Significant Improvement of Prognosis After the Advent of Immune Checkpoint Inhibitors in Patients with Advanced, Unresectable, or Metastatic Urothelial Carcinoma: A Propensity Score Matching and Inverse Probability of Treatment Weighting Analysis on Real-World Data

Abstract

Purpose: The treatment landscape for advanced, unresectable, or metastatic urothelial carcinoma (aUC) has shifted substantially since the advent of immune checkpoint inhibitors (ICIs). We investigated the extent to which pembrolizumab therapy is superior to conventional chemotherapy as a second-line treatment.

Patients and methods: A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 94 patients (21%) who received second-line pembrolizumab and 75 (17%) who received second-line chemotherapy but never received third-line or later ICI therapy were included. We compared overall survival (OS) from the initial date of first-line chemotherapy between two groups by adjusting for prognostic factors through propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). The IPTW-adjusted hazard ratio and 95% confidence interval were estimated using a multivariate Cox regression analysis. To identify patients who were more likely to benefit from second-line pembrolizumab than from chemotherapy, we performed a subgroup analysis for OS with an IPTW-adjusted model.

Results: The PSM-adjusted comparison showed a significant improvement in the prognosis with second-line pembrolizumab use (P = 0.01). The OS benefit with the advent of pembrolizumab was 8 months (18 months vs 26 months). Multivariable analyses using IPTW adjustment demonstrated that lymph node metastasis (P = 0.001), lung metastasis (P = 0.013), and bone metastasis (P = 0.003) were poor independent prognostic factors, and pembrolizumab use (P = 0.021) was a favorable independent prognostic factor. Subgroup analyses revealed that pembrolizumab was associated with survival benefits over chemotherapy in all subgroups, including young patients (age <70 years), those who received radical surgery, and those without visceral metastasis.

Conclusion: We demonstrated a significant improvement in prognosis after the advent of pembrolizumab for patients with aUC. ICIs should not be restricted based on patient characteristics.

Keywords: chemotherapy; immunotherapy; propensity score; survival; urinary bladder neoplasms.

Figure 1

Flow chart for creation of patient cohort dataset. Among the 454 registered patients with aUC, 169 (37%) were eligible for this study.

Figure 2

Overall survival curves for second-line therapy. Overall survival curves from the date of first-line chemotherapy initiation are plotted for patients with aUC who received first-line chemotherapy followed by second-line chemotherapy (red) or pembrolizumab (blue). Survival rates were compared between the second-line chemotherapy (n = 74) and pembrolizumab (n = 94) groups before propensity score matching (left) and between the adjusted second-line chemotherapy group (n = 59) and adjusted pembrolizumab (n = 75) groups after propensity score matching (right). The median survival duration is shown in the figures. The number of patients at risk over time is shown in the bottom.

Figure 3

Overall survival curves for second-line therapy in patients with the prognostic factors. Overall survival curves from the date of first-line chemotherapy initiation are plotted for patients with the prognostic factors which are identified in the Cox regression analyses. Survival rates were compared between the second-line chemotherapy (red line) and pembrolizumab (blue line) groups by Log rank test. The number of patients at risk over time is shown in the bottom.

Figure 4

An analysis of overall survival in key subgroups in inverse probability of treatment weighting (IPTW) population. The dashed line indicates the rate of overall survival in the entire population.