First line avelumab in PD-L1+ve metastatic or locally advanced Urothelial Cancer (aUC) patients unfit for cisplatin: The ARIES trial

Introduction & Objectives: Avelumab was approved as maintenance therapy after platinum-based first line (1L) therapy for patients with aUC based on phase III Javelin Bladder 100 study (NCT02603432), showing significant overall survival (OS) improvement. Here we tested the activity of avelumab as 1L of therapy in patients with aUC and PD-L1+ve expression. Materials & Methods: ARIES is a single-arm, multi-site, open-label phase II trial. Enrolled patients had aUC, were cis-unfit (at least one among: ECOG-PS=2, CrCl <60 mL/min, grade ≥2 peripheral neuropathy/hearing loss, progression within 6-mos before the end of neo/adjuvant chemotherapy), had not previously received chemotherapy for aUC and PD-L1≥5% (SP263) centrally assessed. Patients received avelumab 10 mg/Kg IV Q2Weeks until progression, unacceptable toxicity and withdrawal, whichever occurred first. The primary endpoint was the 1-year OS. Key secondary endpoints were median-OS, -PFS, ORR and safety. Results: A total of 198 eligible cisplatin-unfit pts have been tested for PD-L1 and 71 (35.6%) have been found positive. Among enrolled patients (N=71), median age was 75 y, 35 (49.3%) had visceral disease, and 22 (31.0%) had ECOG-PS=2; 50 (70.4%) had CrCl <60 mL/min and 9 (12.7%) progressed within 6-months from the end of neo/adjuvant chemotherapy. At the cut-off data (Sep 15, 2021), median follow up was 9.0 mo and 13 patients are still on treatment. The median OS was 10.0 months (95% CI, 5.7-14.3), and 40.8% of patients were alive at 1-year. The ORR for all patients was 22.5%; complete response, 1.4% (n=1); partial response, 21.1% (n=15). Clinical benefit was 43.6% (n=31). Median PFS was 2.0 months (95% CI, 1.4-2.6). Among the 56 patients who received at least 3 cycles (29 days) of therapy the median OS was 16.0 vs 1.0 month. Five (7.0%) grade 3 avelumab-related adverse events, and no treatment-related death were reported. Conclusions: Avelumab is active and safe in patients with cisplatin-unfit, PD-L1+ve aUC and poor baseline characteristics.