Avelumab first-line maintenance is recommended for patients with advanced urothelial carcinoma who are progression free after platinum-based chemotherapy. However, data on its effectiveness and subsequent treatment sequencing in routine clinical practice remain limited.
The French AVENANCE study evaluated real-world outcomes with avelumab first-line maintenance in a large and heterogeneous population of patients with advanced urothelial carcinoma, including exploratory analyses according to the treatment patients received after avelumab.
The study, titled “Real-world Study of Avelumab First-line Maintenance Treatment in Patients with Advanced Urothelial Carcinoma in France: Overall Results from the Noninterventional AVENANCE Study and Analysis of Outcomes by Second-line Treatment,” was published in the April 2025 issue of European Urology Oncology.
Authors: Philippe Barthélémy, Constance Thibault, Aude Fléchon, Marine Gross-Goupil, Eric Voog, Jean-Christophe Eymard, Christine Abraham, Matthieu Chasseray, Véronique Lorgis, Werner Hilgers, Aurélien Gobert, Sylvestre Le Moulec, Camille Simon, Emanuel Nicolas, Anne Escande, Damien Pouessel, Guillaume Mouillet, Constant Josse, Marie-Noelle Solbes, Prisca Lambert, and Yohann Loriot.
The AVENANCE Study
AVENANCE (NCT04822350) is an ongoing ambispective, noninterventional study conducted in France. It included adults with locally advanced or metastatic urothelial carcinoma, irrespective of PD-L1 status, whose disease had not progressed following first-line platinum-based chemotherapy and who had received, were receiving, or were planned to receive avelumab first-line maintenance.
Patients were enrolled across 82 centers between July 2021 and May 2022. Of 604 patients screened, 595 were included in the effectiveness population and 596 in the safety population.
The study included both patients who had received avelumab through the French early access program and patients treated after European approval. The primary endpoint was overall survival from the initiation of avelumab. Progression-free survival, treatment duration, and safety were also evaluated, together with exploratory analyses of overall survival from the start of first-line platinum-based chemotherapy and according to subsequent second-line treatment. At the December 7, 2023 data cutoff, median follow-up from avelumab initiation was 26.3 months.
Who Was Treated?
The median age at avelumab initiation was 73 years. Among patients with available performance-status data, 91% had an ECOG performance status of 0 or 1, while 9.3% had an ECOG performance status of 2 or higher. Most patients had pure urothelial carcinoma, reported in 92% of those with available histology. At avelumab initiation, 76% had metastatic disease, 6.2% had locally advanced disease, and 18% had no evidence of disease.
Carboplatin plus gemcitabine was the most frequently used first-line chemotherapy regimen, administered to 61% of patients, followed by cisplatin plus gemcitabine in 28% and dose-dense MVAC in 4.2%. Among patients with available response data, 20% achieved a complete response to first-line chemotherapy, 56% had a partial response, and 23% had stable disease. The median interval between the end of chemotherapy and the initiation of avelumab was 4.6 weeks.
Real-World Outcomes With Avelumab Maintenance
The median duration of avelumab treatment was 5.6 months. At the data cutoff, 125 patients remained on avelumab. Median overall survival from the start of avelumab was 21.3 months (95% CI, 17.6–24.6), based on 323 events. Median progression-free survival from avelumab initiation was 5.7 months (95% CI, 5.2–6.5), with 414 events.
In an exploratory analysis restricted to this population without progression following first-line chemotherapy, median overall survival measured from the start of first-line chemotherapy was 26.5 months (95% CI, 23.4–30.1).
In univariate analyses, factors associated with overall survival included response to first-line chemotherapy, ECOG performance status at avelumab initiation, Bajorin risk at chemotherapy initiation, the number of chemotherapy cycles received, and the type of second-line treatment.
What Happened After Avelumab?
At the data cutoff, 330 patients, representing 55% of the effectiveness population and 70% of patients who had discontinued avelumab, had received second-line treatment.
Among these patients, 244 received chemotherapy, including 81 who received platinum-based chemotherapy and 163 who received non-platinum chemotherapy. Sixty-two patients received an antibody-drug conjugate, including 56 treated with enfortumab vedotin and six treated with sacituzumab govitecan. Median overall survival from avelumab initiation was 31.3 months among patients who subsequently received any antibody-drug conjugate and 36.0 months in the subgroup that received enfortumab vedotin.
For patients who received second-line chemotherapy, median overall survival from avelumab initiation was 14.4 months. It was 16.7 months among those who received second-line platinum-based chemotherapy and 13.6 months among those who received non-platinum chemotherapy.
The investigators also explored overall survival from the beginning of first-line chemotherapy. Median overall survival was 40.8 months among patients who subsequently received an antibody-drug conjugate and 41.5 months in the subgroup that received second-line enfortumab vedotin. By comparison, median overall survival from the start of first-line chemotherapy was 24.5 months among patients who later received second-line platinum-based chemotherapy.
These analyses were exploratory and should be interpreted cautiously. Patient characteristics, including prognostic factors, likely influenced second-line treatment selection, and the number of patients in some subgroups, including the enfortumab vedotin group, was relatively small.
Safety in Routine Clinical Practice
Among 596 patients in the safety population, 443, or 74%, experienced a treatment-emergent adverse event. Avelumab-related treatment-emergent adverse events were reported in 330 patients, representing 55% of the safety population.
The most frequently reported avelumab-related events were intentional product misuse, reported in 23% of patients and consisting mainly of delayed doses, as well as pruritus and asthenia, each reported in 9.9%.
Serious treatment-emergent adverse events occurred in 22% of patients and were considered related to avelumab in 5.7%. Treatment-emergent adverse events led to death in 25 patients, or 4.2%, and were considered related to avelumab in three patients. The investigators reported no new safety concerns.
How Do the Results Compare With JAVELIN Bladder 100?
The authors noted that survival outcomes observed in AVENANCE were comparable with long-term results from the phase 3 JAVELIN Bladder 100 trial. Median overall survival and progression-free survival from avelumab initiation were 21.3 and 5.7 months, respectively, in AVENANCE, compared with 23.8 and 5.5 months in the long-term follow-up of JAVELIN Bladder 100.
However, AVENANCE included a heterogeneous and unselected real-world population. Patients were older than those enrolled in JAVELIN Bladder 100, with higher proportions having ECOG performance status of 1 or higher and visceral metastases, and more patients having received first-line carboplatin plus gemcitabine.
AVENANCE also included patients who would not have been eligible for JAVELIN Bladder 100, including patients with ECOG performance status of 2 or higher and patients treated with first-line dose-dense MVAC.
Limitations
The authors highlighted several limitations inherent to the noninterventional design. Data availability depended on assessments performed by treating physicians during routine clinical practice, and some information was collected retrospectively.
The exploratory analyses of overall survival from the beginning of first-line chemotherapy cannot be directly compared with outcomes in an unselected first-line population because AVENANCE specifically enrolled patients who had already achieved disease control with platinum-based chemotherapy.
Analyses according to second-line treatment also excluded patients who died or discontinued avelumab without receiving another systemic treatment, as well as patients who remained on avelumab. Treatment selection may additionally have been influenced by patients’ prognostic characteristics. Finally, some treatment subgroups were relatively small, particularly the group receiving second-line enfortumab vedotin.
Takeaway
The AVENANCE study provides real-world evidence supporting the effectiveness and safety of avelumab first-line maintenance in patients with advanced urothelial carcinoma whose disease has not progressed following platinum-based chemotherapy. In this French cohort, median overall survival was 21.3 months from avelumab initiation and 26.5 months from the start of first-line chemotherapy.
Exploratory analyses also showed favorable long-term outcomes among the relatively small subgroup of patients treated sequentially with platinum-based chemotherapy, avelumab maintenance, and second-line enfortumab vedotin, with median overall survival reaching 41.5 months from the start of first-line chemotherapy.
The authors emphasize, however, that these sequencing analyses should be interpreted cautiously and that further analyses of treatment sequencing are needed.
The full article is available in European Urology Oncology.