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

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.

Organ-Specific and Mixed Responses to Pembrolizumab in Patients with Unresectable or Metastatic Urothelial Carcinoma: A Multicenter Retrospective Study

“…For patients with unresectable or metastatic urothelial carcinoma (ur/mUC), pembrolizumab, which is a programmed death-1 (PD-1) inhibitor, and avelumab, a programmed death ligand-1 (PD-L1) inhibitor, are currently approved and widely used, following the KEYNOTE-045 and JAVELIN Bladder 100 trials [ 1 , 2 ]. The appearance of ICIs has certainly improved the prognosis of ur/mUC; however, the response rate is insufficient [ 3 ]. Furthermore, the activity of ICIs may be affected depending on the different immunities of metastatic locations [ 4 , 5 ], and some small and limited reports have shown that the effect of ICIs differs depending on the metastatic organ [ 6 , 7 ].…”

Safety and effectiveness of pembrolizumab monotherapy in Japanese patients with unresectable urothelial carcinoma: a nation-wide post-marketing surveillance

“…Finally, this study evaluated only ORR as a measure of effectiveness. A recent real-world study of pembrolizumab in patients with advanced, unresectable, or metastatic urothelial carcinoma reported overall survival as a measure of effectiveness [ 29 ]. In that study, overall survival was longer in those treated with pembrolizumab versus those treated with conventional chemotherapy, regardless of their background characteristics.…”

Real‐world outcomes of pembrolizumab for platinum‐refractory advanced urothelial carcinoma: Efficacy, safety, and evidence for trial‐unfit patients

“…Regarding the benefit over second‐line chemotherapy, several studies retrospectively compared the efficacy of pembrolizumab with conventional chemotherapy as a historical control 20,24 . After the inverse probability of treatment weighting adjustment, the OS was significantly longer in the pembrolizumab group in both reports.…”