Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study.
Vadim S Koshkin, Nicholas Henderson, Marihella James, Divya Natesan, Dory Freeman, Amanda Nizam, Christopher T Su, Ali Raza Khaki, Chelsea K Osterman, Michael J Glover, Ryan Chiang, Dimitrios Makrakis, Rafee Talukder, Emily Lemke, T Anders Olsen, Jayanshu Jain, Albert Jang, Alicia Ali, Tanya Jindal, Jonathan Chou, Terence W Friedlander, Christopher Hoimes, Arnab Basu, Yousef Zakharia, Pedro C Barata, Mehmet A Bilen, Hamid Emamekhoo, Nancy B Davis, Sumit A Shah, Matthew I Milowsky, Shilpa Gupta, Matthew T Campbell, Petros Grivas, Guru P Sonpavde, Deepak Kilari, Ajjai S Alva
Author Information
Vadim S Koshkin: Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, California. ORCID
Nicholas Henderson: Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
Marihella James: The University of Texas MD Anderson Cancer Center, Houston, Texas.
Divya Natesan: Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, California.
Dory Freeman: Dana-Farber Cancer Center, Boston, Massachusetts.
Amanda Nizam: Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
Christopher T Su: Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. ORCID
Ali Raza Khaki: Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington. ORCID
Chelsea K Osterman: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
Michael J Glover: Stanford University, Stanford, California.
Ryan Chiang: Stanford University, Stanford, California.
Dimitrios Makrakis: Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
Rafee Talukder: Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
Emily Lemke: Medical College of Wisconsin, Milwaukee, Wisconsin.
T Anders Olsen: Winship Cancer Institute of Emory University, Atlanta, Georgia.
Jayanshu Jain: University of Iowa, Iowa City, Iowa.
Albert Jang: Tulane University Medical School, New Orleans, Louisiana.
Alicia Ali: Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
Tanya Jindal: Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, California.
Jonathan Chou: Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, California. ORCID
Terence W Friedlander: Helen Diller Family Cancer Center, University of California San Francisco, San Francisco, California.
Christopher Hoimes: Duke University, Durham, North Carolina.
Arnab Basu: University of Alabama at Birmingham, Birmingham, Alabama.
Yousef Zakharia: University of Iowa, Iowa City, Iowa.
Pedro C Barata: Tulane University Medical School, New Orleans, Louisiana. ORCID
Mehmet A Bilen: Winship Cancer Institute of Emory University, Atlanta, Georgia.
Hamid Emamekhoo: University of Wisconsin, Madison, Wisconsin. ORCID
Nancy B Davis: Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Sumit A Shah: Stanford University, Stanford, California.
Matthew I Milowsky: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. ORCID
Shilpa Gupta: Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
Matthew T Campbell: The University of Texas MD Anderson Cancer Center, Houston, Texas.
Petros Grivas: Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington. ORCID
Guru P Sonpavde: Dana-Farber Cancer Center, Boston, Massachusetts.
Deepak Kilari: Medical College of Wisconsin, Milwaukee, Wisconsin. ORCID
Ajjai S Alva: Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
BACKGROUND: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials. METHODS: UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy. RESULTS: The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06). CONCLUSIONS: In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities. LAY SUMMARY: Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations.
von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602-4608.
Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015-1026.
Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383:1218-1230.
Sternberg CN, Yagoda A, Scher HI, et al. M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol. 1988;139:461-469.
Rosenberg JE, Hoffman-Censits J, Powles T, 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;387:1909-1920.
Sternberg CN, de Mulder PH, Schornagel JH, 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;19:2638-2646.
Balar AV, Galsky MD, Rosenberg JE, 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;389:67-76.
Balar AV, Castellano D, O'Donnell PH, 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;18:1483-1492.
Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76:3003-3013.
Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: a phase I study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma. J Clin Oncol. 2020;38:1041-1049.
Heath EI, Rosenberg JE. The biology and rationale of targeting nectin-4 in urothelial carcinoma. Nat Rev Urol. 2021;18:93-103.
Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol. 2019;37:2592-2600.
Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384:1125-1135.
Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2020;38(suppl):441.
Chu CE, Sjöström M, Egusa EA, et al. Heterogeneity in NECTIN4 expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin. Clin Cancer Res. 2021;27:5123.
Harris PA, Taylor R, Thielke R, et al. Research Electronic Data Capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377-381.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 cohort 2: enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl):394.
Siefker-Radtke AO, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma (mUC): long-term outcomes in BLC2001. J Clin Oncol. 2020;38:5015.
Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39:2474-2485.
Hoffman-Censits JH, Choi W, Lombardo K, et al. Expression of nectin-4 in bladder cancer with variant histology. J Clin Oncol. 2020;38(suppl):546.
Hoffman-Censits JH, Lombardo KA, Parimi V, et al. Expression of nectin-4 in bladder urothelial carcinoma, in morphologic variants, and nonurothelial histotypes. Appl Immunohistochem Mol Morphol. 2021;29:619-625.
Kim K, Hu W, Audenet F, et al. Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts. Nat Commun. 2020;11:1975.
Teo MY, Ratna N, Regazzi AM, et al. Enfortumab vedotin in FGFR3-mutated advanced urothelial carcinoma. J Clin Oncol. 2021;39(suppl):458.
