Enfortumab vedotin active in cisplatin-ineligible muscle-invasive bladder cancer
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SAN FRANCISCO — Neoadjuvant treatment with enfortumab vedotin demonstrated promising activity among cisplatin-ineligible patients with muscle-invasive bladder cancer, according to study results presented at ASCO Genitourinary Cancers Symposium.
More than one-third of patients achieved pathologic complete response and half achieved pathologic downstaging.
“I think these are very exciting findings. This potentially could give patients another therapeutic option in this clinical setting,” Daniel P. Petrylak, MD, director of genitourinary oncology at Yale Cancer Center and a HemOnc Today Editorial Board member, told Healio.
Up to one-quarter of patients with urothelial cancer present with muscle-invasive disease, and these patients are at considerable risk for disease progression or metastasis.
Neoadjuvant chemotherapy followed by radical cystectomy and pelvic lymph node dissection has extended OS among patients who are eligible for cisplatin.
However, standard treatment for cisplatin-ineligible patients who undergo surgery does not include neoadjuvant chemotherapy, according to study background.
“Patients may be ineligible for cisplatin for a variety of reasons, such as creatinine, neuropathy, hearing loss or performance status,” Petrylak said. “These patients really do not have any therapeutic options aside from cystectomy or radiation therapy to the bladder, and that does not take care of micrometastatic disease.”
Consequently, there is a high unmet need for effective and safety therapies that can be administered to this patient population in the neoadjuvant setting.
Enfortumab vedotin (Padcev; Astellas, Seagen) is a first-in-class antibody-drug conjugate directed against nectin-4, a protein highly expressed in urothelial cancers.
Phase 2 and phase 3 trials have shown the agent benefits patients with locally advanced or metastatic urothelial cancers, including those who are ineligible for cisplatin.
The agent is approved in the United States to treat adults with bladder cancer and cancers of the urinary tract that have spread or cannot be surgically removed. The indications apply to patients who received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy or those who are cisplatin-ineligible but have received at least one other prior therapy.
At ASCO GU, Petrylak presented results of an analysis of Cohort H of the phase 1B/phase 2 EV-103 trial. The cohort included patients with cisplatin-ineligible cT2-T4aN0M0 muscle-invasive bladder cancer who were eligible for radial cystectomy and pelvic lymph node dissection. All patients had an ECOG performance status of 0 to 2.
Patients received three cycles of neoadjuvant enfortumab vedotin dosed at 1.25 mg/kg on days 1 and 8 of each 3-week cycle.
Pathologic complete response rate assessed by central review served as the primary endpoint. Key secondary endpoints included pathologic downstaging rate and safety.
Petrylak presented results of a preliminary analysis that included 22 patients with cT2 (68.2%), cT3 (27.3%) or cT4 (4.5%) tumors. About two-thirds (68.2%) had predominant urothelial cancer and one-third (31.8%) had mixed histology.
Nineteen (86.3%) patients completed all three cycles of enfortumab vedotin.
Twenty-one (95.4%) underwent radical cystectomy and pelvic lymph node dissection, and one underwent partial cystectomy.
Researchers reported a 36.4% pathologic complete response rate. Fifty percent of patients achieved pathologic downstaging, with central pathology review pending for one patient.
“I think the most meaningful efficacy outcome is pathologic complete response rate,” Petrylak said. “In other studies, that has been potentially deemed as a surrogate for overall survival. To me, that is most indicative of how active this drug is in this setting.”
Enfortumab vedotin administration did not delay any surgeries, and adverse events appeared consistent with the agent’s known safety profile, according to investigators.
The most common treatment-related adverse events included fatigue (45.5%), alopecia (36.4%) and dysgeusia (36.4%). Fewer than one in five (18.2%) patients experienced grade 3 or higher treatment-related adverse events.
Three patients experienced grade 5 adverse events while on study, none related to enfortumab vedotin. Two of these events occurred more than 30 days after radical cystectomy and pelvic lymph node dissection.
These results support ongoing phase 2 and phase 3 research evaluating enfortumab vedotin in muscle-invasive bladder cancer, Petrylak and colleagues concluded.
One phase 3 trial is underway assessing enfortumab vedotin in combination with pembrolizumab (Keytruda, Merck), an anti-PD-1 therapy.
“I see this drug being looked at in different combinations,” Petrylak said. “There are a variety of different ways this can be moved forward.”
Perspective
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Daniel M. Geynisman, MD
Neoadjuvant cisplatin-based chemotherapy is a level one standard of care for patients with localized muscle-invasive bladder cancer prior to cystectomy. Unfortunately, approximately half of patients are cisplatin-ineligible and, thus, are not able to receive this therapy.
A search for alternative options has led investigators to evaluate enfortumab vedotin — an antibody-drug conjugate approved in the metastatic setting — in this space.
In this small cohort of 22 patients, enfortumab vedotin led to similar pathologic complete response as we see with cisplatin-based chemotherapy or immunotherapy, with approximately 36% of patients achieving complete response and 50% experiencing some degree of downstaging.
Pathologic complete response generally is an accepted surrogate for long-term survival in urothelial carcinoma, and these response rates are promising. Of note, a majority of patients had cT2 disease and almost half were cisplatin ineligible based on hearing loss, something that is not typically seen in daily practice. Also, the creatinine clearance cutoff of 60 mL/min is higher than is often used in practice, as oncologists may split-dose cisplatin and treat at a glomerular filtration rate of 50 mL/min to 60 mL/min.
Finally, 14% of patients died after cystectomy, a concerning rate that needs to be closely monitored in the follow-up trials. As such, it is critical to await further data on enfortumab vedotin in the perioperative setting: EV-103 cohort L, examining single-agent enfortumab vedotin; the phase 3 trial of enfortumab vedotin in combination with pembrolizumab vs. cisplatin; and the phase 3 trial of pembrolizumab with enfortumab vedotin vs. pembrolizumab vs. cystectomy alone. Until those are completed, neoadjuvant enfortumab vedotin is not a standard-of-care in muscle-invasive bladder cancer.
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Petrylak DP, et al. Abstract 435. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.
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