In the phase 2 ARIES clinical trial (NCT03891238), treatment with avelumab (Bavencio) did not demonstrate an improvement in overall survival (OS) at 1 year as frontline treatment in patients with cisplatin-ineligible, PD-L1–positive advanced urothelial cancer, but the agent did elicit a notable objective response rate (ORR) and disease control rate (DCR) with a favorable safety profile.

At a median follow-up of 9 months, the median OS was 10 months (95% CI, 5.7-14.3). The estimated 1-year OS rate was 44.9%, and the 1-year OS rate was 40.8%, according to finding presented during the 2020 ASCO Genitourinary Cancers Symposium.

“The ARIES trial confirmed the favorable safety profile of avelumab in advanced urothelial cancer. Although avelumab was unable to improve the 1-year OS rate as expected, patients able to receive at least 1 month of therapy had longer OS,” lead study author Roberto Iacovelli, MD, PhD, a medical oncologist at the Fondazione Policlinico Gemelli IRCCS in Rome, Italy, said in a presentation of the data.

Cisplatin-based chemotherapy is the standard frontline treatment in advanced urothelial cancer. However, approximately half of patients are cisplatin ineligible, and some are entirely platinum ineligible, leading to poor prognosis.

Avelumab is a PD-L1 antibody that has shown improved progression-free survival (PFS) and OS as maintenance therapy in patients with advanced urothelial cancer with responsive or stable disease after frontline platinum-based therapy.

In the ARIES trial, the efficacy and safety of avelumab was evaluated in patients with cisplatin-ineligible, PD-L1–positive advanced urothelial cancer.

To be eligible for enrollment, patients must have had a histologic diagnosis of advanced urothelial cancer; an ECOG performance status between 0 and 2, and cisplatin-ineligible disease due to at least one of the following: an ECOG performance status of 2; eGFR below 60 mL/min; grade 2 or worse peripheral neuropathy or hearing loss; prior cisplatin for neoadjuvant or adjuvant chemotherapy with disease progression within 6 months.

A total of 198 patients underwent central assessment for PD-L1 expression of at least 5%, and 71 eligible patients received 10 mg/kg of avelumab every 2 weeks.

The primary end point was 1-year OS; secondary end points were median OS, median PFS, ORR, safety, quality of life, and outcome based on PD-L1 expression.

The study was designed such that 67 patients were required to show an improvement in the 1-year OS rate from 40% to 57% with 80% power and a 2-sided type I error equal to .05.

Regarding baseline characteristics, most patients were at least 65 years of age (93%; n = 55), male (77.5%; n = 55), had an ECOG performance status of 1 (47.9%; n = 34), and had a primary tumor location of the bladder (70.4%; n = 50).

A total of 11 patients (15.5%) had hemoglobin less than 10 mg/dL.

The primary location of metastasis was the lymph nodes (66.2%; n = 47), followed by the lung (43.7%; n = 31), liver (25.3%; n = 18), bone (18.3%; n = 13), and lymph nodes only (15.5%; n = 11).

Reasons for cisplatin ineligibility were a result of patients having a creatinine clearance of less than 60 ml/min (70.4%; n = 50), an ECOG performance status of 2 (31%; n = 22), grade 2 or worse peripheral neuropathy or hearing loss (5.8%; n = 4), and prior treatment with cisplatin for adjuvant intent in 6 months (12.7%; n = 9).

Additional results showed that 56 patients had a PD-L1 combined positive score (CPS) of at least 10%, 11 had a CPS below 10%, and 4 were not evaluable.

Notably, the median OS was 13 months (95% CI, 2.4-23.6) in patients with a CPS of at least 10% vs 7 months (95% CI, 2.8-11.2) in patients with a CPS below 10%, showing a numerical but not statistically significant improvement (P = .09). The 1- and 2-year OS rates were 50.4% and 39% in the CPS of at least 10% group vs 27.3% and 13.6% in the CPS below 10% group, respectively.

The median PFS in the overall population was 2 months (95% CI, 1.4-2.6). When broken down by CPS, the median PFS was no different at 2 months (95% CI, 1.2-2.8) in patients with a CPS of at least 10% vs 2 months (95% CI, 1.1-2.9) in patients with a CPS below 10% (P = .46).

The confirmed ORR, which was evaluated locally per RECIST version 1.1 criteria, was 22.5% (n = 16), consisting of 1 complete response (1.4%) and 15 partial responses (21.1%). A total of 15 patients (21.1%) had stable disease, reflecting a DCR of 43.6%.

A total of 28 patients (39.4%) had progressive disease and 12 (16.9%) were not evaluable.

A post-hoc analysis was also conducted in patients who received at least 1 month of therapy or 3 treatment infusions. Among 56 evaluable patients, the median OS was 16 months (95% CI, 7.5-24.5), and the estimated 1-year OS rate was 53.9%.

In the overall population, 13 patients (19.4%) remained on treatment at data cutoff.

Regarding safety, any-grade adverse effects (AEs) occurred in 67 patients (94.4%), and grade 3-5 AEs occurred in 30 patients (42.3%).

Fatal AEs were reported in 2 patients (2.8%) and were attributed to sepsis and an unknown cause.

All-grade AEs included fever (29.6%; n = 21), fatigue (28.2%; n = 20), constipation (22.5%; n = 16), anemia (21.1%; n = 15), diarrhea (19.7%; n = 14), back pain (16.9%; n = 12), pruritus (14.1%; n = 10), rash (14.1%; n = 10), hypothyroidism (12.7%; n = 9), edema of the limbs (11.3%; n = 8), abdominal pain (9.9%; n = 7), infusion reactions (9.9%; n = 7), anorexia (8.5%; n = 6), bone pain (8.5%; n = 6), hematuria (8.5%; n = 6), cough (7%; n = 5), dyspnea (7%; n = 5), vomiting (7%; n = 5), nausea (5.6%; n = 4), and sepsis ((5.6%; n = 4).

Grade 3-5 included fever (1.4%; n = 1), fatigue (1.4%; n = 1), anemia (5.6%; n = 4), abdominal pain (1.4%; n = 1), infusion reaction (4.2%; n = 3), anorexia (1.4%; n = 1), bone pain (1.4%; n = 1), dyspnea (1.4%; n = 1), and sepsis (5.6%; n = 4).

“Patients with advanced urothelial cancer who are unfit for cisplatin have a dismal prognosis. Clinical selection is critical to maximize the efficacy of available therapeutic options, including immunotherapy,” Iacovelli concluded.

_Reference

_{Iacovelli R, Ciccarese C, Brunelli M, et al. First line avelumab in PD-L1+ve metastatic or locally advanced urothelial cancer (aUC) patients unfit for cisplatin (cis): the ARIES trial. J Clin Oncol. 2022;40(suppl 6):439. doi:10.1200/JCO.2022.40.6_suppl.439}