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Programmed death-1 or programmed death ligand-1 blockade in patients with platinum-resistant metastatic urothelial cancer: A systematic review and meta-analysis

  • Scot A. Niglio,
  • Rachel Jia,
  • Jiayi Ji,
  • Samuel Ruder,
  • Vaibhav G. Patel,
  • Alberto Martini,
  • John P. Sfakianos,
  • Kathryn E. Marqueen,
  • Nikhil Waingankar,
  • Reza Mehrazin,
  • Peter Wiklund,
  • William K. Oh,
  • Madhu Mazumdar,
  • Bart S. Ferket,
  • Matthew D. Galsky

Publication: European Urology, June 2019

DOI: 10.1016/j.eururo.2019.05.037





Context:

Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown.

Objective:

To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors.

Evidence acquisition:

We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated.

Evidence synthesis:

From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18mo of follow-up were 7.8mo (95% CI 7.6, 8.1) and 10mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18mo with PD-1 versus PD-L1 blockade (1.0mo; 95% CI -0.5, 2.3mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18mo follow-up were 7.8mo (95% CI 7.7, 8.2) versus 7.8mo (95% CI 7.5, 8.2) and 10.1mo (95% CI 9.6, 10.7) versus 10mo (95% CI 9.5, 10.6), respectively.

Conclusions:

Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes.

Patient summary:

In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.


Expert's summary

The recent advent of systemic immunotherapy dramatically changed the paradigm of treatment of advanced and mUC patients. Nowadays, immunotherapy with PD-1/PD-L1 inhibitors is recommended, whenever available, for the treatment of patients with mUC experiencing progression after systemic platinum-based chemotherapy. To date, two PD-1 checkpoint inhibitors (nivolumab and pembrolizumab) and one PD-L1 inhibitor (atezolizumab) have been approved from the European Commission, while in the United States other two agents (durvalumab and avelumab) have been approved from the Food and Drug Administration. These agents have been tested alternatively in phase-I/II trials (avelumab, nivolumab, durvalumab) or in phase-III trials versus chemotherapy (atezolizumab, pembrolizumab). However, to date, data on direct comparison between different checkpoint inhibitors, especially between PD-1 and PD-L1 agents, is missing, and it is unlikely that a head-to-head clinical trial will be initiated in the next future. Moreover, trying to set a benchmark for the evaluation of immunotherapy efficacy in terms of overall survival is made it difficult due to the lack of publicly available individual patient data from clinical trials. Despite the limitations, this systematic review and meta-analysis addressed these key-points by setting a standard of efficacy useful for clinical practice and future trial design and by stating a substantial equivalence in terms of overall survival between PD-1 and PD-L1 inhibitors.  

Expert's comment

In this systematic review and meta-analysis, the authors aimed to set a benchmark for survival outcomes in patients with platinum-resistant metastatic urothelial cancer (mUC) treated with PD-1/PD-L1 inhibitors and to evaluate differences in oncological outcomes between PD-1 and PD-L1 therapies. Overall, six studies and 2051 patients were included in the final analyses. Of these, 1315 and 736 were treated with PD-1/PD-L1 inhibitors and systemic chemotherapy, respectively. Overall survival rates for patients treated with checkpoint inhibitors, extrapolated from the Kaplan-Meier curves, were 62%, 42% and 31% at 6, 12 and 18 months, respectively. Of note, extracted survival data showed an excellent agreement from those reported in the original published trials. When comparing PD-1 to PD-L1 treatments, no difference in terms of overall survival were noticed. These data are of fundamental importance to inform about current survival outcomes in the setting of platinum-resistant mUC and to set a standard for future trials design.