001/jamaoncol.2017.2411. Epub 2017 Sep 14. JAMA Oncol. 2017. PMID: 28817753 Free PMC article. Clinical Trial.
- Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial.Levy A, Massard C, Soria JC, Deutsch E. Levy A, et al. Eur J Cancer. 2016 Nov;68:156-162. doi: 10.1016/j.ejca.2016.09.013. Epub 2016 Oct 17. Eur J Cancer. 2016. PMID: 27764686 Clinical Trial.
- Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma.Faiena I, Cummings AL, Crosetti AM, Pantuck AJ, Chamie K, Drakaki A. Faiena I, et al. Drug Des Devel Ther. 2018 Jan 23;12:209-215. doi: 10.2147/DDDT.S141491. eCollection 2018. Drug Des Devel Ther. 2018. PMID: 29416316 Free PMC article. Review.
- Durvalumab in non-small-cell lung cancer patients: current developments.Mezquita L, Planchard D. Mezquita L, et al. Future Oncol. 2018 Feb;14(3):205-222. doi: 10.2217/fon-2017-0373. Epub 2017 Nov 15. Future Oncol. 2018. PMID: 29140105 Review.
- Nuclear PD-L1 promotes EGR1-mediated angiogenesis and accelerates tumorigenesis.Yu J, Zhuang A, Gu X, Hua Y, Yang L, Ge S, Ruan J, Chai P, Jia R, Fan X. Yu J, et al. Cell Discov. 2023 Mar 28;9(1):33. doi: 10.1038/s41421-023-00521-7. Cell Discov. 2023. PMID: 36977660
- Prognostic Value of the Lung Immune Prognosis Index Score for Patients Treated with Immune Checkpoint Inhibitors for Advanced or Metastatic Urinary Tract Carcinoma.Parent P, Auclin E, Patrikidou A, Mezquita L, Martínez Chanzá N, Dumont C, Rodriguez-Vida A, Llacer C, Lozano R, Ratta R, Merseburger AS, Sternberg CN, Baciarello G, Colomba E, Fuerea A, Besse B, Loriot Y, Lavaud P. Parent P, et al. Cancers (Basel). 2023 Feb 7;15(4):1066. doi: 10.3390/cancers15041066. Cancers (Basel). 2023. PMID: 36831409 Free PMC article.
- Head and Neck Cancer Immunotherapy: Molecular Biological Aspects of Preclinical and Clinical Research.Chakraborty R, Darido C, Liu F, Maselko M, Ranganathan S. Chakraborty R, et al. Cancers (Basel). 2023 Jan 30;15(3):852. doi: 10.3390/cancers15030852. Cancers (Basel). 2023. PMID: 36765809 Free PMC article. Review.
- Immunotherapy for Urological Tumors on YouTubeTM: An Information-Quality Analysis.Di Bello F, Di Mauro E, Collà Ruvolo C, Creta M, La Rocca R, Celentano G, Capece M, Napolitano L, Fraia A, Pezone G, Morra S, Imbimbo C, Mirone V, Longo N, Califano G. Di Bello F, et al. Vaccines (Basel). 2022 Dec 30;11(1):92. doi: 10.3390/vaccines11010092. Vaccines (Basel). 2022. PMID: 36679937 Free PMC article.
- Increasing cure rates of solid tumors by immune checkpoint inhibitors.Ma W, Xue R, Zhu Z, Farrukh H, Song W, Li T, Zheng L, Pan CX. Ma W, et al. Exp Hematol Oncol. 2023 Jan 16;12(1):10. doi: 10.1186/s40164-023-00372-8. Exp Hematol Oncol. 2023. PMID: 36647169 Free PMC article. Review.
- Clinical Trial, Phase I
- Clinical Trial, Phase II
- Multicenter Study
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal / adverse effects
- Antibodies, Monoclonal / therapeutic use*
- Antineoplastic Agents / adverse effects
- Antineoplastic Agents / therapeutic use*
- B7-H1 Antigen / antagonists & inhibitors*
- B7-H1 Antigen / metabolism
- Biopsy
- Female
- Humans
- Immunohistochemistry
- Male
- Middle Aged
- Time Factors
- Treatment Outcome
- Urinary Bladder Neoplasms / drug therapy*
- Urinary Bladder Neoplasms / metabolism
- Urinary Bladder Neoplasms / mortality
- Urinary Bladder Neoplasms / pathology
- Urothelium / drug effects*
- Urothelium / metabolism
- Urothelium / pathology
- Antibodies, Monoclonal
- Antineoplastic Agents
- B7-H1 Antigen
- CD274 protein, human
- durvalumab
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
![Fig 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5569690/bin/JCO679761f2.jpg)
Fig 3.
Time to response and duration…
Fig 3.
Time to response and duration of response. Note: programmed cell death ligand-1–positive was…
![Fig 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5569690/bin/JCO679761f3.jpg)
Source: PubMed