ASCO GU 2022: Study EV-103 Cohort L: Evaluating Perioperative Enfortumab Vedotin Monotherapy in Cisplatin-Ineligible MIBC

(UroToday.com) The 2022 GU ASCO Annual meeting included a urothelial carcinoma trials in progress session featuring EV-103 cohort L trial, presented by Dr. Christopher Hoimes, evaluating perioperative enfortumab vedotin monotherapy in cisplatin -ineligible muscle invasive bladder cancer (MIBC). The current standard of care for patients with newly diagnosed MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection. For the 20-50% of patients who are cisplatin-ineligible, the current standard of care is radical cystectomy and pelvic lymph node dissection alone.¹

Adjuvant therapy is currently recommended for cisplatin-ineligible patients with high-risk features at cystectomy. Due to the high rates of recurrence in cisplatin-ineligible patients with radical cystectomy and pelvic lymph node dissection alone, there is a need to develop new therapies in this setting. Enfortumab vedotin, an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in urothelial cancer. In EV-301, a phase 3 study, enfortumab vedotin showed overall survival (OS) benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor.² Enfortumab vedotin has also demonstrated activity and a tolerable safety profile in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma.³ Given the efficacy of enfortumab vedotin in locally advanced or metastatic urothelial carcinoma, it is being evaluated as perioperative therapy in cisplatin-ineligible MIBC in EV-103 cohort L.

The study of EV-103 (NCT03288545) in locally advanced or metastatic urothelial carcinoma and MIBC cohorts were described previously at ASCO 2019 and GU ASCO 2020. Cohort L was added to evaluate enfortumab vedotin monotherapy (n = 50) as perioperative therapy in cisplatin-ineligible patients with MIBC (cT2-T4aN0M0 or cT1-T4aN1M0). Eligible patients are previously untreated for MIBC, ECOG 0-2, have CrCl ≥30 mL/min, and are medically fit for and agree to undergo curative intent radical cystectomy and pelvic lymph node dissection. Patients with pT1 disease are eligible only if they have N1 disease. Patients receive 3 cycles of neoadjuvant enfortumab vedotin (1.25 mg/kg IV) on Days 1 and 8 of each 3-week cycle, followed by radical cystectomy and pelvic lymph node dissection and then 6 cycles of adjuvant enfortumab vedotin starting 8 weeks post-radical cystectomy on the same schedule. The study design for EV-103 cohort L is as follows:

Pathological complete response rate per central pathology review is the primary endpoint. Secondary endpoints include event-free survival and disease-free survival by blinded independent central review and investigator, pathological downstaging rate per central pathology review, OS, safety, and tolerability. A complete list of objectives and endpoints for this trial are as follows:

Cohort L is currently enrolling patients in the US and Canada (active sites are in blue):

Co-Authors: Thomas W. Flaig, Sandy Srinivas, Nataliya Mar, Daniel P. Petrylak, Peter H. O'Donnell, Mehmet Asim Bilen, Carolyn Sasse, Yao Yu, Matthew Birrenkott, Jonathan E. Rosenberg

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022 

References:

1. Galsky MD, Hoimes CJ, Necchi A, et al. Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303. Future Oncol. 2021 Aug;17(24):3137-3150.
2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021 Mar 25;384(12):1125-1135.
3. Yu EY, Petrylak DP, O’Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 May 12;S1470-2045(21)00094-2.