Neoadjuvant Enfortumab Vedotin Associated With Substantial Antitumor Activity in Muscle-Invasive Bladder Cancer


The rate of pathologic complete responses with enfortumab vedotin was 36.4% among patients with muscle-invasive bladder.

Thomas W. Flaig

Thomas W. Flaig

Patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC) achieved a high event-free survival (EFS) and promising response rates following single-agent neoadjuvant enfortumab vedotin-ejfv (Padcev), according to updated findings from cohort H of the phase 1b/2 EV-103/KEYNOTE-869 trial (NCT03288545).

Findings presented at the 2023 ASCO Annual Meeting showed that 36.4% (95% CI, 17.2%-59.3%) of patients who received enfortumab vedotin monotherapy achieved a pathologic complete response (pCR; n = 8). Of these patients, 7 continued to be disease free at the time of the of January 17, 2023, data cutoff. The pathological downstaging (pDS) rate was 50.0% (95% CI, 28.2%-71.8%). Moreover, treatment with the agent resulted in an EFS rate of 76.4% (95% CI, 52.2%-89.4%). The median EFS was not yet been reached.

“All patients were able to undergo surgery with no delays due to neoadjuvant enfortumab vedotin–related [AEs] in this understudied population,” lead study author Thomas W. Flaig, MD, vice chancellor for research at the University of Colorado Cancer Center Anschutz Medical Campus, and colleagues, emphasized in a poster of the data.

Preliminary results from cohort H of this study were presented at the 2022 Genitourinary Cancer Symposium and showed that the agent had early efficacy and safety. At the 2023 ASCO Annual Meeting, investigators presented updated results from cohort H, including EFS data, subsequent cancer-related therapy, safety, and tolerability.

Cohort H included patients with clinical T2-T4aN0M0 MIBC who were eligible for surgical resection but cisplatin ineligible. Patients were required to have greater than 50% ulcerative colitis histology and an ECOG performance status between 0 and 2. They needed to be medically fit for surgery and undergo transurethral resection of the bladder tumor up to 90 days after the start of treatment. Those with upper tract or urethral tumors were not allowed on the study.

Patients were given 1.25 mg/kg of neoadjuvant enfortumab vedotin on days 1 and 8 of a 21-day cycle. A total of 3 cycles were administered. Standard-of-care (SOC) radical cystectomy and pelvic lymph node dissection (RC + PLND) was performed 4 to 12 weeks after the last dose of study treatment was administered. Imaging was conducted 4 or fewer weeks before and after neoadjuvant treatment. Follow-up imaging occurred every 12 weeks for 2 years and continued every 24 weeks thereafter.

The primary end point was pCR rate according to central pathology review. Key secondary end points included pDS rate, EFS based on investigator assessment, and safety.

A total of 22 patients were enrolled in cohort H. The median age in this patient population was 74.5 years (range, 56-81). All patients were Caucasian, and 90.9% of patients were male; 95.5% were current or former smokers. Regarding ECOG performance status, 59.1%, 36.4%, and 4.5% of patients had a status of 0, 1, and 2, respectively. Histological subtypes included transitional cell carcinoma only (68.2%), TCC with squamous differentiation (13.6%), and TCC with other histologic variants (18.2%). The current stages were cT2N0 (68.2%), cT3N0 (27.3%), and cT4aN0 (4.5%).

Half of patients were cisplatin ineligible due to a creatinine clearance rate of 30 mL/min to less than 60 mL/min, and 40.9% were ineligible due to grade 2 or higher hearing loss. A total of 4.5% of patients were cisplatin ineligible due to both factors, and 4.5% were ineligible because they had an ECOG status of 2.

The median duration of treatment was 2.1 months (range, 0.7-2.3). All patients were treated with enfortumab vedotin monotherapy at cycle 1. A total of 19 patients (86.4%) received all 3 cycles of enfortumab vedotin monotherapy. All participants underwent surgery without delay. The median time to RC + PLND was 1.8 months (range, 1.0-2.7).

Additional data indicated that 36.4% of patients went on to receive a subsequent cancer-related therapy. Specifically, 18.2% of patients were given systemic therapy for residual MIBC or high-risk MIBC at cystectomy as their first subsequent treatment; this consisted of pembrolizumab (Keytruda; 9.1%), carboplatin-based therapy (4.5%), or erdafitinib (Balversa; 4.5%).

Those who received subsequent systemic therapy for progressive disease were given avelumab (Bavencio) plus carboplatin-based therapy (4.5%). Other patients received radiation therapy for a second malignancy (4.5%), laparoscopic distal pancreatectomy (4.5%), or partial cystectomy with prostatectomy (4.5%).

Most patients were still on study at the time of data cutoff (77.3%); the remaining 22.7% of patients died. Notably, 1 patient died due to an acute kidney injury, but this was not determined to be treatment related. The remaining 2 patients died from cardiac arrest and pulmonary embolism, respectively, both of which were related to RC + PLND.

The safety profile for enfortumab vedotin was consistent with previous data across different disease settings.

No grade 4 or 5 enfortumab vedotin–related treatment-related adverse effects (TRAEs) occurred in this population, although 18.2% of patients experienced a grade 3 event. These included dehydration, erythema multiforme, hyperglycemia, postprocedural urine leak, rash maculopapular, and small intestinal obstruction.

Any-grade TRAEs occurring in 20% or more of patients consisted of fatigue (45.5%), dysgeusia (36.4%), alopecia (31.8%), diarrhea (27.3%), nausea (27.3%), peripheral sensory neuropathy (27.3%), dry eye (22.7%), and maculopapular rash (22.7%).

Dose interruption was required for 9.1% of patients who experienced grade 1 diarrhea (4.5%) and grade 2 fatigue (4.5%). Moreover, 9.1% of patients had grade 2 dysgeusia (4.5%) and grade 2 diarrhea (4.5%) leading to dose reduction. Three patients discontinued treatment due to grade 3 dehydration (4.5%), grade 3 erythema multiforme (4.5%) and grade 3 maculopapular rash (4.5%).

Adverse effects of special interest were predominantly low grade. These included skin reactions (any grade, 63.6%; grade 3 or higher, 9.1%), ocular disorder (40.9%; 0%), peripheral neuropathy (36.4%; 0%), hyperglycemia (22.7%; 13.6%), and infusion-related reactions (9.1%; 0%).

The median time to onset for skin reactions was 0.5 months (range, 0.2-1.2), 1.3 months (range, 0.3-1.8) for peripheral neuropathy, and 0.7 months (range, 0.3 to 0.7) for hyperglycemia. All skin reaction and hyperglycemia events resolved by a median of 0.8 months (range for skin reactions, 0.1-4.6; hyperglycemia, 0.03-3.7), and 44% of peripheral neuropathy events resolved in 2.6 months (range, 0.5-5.5).

The data support the continued investigation of enfortumab vedotin in patients with MIBC, according to the study investigators.

The agent is currently being evaluated alone or in combination with pembrolizumab in patients with MIBC in several phase 3 studies, including KEYNOTE-905/​EV-303 (NCT03924895), KEYNOTE-B15/EV-304 (NCT04700124). Cohort L of the phase 1/2 EV-103 study (NCT03288545) will also investigate perioperative enfortumab vedotin monotherapy in cisplatin-ineligible patients.

Disclosures: Dr Flaig reported serving as a consultant or in an advisory role for Janssen and Seagen. He reports recieving institutional research funding from Agensys, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca/MedImmune, Bavarian Nordic, Bristol-Myers Squibb, Dendreon, Exelixis; GTx, Janssen, La Roche-Posay, Lilly, Medivation, Merck, Novartis, Pfizer, Roche/Genentech, Sanofi, Seagen, Sotio, and Tokai Pharmaceuticals. He has a leadership role with Aurora Oncology and University of Colorado/UC Health. He has received monetary support for travel and accommodations from Astellas Pharma, AstraZeneca/MedImmune, Genentech/Roche, and Jounce Therapeutics. He currently has 2 patents filed with the University of Colorado.


Flaig TW, Rosenberg JE, Hoimes CJ, et al. Study EV-103: neoadjuvant treatment with enfortumab vedotin monotherapy in cisplatin-ineligible patients (pts) with muscle invasive bladder cancer (MIBC): updated results for cohort H. J Clin Oncol. 2023;41(suppl 16):4595. doi:10.1200/JCO.2023.41.16_suppl.4595

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