Unfavorable early progression-free survival of immunotherapy compared to chemotherapy in bladder cancer: A meta-analysis of randomized trials

Introduction: Platinum-based chemotherapy has long served as the first-line standard for advanced urothelial carcinoma. However, the advent of immune checkpoint inhibitors (ICIs) has spurred efforts to evaluate their suitability as initial therapy, especially in patients with strong PD-L1 expression or those who cannot tolerate cisplatin. Early results from randomized controlled trials (RCTs) suggest that ICI-only regimens may produce inferior short-term progression-free survival (PFS) compared with chemotherapy, potentially due to delayed immune activation, lack of rapid tumor shrinkage, or hyperprogressive disease in select cases. To characterize this time-dependent efficacy pattern, we performed a meta-analysis comparing ICI-only regimen with chemotherapy in advanced bladder cancer. Methods: A comprehensive search of PubMed, Embase, and the Cochrane Library identified phase II-III RCTs comparing first-line ICI-only regimen(Durvalumab, Durvalumab+Tremelimumab, Pembrolizumab) and platinum-based chemotherapy for advanced bladder cancer. Studies conducted exclusively in first-line treatment settings were selected for inclusion. Kaplan-Meier PFS curves from eligible trials were extracted and digitized, and reconstructed patient-level survival data were generated using the Guyot algorithm. Combined Kaplan-Meier estimates were produced from pooled data, and hazard ratio (HR) values comparing immunotherapy with chemotherapy were calculated at 3, 6, 9, and 12 months to evaluate temporal changes in treatment effect. HRs were obtained through two-stage meta-analysis, incorporating study-specific weights to account for differences in sample size and variance across trials. Results: Three immunotherapy regimens in two RCTs met the inclusion criteria. ICI-only regimens demonstrated worse early PFS outcomes compared to chemotherapy, with HRs of 4.08(95% CI, 2.85-5.82) at 3 months, 2.87(2.23-3.70) at 6 months, 2.05(1.80-2.33) at 9 months and 1.92(1.63-2.25) at 12 months. HRs gradually decreased throughout the 12-month period, indicating slow convergence of survival trajectories. Pooled KM curves showed that immunotherapy exhibited reduced short-term benefit compared to chemotherapy that gradually improved with longer follow-up and ultimately crossed over at 10 months. Conclusion: In advanced bladder cancer, first-line ICI-only regimen underperforms relative to chemotherapy in the early phase. Survivability slowly improves with follow-up and benefits are apparent around 10 months as the KM curves cross over. These findings underscore the need for vigilant early assessment and support combination or sequential treatment strategies to offset early progression while preserving long-term immunologic benefit.