The standard of care for patients with muscle-invasive bladder cancer (MIBC) is cisplatin-based chemotherapy with radical cystectomy and pelvic lymph node dissection (PLND). Neoadjuvant therapy with enfortumab vedotin (Padcev) showed promising antitumor activity in patients with MIBC who were ineligible for cisplatin therapy, based on the preliminary findings for cohort H from the phase 1b/2 EV-103 clinical trial.
Enfortumab vedotin is an antibody–drug conjugate (ADC) that delivers monomethyl auristatin E to targeted tumor cells that express Nectin-4. Enfortumab vedotin improves overall survival compared with chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. Preclinical studies suggest that ADCs that use monomethyl auristatin E can induce immunogenic cell death and may enhance antitumor immunity.
Based on previous results from eV-103, the FDA granted a breakthrough therapy designation to enfortumab vedotin plus pembrolizumab (Keytruda) as a first-line treatment for patients with unresectable, locally advanced or metastatic urothelial cancer who cannot receive cisplatin-based chemotherapy.
Analysis of data from 22 patients in cohort H, which enrolled patients who were eligible for surgical treatment but were ineligible for cisplatin-based chemotherapy, showed a pathologic complete response (pCR) rate of 36.4%, said Daniel P. Petrylak, MD, Professor, Medical Oncology and Urology, and Co-Leader, Cancer Signaling Networks, Yale Cancer Center, Smilow Cancer Hospital at Yale New Haven, CT, at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium.
“All patients were able to undergo surgery, and there was no delay in surgery due to neoadjuvant enfortumab vedotin,” said Dr Petrylak.
“Cisplatin-ineligible patients do not have established neoadjuvant treatment options known to prolong survival prior to undergoing radical cystectomy and PLND,” he said, creating an unmet need in this patient population.
Cohort H of the single-arm phase 1b/2 EV-103 trial enrolled 22 patients with clinical stage T2-T4aN0M0 MIBC who were eligible for surgical treatment but ineligible for cisplatin-based chemotherapy. The patients received 3 cycles of neoadjuvant enfortumab vedotin monotherapy on days 1 and 8 of every 3-week cycle, followed by radical cystectomy and PLND within 4 weeks and follow-up imaging every 12 weeks for the first 2 years, and then every 24 weeks.
A total of 68.2% of patients had cT2N0 disease. In all, 68.2% of patients had a histologic type of transitional-cell carcinoma only, 13.6% had transitional-cell carcinoma with squamous differentiation, and 18.2% had transitional-cell carcinoma with other histologic variants.
The most common reasons for cisplatin ineligibility were a creatinine clearance <60 mL/min and ≥30 mL/min (N = 11) and grade ≥2 hearing loss (N = 9).
Of the 22 patients, 19 completed all 3 cycles of neoadjuvant enfortumab vedotin, and all patients underwent surgery without delay. The median duration of neoadjuvant treatment was 2.1 months, with 1.8 months from the end of neoadjuvant treatment to surgery. Of the 3 off-study patients who died during the perioperative period, 1 died from acute kidney injury, 1 from cardiac arrest, and 1 from pulmonary embolism.
In addition to the pCR rate of 36.4%, 11 (50.0%) patients were downstaged by central pathology review following neoadjuvant treatment.
The safety profile of neoadjuvant enfortumab vedotin monotherapy in this study was consistent with the known safety profile of the drug in other settings. The most common treatment-emergent adverse events were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). A total of 4 patients had grade 3 treatment-emergent adverse events.
In addressing the seemingly high rate of perioperative deaths, Dr Petrylak noted that “these are an older group of patients, and 2 of those 3 patients had residual disease, and previous research has shown that bladder cancer treatments may cause thrombogenic events, pointing to the 2 events that were cardiovascular in nature. It is a concern, and this is going to be monitored in phase 3 studies, and, of course, if there is a safety signal that is concerning, the studies will be appropriately evaluated,” he said.
Discussant Guru P. Sonpavde, MD, Director, Bladder Cancer Program, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, said that ADC development in earlier disease settings such as MIBC is rational. While the pCR rate in EV-103 is impressive, “will pCR here translate into improved long-term outcomes [and cure more patients]?” he asked. “Is this good-quality pCR or just a shallow pCR? I think this remains to be seen.” The stakes are higher in the perioperative setting, he added, where a better therapeutic index is needed.