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In the present era dominated by the success of combined enfortumab vedotin (EV) and pembrolizumab (P), what is the current status of utilizing avelumab as the initial maintenance treatment for advanced urothelial cancer (UC)?

was a landmark trial that showed a meaningful improvement in median overall survival (mOS ) (21.4 vs 14.3 months, HR 0.69, 95% CI 0.56-0.86, P=0.001) in advanced or metastatic UC patients with maintenance avelumab in patients who achieved a clinical response after 4-6 cycles of platinum-based chemotherapy.

The results of this study gave our UC patients their first maintenance immunotherapy, avelumab ( on June 30, 2020). Since then, the field has changed dramatically with the results from the . This study demonstrated a substantial advantage with the use of EV+P at a median follow-up of 17.2 months, showcasing a noteworthy improvement in median overall survival (mOS) with a doubling effect (31.5 vs 16.1 months, HR 0.47, 95% CI 0.38-0.58, P<0.00001), as well as progression-free survival (mPFS) (12.5 vs 6.3 months, HR 0.45, 95% CI 0.38-0.54, P<0.00001).

Furthermore, a complete response (CR) rate of 29.1% was observed, leading to the subsequent FDA approval. The study compared EV+P × 35 cycles vs gemcitabine + cisplatin (GC) or gemcitabine + carboplatin (GCa) × 6 cycles.

Additionally, results from with the triplet combination of anti-PD-1, nivolumab Q3 weeks + GC × 6 cycles followed by maintenance nivolumab Q4 weeks for 2 years vs GC alone for 6 cycles also showed an OS benefit (mOS 21.7 vs 18.9 months HR 0.78 (95% CI 0.63-0.96, P=0.02), with a median duration of complete response of 37.1 vs 13.2 months.

While the results of recent studies -- in particular, EV+P -- have generated a lot of excitement, at the same time we are unclear on how to approach the use of maintenance avelumab in metastatic UC.

So, the in the Journal of Clinical Oncology highlighting the long-term follow-up of ≥2 years is very timely. Dr. Powles and colleagues present long-term follow-up data (median follow-up of 38 months in the avelumab arm) for the JAVELIN Bladder 100 study with an N of 350 in each arm (avelumab + BSC vs BSC alone).

It is very reassuring to see that the mOS differences have further improved from a 7.2-month (initial analyses) to an 8.8-month benefit (23.8 vs 15 months, HR 0.76, 95% CI 0.63-0.91, P=0.0036) with no new safety signals being reported with a longer follow-up.

The OS benefit is maintained even when the majority of patients (72%) on the BSC-alone arm got subsequent anti-cancer therapies including anti-PD (L)-1 therapy (53.8%), emphasizing the importance of using these therapies in the upfront maintenance setting.

Additionally, the side effect profile was similar to what was reported in the initial analyses. Moreover, the therapy was tolerable as evidenced by 19.5% of patients receiving ≥2 years of maintenance avelumab. In patients who received avelumab, ≥ grade 3 treatment-related adverse events (TRAEs) were observed in 19.5% of patients. Amongst patients who were on avelumab ≥12 months, 86.4% had any-grade AEs while 47.5% had ≥grade 3 AEs.

TRAEs causing discontinuation of avelumab after ≥12 months occurred in 12 patients (10%), and one patient died due to immune-related nephritis.

Any grade immune-related TRAEs ≥12 months were seen in 22.9% and ≥grade 3 in 4.2% of patients. Furthermore, the for mUC was 29.7 months in the avelumab+BSC arm vs 20.5 months in the BSC arm (HR 0.77, 95% CI 0.636-0.921).

Overall this reflects long-term tolerability with manageable toxicity with meaningful efficacy of avelumab maintenance in advanced UC patients. So, while EV+P has changed the landscape of mUC, maintenance avelumab could still be a viable option in patients with comorbidities -- in particular, patients with significant neuropathy or poorly controlled diabetes.

EV+P therapy carries the risk of unique toxicities such as any-grade skin reactions (66.8%), peripheral neuropathy (63.2%), and hyperglycemia (13%). Peripheral neuropathy is the most concerning toxicity from EV+P that could have a larger bearing on the quality of life and tolerance, thus making maintenance avelumab a viable option for some patients.

Monika Joshi, MD, MRCP, is Professor of Medicine, Endowed Professorship in Cancer Clinical Care, Co-Leader of the GU Disease Team, and Medical Director of the Clinical Trial Office at Penn State Cancer Institute in Hershey, and Chief Scientific Officer of the Big Ten Cancer Research Consortium.

Read the study here and an interview about it here.