Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies
Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials.
The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials.
Patient and Methods
This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017.
Seventy-nine patients, median age 72 years (range 29–93), 71% men and 76% ECOG PS 0–1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8–3.6) and median PFS was 3.2 months (95%CI, 1.6–4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0–5.0) while 42% were referred to palliative care/hospice or died.
Compliance with Ethical Standards
No external funding was used in the preparation of this manuscript.
Conflict of Interest
The authors declare no conflict of interest specifically relevant to this study. PG was one of the lead co-investigators on the IMvigor210 trial. Unrelated consulting is included in the comments. This retrospective study was approved by the Cleveland Clinic IRB (research protocol IRB#14–1222). Patient data was collected in compliance with guidelines and informed consent was waived for this study.
- 3.Sternberg CN, de Mulder PH, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19(10):2638–46. https://doi.org/10.1200/jco.2001.19.10.2638.
- 4.Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Canc. 2006;42(1):50–4. https://doi.org/10.1016/j.ejca.2005.08.032.
- 5.Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10(7):1066–73. https://doi.org/10.1200/jco.1922.214.171.1246.
- 6.De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191–9. https://doi.org/10.1200/jco.2011.37.3571.
- 7.Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27(27):4454–61. https://doi.org/10.1200/jco.2008.20.5534.
- 8.McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15(5):1853–7. https://doi.org/10.1200/jco.19126.96.36.1993.
- 10.Krege S, Rembrink V, Börgermann CH, Otto T, Rübben H. Docetaxel and Ifosfamide as second-line treatment for patients with advanced or metastatic urothelial cancer after failure of platinum chemotherapy: a phase 2 study. J Urol. 2001;165(1):67–71. https://doi.org/10.1097/00005392-200101000-00017.CrossRefPubMedGoogle Scholar
- 11.Albers P, Siener R, Hartlein M, Fallahi M, Haeutle D, Perabo FG, et al. Gemcitabine monotherapy as second-line treatment in cisplatin-refractory transitional cell carcinoma - prognostic factors for response and improvement of quality of life. Onkologie. 2002;25(1):47–52. doi:55202PubMedGoogle Scholar
- 12.Food, Administration D. FDA approves new, targeted treatment for bladder cancer. May 18, 2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm501762.htm.
- 13.Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20. https://doi.org/10.1016/S0140-6736(16)00561-4.
- 14.Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, et al. Avelumab, an anti–programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J Clin Oncol. 2017;35(19):2117–24. https://doi.org/10.1200/jco.2016.71.6795.CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and efficacy of Durvalumab (MEDI4736), an anti–programmed cell death Ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer. J Clin Oncol. 2016;34(26):3119–25. https://doi.org/10.1200/jco.2016.67.9761.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22. https://doi.org/10.1016/s1470-2045(17)30065-7.
- 18.Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and safety of Durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411. https://doi.org/10.1001/jamaoncol.2017.2411.
- 19.Powles T, Loriot Y, Duran I, Ravaud A, Retz M, Vogelzang NJ et al. IMvigor211: a phase III randomized study examining atezolizumab vs. chemotherapy for platinum. Special Conference EACR AACR SIC; June 24–27; Florence, Italy 2017.Google Scholar
- 21.Balar A, Bellmunt J, O’Donnell PH, Castellano D, Grivas P, Vuky J, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: Preliminary results from the phase 2 KEYNOTE-052 study. Ann Oncol. 2016;27(suppl_6):LBA32_PR-LBA_PR. https://doi.org/10.1093/annonc/mdw435.25.CrossRefGoogle Scholar
- 22.Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67–76. https://doi.org/10.1016/s0140-6736(16)32455-2.
- 23.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.
- 24.Bellmunt J, Albanell J, Paz-Ares L, Climent MA, González-Larriba JL, Carles J, et al. Pretreatment prognostic factors for survival in patients with advanced urothelial tumors treated in a phase I/II trial with paclitaxel, cisplatin, and gemcitabine. Cancer. 2002;95(4):751–7. https://doi.org/10.1002/cncr.10762.CrossRefPubMedGoogle Scholar
- 25.Bajorin DF, Dodd PM, Mazumdar M, Fazzari M, McCaffrey JA, Scher HI et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17(10):3173–81. https://doi.org/10.1200/jco.19188.8.131.5273.
- 26.Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16 https://doi.org/10.1186/s13063-015-1023-4.
- 27.Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483–92. https://doi.org/10.1016/S1470-2045(17)30616-2.CrossRefPubMedGoogle Scholar
- 28.Necchi A, Joseph R, Loriot Y, Hoffman-Censits J, Perez-Gracia J, Petrylak D, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017;28(12): 3044–50.Google Scholar
- 29.Sonpavde G, Pond GR, Mullane S, Ramirez AA, Vogelzang NJ, Necchi A, et al. Outcomes in patients with advanced urothelial carcinoma after discontinuation of programmed death (PD)-1 or PD ligand 1 inhibitor therapy. BJU Int. 2017;119(4):579–84. https://doi.org/10.1111/bju.13674.CrossRefPubMedGoogle Scholar
- 31.Szabados B, Heijden MSVD, Lista AGDL, Tang YZ, Powles T. Responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy. J Clin Oncol. 2017;35(15_suppl):e16004-e. https://doi.org/10.1200/JCO.2017.35.15_suppl.e16004.Google Scholar
- 33.Kirchberger MC, Schilling B, Haferkamp S, Bosserhoff A, Schuler G, Heinzerling L. Can checkpoint inhibitor therapy improve response to chemotherapy? J Clin Oncol. 2017;35(15_suppl):e21024-e. https://doi.org/10.1200/JCO.2017.35.15_suppl.e21024.Google Scholar
- 34.Anantharaman A, Friedlander T, Lu D, Krupa R, Premasekharan G, Hough J, et al. Programmed death-ligand 1 (PD-L1) characterization of circulating tumor cells (CTCs) in muscle invasive and metastatic bladder cancer patients. BMC Cancer. 2016;16. https://doi.org/10.1186/s12885-016-2758-3.
- 35.Rosenberg JE, Petrylak DP, Heijden MSVD, Necchi A, O’Donnell PH, Loriot Y, et al. PD-L1 expression, Cancer Genome Atlas (TCGA) subtype, and mutational load as independent predictors of response to atezolizumab (atezo) in metastatic urothelial carcinoma (mUC; IMvigor210). J Clin Oncol. 2016;34(15_suppl):104. https://doi.org/10.1200/JCO.2016.34.15_suppl.104.Google Scholar
- 37.Barata PC, Koshkin VS, Funchain P, Sohal D, Pritchard A, Klek S, et al. Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance. Ann Oncol. 2017;28(10):2458–63. https://doi.org/10.1093/annonc/mdx405.CrossRefPubMedGoogle Scholar