Avelumab Maintenance Improves OS and PFS in Advanced Urothelial Carcinoma, Regardless of Diabetes Status

Treatment with avelumab (Bavencio) plus best supportive care (BSC) in the first-line maintenance setting prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in patients with advanced urothelial carcinoma, regardless of diabetes mellitus status, according to exploratory analyses from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) presented at the 2025 Genitourinary Cancers Symposium.1

In the subgroup of patients with diabetes mellitus, those who received avelumab plus BSC (n=55) achieved a median OS of 20.8 months (95% CI, 18.0-32.4) vs 14.5 months (95% CI, 11.7-21.3) with BSC alone (HR, 0.60; 95% CI, 0.37-0.95). At two years, OS rates were 44.5% (95% CI, 30.7%-57.3%) and 34.1% (95% CI, 22.2%-46.3%), respectively. At three years, OS rates were 33.1% (95% CI, 20.4%-46.4%) and 20.3% (95% CI, 10.8%-31.9%), respectively. Among patients without diabetes, median OS was 24.7 months (95% CI, 19.9-30.0) with avelumab plus BSC vs 15.8 months (95% CI, 13.3-18.7) with BSC alone (HR, 0.78; 95% CI, 0.64-0.96). The 2-year OS rates were 50.7% (95% CI, 44.8%-56.4%) and 39.4% (95% CI, 33.6%-45.2%), respectively. The respective 3-year OS rates were 36.6% (95% CI, 30.6%-42.6%) and 31.9% (95% CI, 26.3%-37.7%).

Similarly, PFS was prolonged in both patient subgroups. In those with diabetes, median PFS was 5.6 months (95% CI, 3.7-9.3) with avelumab plus BSC vs 2.0 months (95% CI, 1.9-3.7) with BSC alone (HR, 0.50; 95% CI, 0.33-0.77). At two years, PFS rates were 18.5% (95% CI, 9.1%-30.6%) and 9.2% (95% CI, 3.4%-18.6%), respectively. At three years, PFS rates were 13.5% (95% CI, 5.5%-25.1%) and 5.5% (95% CI, 1.4%-13.8%), respectively. In patients without diabetes, median PFS was 5.4 months (95% CI, 3.8-7.2) with avelumab plus BSC vs 2.1 months (95% CI, 1.9-3.5) with BSC alone (HR, 0.54; 95% CI, 0.45-0.65).The 2-year PFS rates were 24.3% (95% CI, 19.3%-29.7%) and 6.5% (95% CI, 3.8%-10.2%), respectively. The respective 3-year PFS rates were 16.3% (95% CI, 11.7%-21.6%) and 5.3% (95% CI, 2.9%-8.9%).

“Overall, these results show that avelumab frontline maintenance is associated with long-term efficacy benefits and consistent safety in patients with advanced urothelial carcinoma with or without diabetes mellitus who are progression free after first-line platinum-based chemotherapy,” explained lead study author Shilpa Gupta, MD, director of Genitourinary Medical Oncology at the Cleveland Clinic Taussig Cancer Institute in Ohio.

Background and Design of the JAVELIN Bladder 100 Trial

The trial included patients with unresectable locally advanced or metastatic urothelial carcinoma who remained progression free following 4 to 6 cycles of first-line platinum-based chemotherapy. Patients were assigned to receive frontline maintenance with avelumab plus BSC or BSC alone. The exploratory analysis assessed long-term efficacy and safety outcomes in subgroups of patients with or without documented diabetes mellitus at randomization.

At a data cutoff of June 4, 2021, with at least two years of follow-up, median OS was significantly prolonged in the avelumab plus BSC cohort compared with BSC alone, at 23.8 months vs 15.0 months, respectively (HR, 0.76; 95% CI, 0.63-0.91;2-sided P = .0036).2 Similarly, median PFS was 5.5 months in the avelumab arm vs 2.1 months in the BSC alone arm (HR, 0.54; 95% CI, 0.46-0.64; P < .0001), demonstrating the clinical benefit of avelumab maintenance therapy in this setting.

Results also demonstrated the long-term safety of avelumab maintenance therapy, with health-related quality of life preserved throughout treatment.1 These results contributed to the inclusion of avelumab frontline maintenance in updated international guidelines as a recommended treatment option for patients with advanced urothelial carcinoma.

Additionally, the study explored the effects of diabetes mellitus, a known risk factor for bladder cancer that is more prevalent in older adults. Previous research has suggested that diabetes may be associated with reduced efficacy of immunotherapy in some cancers; however, data in urothelial carcinoma remain limited. As a result, this post hoc exploratory analysis from JAVELIN Bladder 100 was conducted to assess outcomes in subgroups of patients with or without diabetes mellitus at randomization.

Baseline Patient Characteristics of JAVELIN Bladder 100 Post Hoc Analysis

Baseline demographics and disease characteristics were assessed by diabetes mellitus status, and median follow-up was at least 38 months in both treatment arms.

The median age among patients with diabetes mellitus was 70 years (range, 51-86) in the avelumab plus BSC arm and 72 years (range, 57-89) in the BSC alone arm. Among patients without diabetes mellitus, the median age was 68 years (range, 37-90) with avelumab and 69 years (range, 32-85) with BSC alone. Most patients were male in both diabetes subgroups (87.3% and 91.5% with avelumab and BSC alone in the diabetes cohort, respectively, and 73.9% and 75.9% in the non-diabetes cohort).

Most patients were enrolled from Europe. Smaller proportions were from North America, Asia, and Australasia.

In the diabetes subgroup, 52.7% of patients in the avelumab arm and 32.2% in the BSC arm were PD-L1 positive. Among patients without diabetes, 54.2% and 51.5% were PD-L1 positive in the avelumab and BSC arms, respectively.

At the start of first-line chemotherapy, visceral metastases were present in 60% of patients with diabetes in the avelumab-containing arm vs 59.3% in the BSC monotherapy arm. A total of 53.6% of patients without diabetes had visceral metastases at the start of chemotherapy in both treatment arms. The most common first-line chemotherapy regimens included cisplatin/gemcitabine and carboplatin/gemcitabine, with carboplatin-based regimens used more frequently in patients with diabetes.

The best response to first-line chemotherapy differed by subgroup. Among patients with diabetes mellitus, 63.6% in the avelumab arm and 78.0% in the BSC alone arm had a complete or partial response (CR/PR). In the non-diabetes subgroup, 73.9% of patients in the avelumab arm and 70.8% in the BSC alone arm achieved a CR/PR.

Adverse Effect Profile

In the avelumab plus BSC arm, grade 3 or greater treatment-related adverse effects (TRAEs) were reported in 24.1% (n=13) of patients with diabetes and 18.6% (n=54) of those without diabetes. The most common grade 3 of higher TRAEs were increased lipase, amylase, and anemia. In the BSC alone arm, 1.7% of patients in both subgroups experienced any-grade TRAEs.

Serious adverse effects (AEs) occurred in 37.0% of patients with diabetes and 29.3% of those without diabetes receiving avelumab. Among these, 9.3% and 10.3%, respectively, were classified as serious TRAEs. In the BSC alone group, 23.7% of patients with diabetes and 20.3% of those without diabetes experienced serious AEs, and no serious TRAEs were reported.

Avelumab discontinuation due to TRAEs occurred in 11.1% of patients with diabetes and 14.8% of those without diabetes, with 9.3% and 12.1% of cases directly attributed to TRAEs. TRAEs leading to death were rare, occurring in 1.9% of patients with diabetes and 2.1% of those without diabetes in the avelumab group.

Immune-related AEs (irAEs) were observed in 31.5% (n=17) of patients with diabetes and 32.4% (n=94) of those without diabetes treated with avelumab, compared with 3.4% and 1.4% of patients in the BSC alone group.

The most commonly reported TRAEs of any grade in the avelumab plus BSC arm included pruritus (11.1% vs 15.5% in the diabetes and non-diabetes cohorts, respectively), hypothyroidism (7.4% vs 11.7%), fatigue (5.6% vs 11.7%), and asthenia (9.3% vs 10.7%). Gastrointestinal-related TRAEs, including diarrhea (7.4% vs 11.0%) and nausea (9.3% vs 6.9%), were also frequently observed.

References

1. Gupta S, Grivas P, Park SH, et al. Avelumab first-line maintenance (1LM) in patients (pts) with advanced urothelial carcinoma (aUC) with or without diabetes mellitus (DM): long-term outcomes from JAVELIN Bladder 100. J Clin Oncol. 2025;43(suppl 5):869. doi:10.1200/JCO.2025.43.5_suppl.869
2. Powles T, Park SH, Caserta C, et al. Avelumab first-line maintenance for advanced urothelial carcinoma: results from the JAVELIN Bladder 100 trial after ≥2 years of follow-up. J Clin Oncol. 2023;41(19):3486-3492. doi:10.1200/JCO.22.01792