Avelumab first-line maintenance treatment for advanced urothelial carcinoma: review of evidence to guide clinical practice

Abstract

The JAVELIN Bladder 100 phase III trial led to the incorporation of avelumab first-line (1L) maintenance treatment into international guidelines as a standard of care for patients with advanced urothelial carcinoma (UC) without progression after 1L platinum-based chemotherapy. JAVELIN Bladder 100 showed that avelumab 1L maintenance significantly prolonged overall survival (OS) and progression-free survival in this population compared with a 'watch-and-wait' approach. The aim of this manuscript is to review clinical studies of avelumab 1L maintenance in patients with advanced UC, including long-term efficacy and safety data from JAVELIN Bladder 100, subgroup analyses in clinically relevant subpopulations, and 'real-world' data obtained outside of clinical trials, providing a comprehensive resource to support patient management. Extended follow-up from JAVELIN Bladder 100 has shown that avelumab provides a long-term efficacy benefit, with a median OS of 23.8 months measured from start of maintenance treatment, and 29.7 months measured from start of 1L chemotherapy. Longer OS was observed across subgroups, including patients who received 1L cisplatin + gemcitabine, patients who received four or six cycles of 1L chemotherapy, and patients with complete response, partial response, or stable disease as best response to 1L induction chemotherapy. No new safety signals were seen in patients who received ≥1 year of avelumab treatment, and toxicity was similar in those who had received cisplatin or carboplatin with gemcitabine. Other clinical datasets, including noninterventional studies conducted in Europe, USA, and Asia, have confirmed the efficacy of avelumab 1L maintenance. Potential subsequent treatment options after avelumab maintenance include antibody-drug conjugates (enfortumab vedotin or sacituzumab govitecan), erdafitinib in biomarker-selected patients, platinum rechallenge in suitable patients, nonplatinum chemotherapy, and clinical trial participation; however, evidence to determine optimal treatment sequences is needed. Ongoing trials of avelumab-based combination regimens as maintenance treatment have the potential to evolve the treatment landscape for patients with advanced UC.

Keywords: avelumab; bladder cancer; first line; maintenance treatment; urothelial carcinoma.

Figure 1

OS in the overall population of the JAVELIN Bladder 100 trial (data cut-off, 4 June 2021). (A) OS measured from randomization at start of maintenance (i.e. after completion of chemotherapy; primary endpoint). (B) OS measured from start of first-line chemotherapy (exploratory analysis) in this selected trial population. (C) Subgroup analysis of OS (measured from randomization at start of maintenance). 1L, first line; BSC, best supportive care; CI, confidence interval; CR, complete response; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; PD-L1, programmed death-ligand 1; OS, overall survival; PR, partial response; SD, stable disease. ^aHRs and CIs were calculated using a Cox proportional hazards model. ^bStratified by best response to 1L chemotherapy (CR or PR versus SD) and metastatic disease site when initiating 1L chemotherapy (visceral versus nonvisceral). Other HRs are unstratified. ^cPatients who switched platinum regimens while receiving 1L chemotherapy. Panels A and C adapted from 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. https://doi.org/10.1200/JCO.22.01792. © 2023 American Society of Clinical Oncology.

Figure 2

OS (measured from randomization at start of maintenance; data cut-off, 4 June 2021) in key subgroups of the JAVELIN Bladder 100 trial, including patients who received first-line chemotherapy with (A) cisplatin + gemcitabine or (B) carboplatin + gemcitabine, and patients whose best response to first-line chemotherapy was (C) complete response, (D) partial response, or (E) stable disease. BSC, best supportive care; CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival.

Figure 3

Treatment sequencing in patients with advanced UC based on international treatment guidelines.^,, Approval statuses and indications for each agent vary between countries; local labels must be consulted. Further details regarding FDA and EMA approvals are provided in footnotes. 1L, first line; 2L+, second line or later; CR, complete response; EMA, European Medicines Agency; EV, enfortumab vedotin; FDA, US Food and Drug Administration; MVAC, methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin; PD, progressive disease; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PR, partial response; SD, stable disease; UC, urothelial carcinoma. ^aEV + pembrolizumab has received accelerated approval in the USA for the treatment of cisplatin-ineligible patients with advanced UC. ^bIn the 1L setting, atezolizumab is approved by the EMA, but not by the FDA, for the treatment of cisplatin-ineligible patients with advanced UC who have a PD-L1+ tumor.^{, c}In the 1L setting, pembrolizumab is approved by the EMA for the treatment of cisplatin-ineligible patients with PD-L1+ advanced UC, and by the FDA for the treatment of patients with advanced UC who are not eligible for any platinum-containing chemotherapy (irrespective of PD-L1 status).^{, d}EV monotherapy has been approved by the EMA and FDA for the treatment of patients with advanced UC who have previously received treatment with platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor; in addition, EV monotherapy has been approved by the FDA for the treatment of cisplatin-ineligible patients who have received ≥1 prior line of therapy.^{, e}Erdafitinib has been approved by the FDA for patients with advanced UC that has susceptible FGFR3 or FGFR2 genetic alterations and ≥1 line of prior platinum-containing chemotherapy; erdafitinib has not been approved by the EMA. ^fVinflunine has been approved by the EMA for patients with advanced UC after failure of prior platinum-containing therapy; vinflunine is not approved in the USA. ^gSacituzumab govitecan has been approved by the FDA for patients with advanced UC who have previously received treatment with platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor; sacituzumab govitecan has not been approved by the EMA for patients with advanced UC.