Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice

Abstract

Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switchmaintenance therapy. In the JAVELIN Bladder 100 phase 3 trial, avelumab administered as 1L maintenance with best supportive care (BSC) significantly prolonged OS vs BSC alone in patients with locally advanced or metastatic UC that had not progressed with 1L platinum-containing chemotherapy (median OS, 21.4 vs 14.3 months; hazard ratio, 0.69 [95% CI, 0.56-0.86]; P = 0.001). Efficacy benefits were seen across various subgroups, including recipients of 1L cisplatin-or carboplatin-based chemotherapy, patients with PD-L1+ or PD-L1− tumors, and patients with diverse characteristics. Results from JAVELIN Bladder 100 led to the approval of avelumab as 1L maintenance therapy for patients with locally advanced or metastatic UC that has not progressed with platinum-containing chemotherapy. Avelumab 1L maintenance is also included as a standard of care in treatment guidelines for advanced UC with level 1 evidence. This review summarizes the data that supported these developments and discusses practical considerations for administering avelumab maintenance in clinical practice, including patient selection and treatment management.

Reassessment of the Efficacy of Carboplatin for Metastatic Urothelial Carcinoma in the Era of Immunotherapy: A Systematic Review and Meta-analysis

“…In our current MA, it was shown that cisplatinand carboplatin-based chemotherapies elicit a greater ORR than and offer similar OS/CR benefits to ICI monotherapy. Switch-maintenance therapy could potentially serve as a novel treatment strategy intended to enhance antitumor activity in UC through the use of agents with different mechanisms of action [31]. Maintenance treatment can target tumor cell populations surviving after first-line chemotherapy, thus increasing the depth of responses and/or prolonging treatment effects, while avoiding cumulative toxicity, potential cross-resistance, and increased treatment cost [32].…”

“…Indeed, the expression of PD-L1 in NSCLC cells is shown to be upregulated following preoperative cisplatin-based chemotherapy in NSCLC patients (before vs after chemotherapy, 11% vs 26%; p = 0.017) [36]. Overall, there is a clear rationale for exploring ICIs as a first-line maintenance therapy for AMUC, given the immunogenic nature of UC, antitumor activity and favorable safety profile of ICIs, and cytotoxic and immunogenic effects of chemotherapy [31]. In the JAVELIN Bladder 100 phase 3 trial, avelumab as first-line maintenance therapy led to significant prolongation of OS, compared with the best supportive care (BSC), in patients with AMUC not experiencing disease progression on first-line platinum-containing chemotherapy [46].…”

The impact of eligibility for maintenance immunotherapy on prognosis in patients with unresectable or metastatic urothelial carcinoma

“…We need to know that avelumab maintenance therapy is effective in selected patients with favorable disease control. Therefore, we could not compare the outcomes of switch maintenance therapy with the other first‐ or second‐line trials in one table 21 . In this regard, our study can provide useful information for proper understanding of treatment, although our study is not useful on deciding to perform immunotherapy or not for each patient.…”

“…Therefore, we could not compare the outcomes of switch maintenance therapy with the other first‐ or second‐line trials in one table. 21 In this regard, our study can provide useful information for proper understanding of treatment, although our study is not useful on deciding to perform immunotherapy or not for each patient. As the goal of this study is to identify selection biases of the eligible population in the JAVELIN Bladder 100 trial, the definition of trial ineligible group and the OS comparison does not necessarily negate the findings of JAVELIN Bladder 100 trial.…”

Solute carrier family 12 member 8 (SLC12A8) is a potential biomarker and related to tumor immune cell infiltration in bladder cancer

“…Nevertheless, 5-year survival from metastatic BC is only 5% [ 7 ]. Compared with traditional chemotherapy, immunotherapy has good efficacy in advanced or metastatic urothelial carcinoma [ 8 ]. Several immune checkpoint inhibitors (ICIs) have been approved as second-line treatments for patients that have progressed during or after previous platinum-based chemotherapy.…”