Perioperative Enfortumab Vedotin Shows Antitumor Activity in Cisplatin-Ineligible MIBC

Perioperative enfortumab vedotin-ejfv (Padcev) elicited responses in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC), according to data from cohort L of the phase 1/2 EV-103 trial (NCT03288545) presented at the 2023 ESMO Congress.¹

The agent elicited a pathologic complete response (pCR) rate of 34.0% (95% CI, 21.2%-48.8%) in this population (n = 50). Moreover, the pathological downstaging rate was 42.0% (95% CI, 28.2%-56.8%). These results proved to be consistent with what had been observed in cohort H, according to lead study author Srikala S. Sridhar, MD, MSc.

“This first data disclosure from EV-103 cohort L supports the ongoing phase 3 programs evaluating enfortumab vedotin in combination with pembrolizumab [Keytruda] in MIBC,” said Sridhar, who is a professor in the Department of Medicine at the University of Toronto and a genitourinary medical oncologist at the Princess Margaret Cancer Center in Ontario, Canada. “Additional follow-up will allow characterization of event-free survival [EFS], disease-free survival [DFS], and overall survival [OS] data from cohort L.”

Of all patients who receive a diagnosis of urothelial cancer, 25% present with MIBC. For this population, neoadjuvant cisplatin-based chemotherapy and subsequent surgery represents the standard of care (SOC) with potential adjuvant therapy in those determined to be at high risk. Those who are not eligible to receive cisplatin-based therapy typically receive surgery alone, but many patients experience recurrence. As such, options are needed in this setting, Sridhar noted.

Prior data from the trial have indicated that enfortumab vedotin given in the neoadjuvant setting has resulted in a pCR rate of 36.4% (95% CI, 17.2%-59.3%) in cisplatin-eligible patients with MIBC enrolled to cohort H (n = 22) and a pDS rate of 50.0% (95% CI, 28.2%-71.8%).²

For cohort L, investigators set out to examine a perioperative approach comprised of neoadjuvant and adjuvant treatment with enfortumab vedotin in patients with previously untreated, cisplatin-ineligible MIBC who are fit to receive curative-intent radical cystectomy and pelvic lymph node dissection within 12 weeks.¹

In the neoadjuvant setting, single-agent enfortumab vedotin was given intravenously at a dose of 1.25 mg/kg on day 1 and 8 every 3 weeks for 3 cycles. Patients proceeded to undergo surgery, and this was followed by adjuvant treatment where the agent was again given at 1.25 mg/kg on days 1 and 8 every 3 weeks for 6 more cycles.

The primary end point of the trial was pCR rate, and key secondary end points include pDS rate, EFS, DFS, OS, safety, and tolerability.

In the 51 total patients who comprised cohort L, the median age was 74.0 years (range, 54-85). Most patients were male (76.5%) and had an ECOG performance status of 0 or 1 (96.1%). Regarding disease stage at baseline, 56.9% had cT2N0, 25.5% had cT3N0, 7.8% had cT4N0, and 9.8% had cT2-3N1. Moreover, 45.1% of patients had creatinine clearance of less than 60 and at least 30 mL/min.

All 51 patients received neoadjuvant enfortumab vedotin and 82.4% completed all 3 cycles of treatment in that setting. The median time from last dose of the agent to surgery was 1.3 months and 82.4% of patients completed surgery. The data cutoff date for the presentation was June 13, 2023.

Regarding safety in the neoadjuvant and surgery phase, treatment-emergent adverse effects (TEAEs) related to enfortumab vedotin were found to be generally manageable with no surgical delays, according to Sridhar. Any-grade enfortumab vedotin–related TEAEs were reported in 90.2% of patients; these effects were grade 3 or higher for 39.2% of patients.

Most enfortumab vedotin–related adverse effects of special interest (AESIs) were grade 2 in severity or less. Of the 51 patients, more than half (56.9%) experienced skin reactions and 33.3% had peripheral neuropathy. One patient died because of Stevens-Johnson syndrome.

The most common enfortumab vedotin–related TEAEs included fatigue (any grade, 52.9%; grade ≥3, 2.0%), maculopapular rash (31.4%; 11.8%), nausea (29.4%; 0%), alopecia (27.5%; 0%), peripheral sensory neuropathy (27.5%; 2.0%), pruritus (23.5%; 0%), and hyperglycemia (13.7%; 11.8%). The most common grade 3 or higher surgery-related toxicities included anemia, ileus, and urinary tract infection.

“No new safety signals [were observed], but close monitoring for toxicities remains important,” Sridhar concluded.

Editor’s Note: Dr Sridhar disclosed that institutional grants were paid by Janssen and Seagen Inc. He also noted receipt of consulting fees from Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Eisai, EMD Serono, Gilead, Ipsen, Janssen, Merck, Pfizer, and Seagen Inc.

References

1. Sridhar S, O’Donneell PH, Flaig TW, et al. 2365MO study EV-103 cohort L: perioperative treatment w/ enfortumab vedotin (EV) monotherapy in cisplatin (cis)-ineligible patients (pts) w/ muscle invasive bladder cancer (MIBC). Ann Oncol. 2023;34(suppl 2):S1203. doi:10.1016/j.annonc.2023.09.1014
2. Petrylak DP, Flaig TW, Mar N, et al. Study EV-103 cohort H: antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible. J Clin Oncol. 2022;40(suppl 6):435. doi:10.1200/JCO.2022.40.6_suppl.435