To date, the standard of care for cisplatin-ineligible patients with muscle invasive bladder cancer undergoing surgery does not include neoadjuvant therapy. Therefore, safe and effective neoadjuvant therapies are an unmet need for these patients. Cohort H of the EV-103 study demonstrated promising activity with neoadjuvant enfortumab vedotin (EV) while adverse events were consistent with the known safety profile of EV.
Cisplatin-ineligible patients do not have established neoadjuvant treatment options known to prolong survival prior to undergoing radical cystectomy and pelvic lymph node dissection. Efficacy and safety of enfortumab vedotin (EV) was established in cisplatin-ineligible patients with previously treated advanced urothelial cancer and is approved by the FDA. At ASCO GU 2022, Dr. Petrylak presented the preliminary data from Cohort H of the EV-103 phase Ib/II trial in patients with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible and treated with neoadjuvant EV monotherapy.
In order to be eligible for enrolment in Cohort H of the EV-103 study, patients had to be ineligible to receive cisplatin and had to have clinical stage T2-T4aN0M0 disease. No upper tract or urethral tumours were allowed and patients had to have more than 50% urothelial carcinoma histology. The patient’s ECOG performance status must be between 0-2 and they had to be medically fit to undergo radical cystectomy plus pelvic lymph node dissection (RC+PLDN). Study participants had to have a transurethral resection of bladder tumour within 90 days of cycle 1, day 1 (C1D1). Patients received three cycles of neoadjuvant EV at 1.25 mg/kg on D1 and D8 of each 21-day cycle. Within four weeks, patients underwent a RC+PLDN. Follow-up imaging was performed every 12 weeks for the first 2 years, and every 24 weeks thereafter. Primary endpoint of the trial was pathological complete response rate (pCR).
In total, 22 patients were enrolled in Cohort H, all patients were white and most of them (90.9%) were male and current or former smokers (95.5%). The median age of the study population was 74.5 years and the median enrolment time from diagnosis was 1.6 months. Patients had cT2N0 (68.2%), cT3N0 (27.3%), and cT4aN0 (4.5%) tumours. Furthermore, 68.2% of patients had transitional cell carcinoma (TCC) only, 13.6% had TCC with squamous differentiation and 18.2% had TCC with other histologic variants. Creatinine clearance of 30-60 ml/min was the most common reason for cisplatin-ineligibility (50% of patients), followed by grade 2 or greater hearing loss (40.9%). In total, 19 out of 22 patients completed all three cycles of neoadjuvant EV and all enrolled patients underwent surgery without delay. The median duration of neoadjuvant treatment was 2.1 months and the time from end of neoadjuvant EV to RC+PLND was 1.8 months. A pCR was obtained in eight patients (36.4%) and pathological downstaging was reported in eleven patients (50.0%).
The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). Overall, 18% of patients had grade ≥3 EV-related TEAEs, including asthenia, dehydration, erythema multiforme, hyperglycaemia, post procedural urine leak, rash maculo-papular and small intestinal obstruction. No EV-related grade 4 TEAEs or deaths were observed. Three deaths occurred on study, due to acute kidney injury, cardiac arrest and pulmonary embolism. In two patients, these AEs occurred more than 30 days after RC+PLND. TEAEs leading to EV dose interruption, dose reduction or discontinuation were reported in 13.6%, 9.1% and 13.6% of patients, respectively. There were no dose reductions due to peripheral neuropathy. Most AEs of special interest were grade 1 or 2 and resolved. There was no pre-existing diabetes mellitus for the five patients who had hyperglycaemia.
Neoadjuvant enfortumab vedotin showed promising antitumour activity in patients with MIBC ineligible for cisplatin as shown by a pCR of 36% and pathological downstaging in 50%. All patients were able to undergo surgery and there was no delay in surgery due to neoadjuvant enfortumab vedotin. The observed safety profile in patients with cisplatin-ineligible MIBC is consistent with the known AE profile of enfortumab vedotin in other settings. This first disclosure of data supports the ongoing phase II and III programs evaluating enfortumab vedotin alone or in combination with pembrolizumab in MIBC.
Petrylak DP, 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. Presented at ASCO GU 2022; Abstract 435.