Optimal PD-L1-high cutoff for association with overall survival in patients with urothelial cancer treated with durvalumab monotherapy

Abstract

Background: Studies have indicated that programmed death ligand 1 (PD-L1) expression may have utility as a predictive biomarker in patients with advanced/metastatic urothelial carcinoma (UC). Different immunohistochemical (IHC) assays are in development to assess PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs).

Methods: In this post hoc analysis of the single-arm, phase 1/2 Study 1108 (NCT01693562), PD-L1 expression was evaluated from tumor samples obtained prior to second-line treatment with durvalumab in patients with advanced/metastatic UC using the VENTANA (SP263) IHC Assay. The primary objective was to determine whether the TC ≥ 25%/IC ≥ 25% algorithm (i.e., cutoff of ≥ 25% TC or ≥ 25% IC with PD-L1 staining at any intensity above background) was optimal for predicting response to durvalumab. PD-L1 expression data were available from 188 patients.

Results: After a median follow-up of 15.8 and 14.6 months, higher PD-L1 expression was associated with longer overall survival (OS) and progression-free survival (PFS), respectively, with significant separation in survival curves for PD-L1-high and-low expressing patients for the TC ≥ 25%/IC ≥ 25% cutoff (median OS: 19.8 vs 4.8 months; hazard ratio: 0.46; 90% confidence interval: 0.33, 0.639). OS was also prolonged for PD-L1-high compared with-low patients when samples were categorized using TC/IC combined positive score ≥ 10 and IC≥ 5% cutoffs. In multivariate analysis, IC but not TC PD-L1 expression was significantly associated with OS, PFS, and objective response rate (P < 0.001 for each), although interaction analysis showed similar directionality of benefit for ICs and TCs.

Conclusions: These findings support the utility of a combined TC/IC algorithm for predicting response to durvalumab in patients with UC, with the TC≥ 25%/IC≥ 25% cutoff optimal when used with the VENTANA (SP263) IHC Assay.

Fig 1. Prevalence of PD-L1–high patients at different TC and IC cutoffs for defining positive PD-L1 expression in study 1108.

IC, tumor-infiltrating immune cells; PD-L1, programmed death ligand-1; TC, tumor cells. Highlighted bar indicates the PD-L1 cutoff previously used to investigate response to durvalumab.

Fig 2. Overall survival in Study 1108 at different cutoffs for PD-L1 expression in tumor cells (TC) with cutoffs of ≥ 1% (A), ≥ 10% (B), ≥ 25% (C), and ≥ 50% (D).

CI, confidence interval; HR, hazard ratio; NA, not applicable; OS, overall survival; PD-L1, programmed death ligand-1; TC, tumor cell.

Fig 3. Overall survival in Study 1108 at different cutoffs for PD-L1 expression in tumor-infiltrating immune cells (IC) with cutoffs of ≥ 1% (A), ≥ 10% (B), ≥ 25% (C), and ≥ 50% (D).

CI, confidence interval; IC, tumor-infiltrating immune cell; HR, hazard ratio; NA, not applicable; OS, overall survival; PD-L1, programmed death ligand-1.

Fig 4. Overall survival in Study 1108 at different cutoffs for PD-L1 expression in tumor cells (TC) or tumor-infiltrating immune cells (IC) with cutoffs of ≥ 1%/≥ 1% (A), ≥ 10%/≥ 25% (B), ≥ 25%/≥ 25% (C), and ≥ 50%/≥ 25% (D).

CI, confidence interval; IC, tumor-infiltrating immune cell; HR, hazard ratio; NA, not applicable; OS, overall survival; PD-L1, programmed death ligand-1; TC, tumor cell.

Fig 5. Median overall survival in Study 1108 at different TC and IC cutoffs for defining positive (PD-L1–high) and negative (PD-L1–low) expression.

IC, tumor-infiltrating immune cells; PD-L1, programmed death ligand-1; TC, tumor cells. Highlighted bar indicates the PD-L1 cutoff previously used to investigate response to durvalumab.

Fig 6. Objective response rates in study 1108 at different TC and IC cutoffs for defining positive (PD-L1–high) and negative (PD-L1–low) expression.

IC, tumor-infiltrating immune cells; PD-L1, programmed death ligand-1; TC, tumor cells. Highlighted bar indicates the PD-L1 cutoff previously used to investigate response to durvalumab.