PD-L1/PD-1 Biomarker for Metastatic Urothelial Cancer that Progress Post-platinum Therapy: A Systematic Review and Meta-analysis

Background: Immune checkpoint inhibitors (ICI) are extremely expensive and most patients with metastatic urothelial carcinoma (mUC) do not benefit significantly from their use. Objective: We performed a systematic review and meta-analysis to determine response rates and survival outcomes on patients with mUC progressing despite prior platinum-based chemotherapy receiving ICI stratified by biomarker status. Methods: We performed a comprehensive literature search for all articles in PubMed and Embase up to 06/15/2019 to identify all studies pertaining to programmed death-lig and 1 (PD-L1) and programmed death 1 (PD-1) receptor targeted therapies for mUC that reported biomarkers. Given that biomarkers are reported on different scales and with different metrics, we defined each biomarker as either positive or negative using the definitions implemented in each individual trial. We meta-analyzed the data, reconstructed overall (OS) and progression-free survival (PFS) curves, and analyzed response rates by biomarker status. OS and PFS were analyzed in a pooled Kaplan-Meier analysis and pseudo-individualized patient data (IPD) extracted. Results: We identified 1429 manuscripts of which 8 met inclusion criteria, with a total of 1837 treated patients with outcomes data. On proportional hazards survival analysis, patients in the biomarker negative group were associated with a lower PFS (HR 1.48, 95% CI: 1.18 - 1.85, p < 0.001) and lower OS (HR 1.54, 95% CI: 1.32 - 1.80, p < 0.001) when compared to the biomarker positive group. Response data was available for 1641 patients and random effects proportion show complete response in 8% and 3% in biomarker positive and negative patients, respectively. Conclusions: ICI therapy for metastatic UC post platinum therapy has a higher overall response rate, OS and PFS in patients who are biomarker positive compared to those who are negative. However, some patients who are biomarker negative do achieve complete responses. A better biomarker for patient selection is essential before biomarkers can be used to stratify candidates for ICI therapy.