Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer

Abstract

PURPOSE Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Endocrine Adverse Events Caused by Different Types and Different Doses of Immune Checkpoint Inhibitors in the Treatment of Solid Tumors: A Meta‐Analysis and Systematic Review

“…A total of 2367 studies describing the correlations between ICIs and endocrine adverse events were retrieved; 1566 in the Pubmed database and 801 in the Embase database, while 130 duplicates were excluded. As a result, 2302 studies remained, and after skimming the titles and abstracts and reading the full texts, 26 RCTs 7–32 were obtained, comprising 13 824 patients (7786 in the intervention groups and 6038 in the control groups). The details of the screening process are shown in Figure 1.…”

“…The basic characteristics of 26 RCTs are shown in Table 1. Nivolumab was used in 8 studies 9–16 ; pembrolizumab was used in 10 studies 7,8,17,18,19–24 ; ipilimumab was used in 3 studies 25–27 ; tremelimumab was used in 2 studies 28,29 ; and atezolizumab, 30 avelumab, 31 and durvalumab 32 were used in 1 study, respectively. Of 26 studies, 2 7,8 were comparative analyses of different doses of the same drug and chemotherapy.…”

Avelumab Maintenance Therapy Improves Survival in Metastatic Urothelial Carcinoma

“…A similar approach has been explored in a randomized phase 2 trial looking at maintenance pembrolizumab after first-line chemotherapy (HCRN GU14-182). 2 This trial similarly showed improvement in PFS; however, OS was not yet mature at the time of data analysis. It should be noted that crossover was permitted in the HCRN study, while this was not allowed in the current Javelin 100 study.…”

New and Emerging Therapies in the Management of Bladder Cancer

“…These results led to the recent FDA approval of avelumab switch maintenance therapy following first-line chemotherapy in patients with mUC. Similarly, the phase II HCRN GU14-182 study enrolled LA/mUC patients who achieved at least stable disease following first-line platinum-based chemotherapy and randomly assigned them to receive maintenance pembrolizumab versus placebo 13 . Patients receiving maintenance pembrolizumab demonstrated an improvement in median PFS compared with placebo (5.4 versus 3.0 months; HR 0.65).…”